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Jennifer Smith is the editor of Oncology Practice, part of MDedge Hematology/Oncology. She was previously the editor of Hematology Times, an editor at Principal Investigators Association, and a reporter at The Oneida Daily Dispatch. She has a BS in journalism.
Orelabrutinib could be ‘preferred’ BTK inhibitor for MCL
ORLANDO – A novel Bruton tyrosine kinase inhibitor has produced favorable results in patients with relapsed or refractory mantle cell lymphoma, according to findings presented at the annual meeting of the American Society of Hematology.
In a phase 2 trial, orelabrutinib produced an overall response rate of 86% and a 12-month progression-free survival rate of 64%. Safety results with orelabrutinib were superior to historical results with ibrutinib.
The efficacy and safety profile of orelabrutinib, as well as its “convenient” dosing, may make it the “preferred therapeutic choice for B-cell malignancy,” said Lijuan Deng, MD, PhD, of Peking University Cancer Hospital & Institute, Beijing, who presented the phase 2 trial of orelabrutinib at ASH 2019.
The trial enrolled 106 patients with relapsed/refractory mantle cell lymphoma who were treated at 22 centers in China. At baseline, the patients had a median age of 62 years (range, 37-73 years), and 79.2% were men. Most patients (94.4%) had stage III-IV disease.
Prior therapies included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based (69.8%), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)-based (22.6%), DHAP (dexamethasone, cytarabine, and cisplatin)-based (22.6%), CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based (12.3%), and ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin)-based (4.7%) regimens, and 88.7% of patients had received prior anti-CD20 therapy.
Patients received orelabrutinib at 100 mg twice daily (n = 20) or 150 mg once a day (n = 86). All 106 patients were evaluable for safety, and 99 were evaluable for efficacy.
Efficacy
“Orelabrutinib achieved high response and durable remissions,” Dr. Deng said.
The overall response rate was 85.9% in the evaluable efficacy population and 83.5% in the 150-mg dosing arm. The complete response rates were 27.3% and 29.1%, respectively. The median time to response, overall, was 1.9 months.
The median duration of response and median progression-free survival were not reached at a median follow-up of 10.5 months. At 12 months, 74.3% of patients were still in response, and the progression-free survival rate was 64%.
Safety
Most adverse events were grade 1-2 in nature. The most common grade 3 or higher events were platelet count decrease (11.3%), neutrophil count decrease (8.5%), anemia (7.5%), hypertension (3.8%), pneumonia (2.8%), white blood count decrease (1.9%), and hypokalemia (1.9%).
Adverse events of interest included grade 3 or higher hypertension (3.8%), diarrhea (6.6%), and infection (10.4%), as well as secondary malignancy (0.9%, n = 1). There were no cases of grade 3 or higher hemorrhage, grade 3 or higher atrial fibrillation/flutter, or grade 5 treatment-related adverse events.
Dr. Deng noted that rates of grade 3 or higher hemorrhage, atrial fibrillation, diarrhea, and infection, as well as rates of secondary malignancies, have historically been higher with ibrutinib (Blood. 2015 Aug 6;126[6]:739-45; Lancet. 2016 Feb 20;387[10020]:770-8).
“Orelabrutinib has an improved safety profile in patients with relapsed or refractory mantle cell lymphoma,” Dr. Deng said. “The most common adverse events were cytopenia and infections, which are considered mechanism based.”
The study was sponsored by InnoCare Pharma. Dr. Deng reported having no conflicts of interest.
SOURCE: Deng L et al. ASH 2019, Abstract 755.
ORLANDO – A novel Bruton tyrosine kinase inhibitor has produced favorable results in patients with relapsed or refractory mantle cell lymphoma, according to findings presented at the annual meeting of the American Society of Hematology.
In a phase 2 trial, orelabrutinib produced an overall response rate of 86% and a 12-month progression-free survival rate of 64%. Safety results with orelabrutinib were superior to historical results with ibrutinib.
The efficacy and safety profile of orelabrutinib, as well as its “convenient” dosing, may make it the “preferred therapeutic choice for B-cell malignancy,” said Lijuan Deng, MD, PhD, of Peking University Cancer Hospital & Institute, Beijing, who presented the phase 2 trial of orelabrutinib at ASH 2019.
The trial enrolled 106 patients with relapsed/refractory mantle cell lymphoma who were treated at 22 centers in China. At baseline, the patients had a median age of 62 years (range, 37-73 years), and 79.2% were men. Most patients (94.4%) had stage III-IV disease.
Prior therapies included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based (69.8%), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)-based (22.6%), DHAP (dexamethasone, cytarabine, and cisplatin)-based (22.6%), CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based (12.3%), and ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin)-based (4.7%) regimens, and 88.7% of patients had received prior anti-CD20 therapy.
Patients received orelabrutinib at 100 mg twice daily (n = 20) or 150 mg once a day (n = 86). All 106 patients were evaluable for safety, and 99 were evaluable for efficacy.
Efficacy
“Orelabrutinib achieved high response and durable remissions,” Dr. Deng said.
The overall response rate was 85.9% in the evaluable efficacy population and 83.5% in the 150-mg dosing arm. The complete response rates were 27.3% and 29.1%, respectively. The median time to response, overall, was 1.9 months.
The median duration of response and median progression-free survival were not reached at a median follow-up of 10.5 months. At 12 months, 74.3% of patients were still in response, and the progression-free survival rate was 64%.
Safety
Most adverse events were grade 1-2 in nature. The most common grade 3 or higher events were platelet count decrease (11.3%), neutrophil count decrease (8.5%), anemia (7.5%), hypertension (3.8%), pneumonia (2.8%), white blood count decrease (1.9%), and hypokalemia (1.9%).
Adverse events of interest included grade 3 or higher hypertension (3.8%), diarrhea (6.6%), and infection (10.4%), as well as secondary malignancy (0.9%, n = 1). There were no cases of grade 3 or higher hemorrhage, grade 3 or higher atrial fibrillation/flutter, or grade 5 treatment-related adverse events.
Dr. Deng noted that rates of grade 3 or higher hemorrhage, atrial fibrillation, diarrhea, and infection, as well as rates of secondary malignancies, have historically been higher with ibrutinib (Blood. 2015 Aug 6;126[6]:739-45; Lancet. 2016 Feb 20;387[10020]:770-8).
“Orelabrutinib has an improved safety profile in patients with relapsed or refractory mantle cell lymphoma,” Dr. Deng said. “The most common adverse events were cytopenia and infections, which are considered mechanism based.”
The study was sponsored by InnoCare Pharma. Dr. Deng reported having no conflicts of interest.
SOURCE: Deng L et al. ASH 2019, Abstract 755.
ORLANDO – A novel Bruton tyrosine kinase inhibitor has produced favorable results in patients with relapsed or refractory mantle cell lymphoma, according to findings presented at the annual meeting of the American Society of Hematology.
In a phase 2 trial, orelabrutinib produced an overall response rate of 86% and a 12-month progression-free survival rate of 64%. Safety results with orelabrutinib were superior to historical results with ibrutinib.
The efficacy and safety profile of orelabrutinib, as well as its “convenient” dosing, may make it the “preferred therapeutic choice for B-cell malignancy,” said Lijuan Deng, MD, PhD, of Peking University Cancer Hospital & Institute, Beijing, who presented the phase 2 trial of orelabrutinib at ASH 2019.
The trial enrolled 106 patients with relapsed/refractory mantle cell lymphoma who were treated at 22 centers in China. At baseline, the patients had a median age of 62 years (range, 37-73 years), and 79.2% were men. Most patients (94.4%) had stage III-IV disease.
Prior therapies included CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)-based (69.8%), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin)-based (22.6%), DHAP (dexamethasone, cytarabine, and cisplatin)-based (22.6%), CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)-based (12.3%), and ESHAP (etoposide, methylprednisolone, cytarabine, and cisplatin)-based (4.7%) regimens, and 88.7% of patients had received prior anti-CD20 therapy.
Patients received orelabrutinib at 100 mg twice daily (n = 20) or 150 mg once a day (n = 86). All 106 patients were evaluable for safety, and 99 were evaluable for efficacy.
Efficacy
“Orelabrutinib achieved high response and durable remissions,” Dr. Deng said.
The overall response rate was 85.9% in the evaluable efficacy population and 83.5% in the 150-mg dosing arm. The complete response rates were 27.3% and 29.1%, respectively. The median time to response, overall, was 1.9 months.
The median duration of response and median progression-free survival were not reached at a median follow-up of 10.5 months. At 12 months, 74.3% of patients were still in response, and the progression-free survival rate was 64%.
Safety
Most adverse events were grade 1-2 in nature. The most common grade 3 or higher events were platelet count decrease (11.3%), neutrophil count decrease (8.5%), anemia (7.5%), hypertension (3.8%), pneumonia (2.8%), white blood count decrease (1.9%), and hypokalemia (1.9%).
Adverse events of interest included grade 3 or higher hypertension (3.8%), diarrhea (6.6%), and infection (10.4%), as well as secondary malignancy (0.9%, n = 1). There were no cases of grade 3 or higher hemorrhage, grade 3 or higher atrial fibrillation/flutter, or grade 5 treatment-related adverse events.
Dr. Deng noted that rates of grade 3 or higher hemorrhage, atrial fibrillation, diarrhea, and infection, as well as rates of secondary malignancies, have historically been higher with ibrutinib (Blood. 2015 Aug 6;126[6]:739-45; Lancet. 2016 Feb 20;387[10020]:770-8).
“Orelabrutinib has an improved safety profile in patients with relapsed or refractory mantle cell lymphoma,” Dr. Deng said. “The most common adverse events were cytopenia and infections, which are considered mechanism based.”
The study was sponsored by InnoCare Pharma. Dr. Deng reported having no conflicts of interest.
SOURCE: Deng L et al. ASH 2019, Abstract 755.
REPORTING FROM ASH 2019
PT-Cy bests conventional GVHD prophylaxis
ORLANDO – Posttransplant cyclophosphamide may be superior to conventional immunosuppression as graft-versus-host disease prophylaxis, according to findings presented at the annual meeting of the American Society of Hematology.
A phase 3 trial showed that posttransplant cyclophosphamide (PT-Cy) reduced graft-versus-host disease (GVHD) without affecting relapse. Rates of acute and chronic GVHD were significantly lower among patients who received PT-Cy than among those who received conventional immunosuppression (CIS). Rates of progression/relapse, progression-free survival, and overall survival were similar between the PT-Cy and CIS arms.
These results suggest PT-Cy provides a “long-term benefit and positive impact on quality of life” for patients undergoing allogeneic hematopoietic stem cell transplant, according to Annoek E.C. Broers, MD, PhD, of Erasmus Medical Center Cancer Institute in Rotterdam, the Netherlands. Dr. Broers presented the results during the plenary session at ASH 2019.
The trial enrolled 160 patients with leukemias, lymphomas, myelomas, and other hematologic malignancies. All patients had a matched, related donor or an 8/8 or greater matched, unrelated donor.
The patients were randomized to receive CIS (n = 55) or PT-Cy (n = 105) as GVHD prophylaxis. The CIS regimen consisted of cyclosporine A (from day –3 to 180) and mycophenolic acid (from day 0 to 84). Patients in the PT-Cy arm received cyclophosphamide at 50 mg/kg (days 3 and 4) and cyclosporine A (from day 5 to 70).
Baseline characteristics were similar between the treatment arms. The median age was 58 years in the CIS arm and 57 years in the PT-Cy arm. A majority of patients were men – 63% and 67%, respectively.
Two patients in the CIS arm received myeloablative conditioning, but all other patients received reduced-intensity conditioning. Most patients in the CIS arm (67%) and the PT-Cy arm (70%) had a matched, unrelated donor. All patients in the CIS arm and 96% in the PT-Cy arm received peripheral blood cell grafts.
PT-Cy significantly reduced the cumulative incidence of acute and chronic GVHD. The incidence of grade 2-4 acute GVHD at 6 months was 48% in the CIS arm and 32% in the PT-Cy arm (P = .014). The incidence of chronic extensive GVHD at 24 months was 50% and 19%, respectively (P = .001).
There were no significant between-arm differences for any other individual endpoint assessed.
“With a median follow-up of 3.2 years, so far, there’s no difference in the cumulative incidence of progression or relapse, nor is there a difference in progression-free or overall survival,” Dr. Broers said.
At 60 months, the rate of relapse/progression was 32% in the PT-Cy arm and 26% in the CIS arm (P = .36). The rate of nonrelapse mortality was 11% and 14%, respectively (P = .53).
At 60 months, the progression-free survival was 60% in the CIS arm and 58% in the PT-Cy arm (P = .67). The overall survival was 69% and 63%, respectively (P = .63).
In addition to assessing endpoints that “determine the success of our transplant strategy,” Dr. Broers said she and her colleagues also looked at a combined endpoint to account for “the effect GVHD has on morbidity and quality of life.” That endpoint is GVHD- and relapse-free survival.
The researchers found that PT-Cy improved GVHD- and relapse-free survival at 12 months. It was 22% in the CIS arm and 45% in the PT-Cy arm (P = .001). PT-Cy conferred this benefit irrespective of donor type, Dr. Broers noted.
Overall, the incidence of adverse events was somewhat higher in the PT-Cy arm (60%) than in the CIS arm (42%). The incidence of infections also was higher in the PT-Cy arm (41%) than in the CIS arm (21%), and this was largely caused by a greater incidence of neutropenic fever with PT-Cy (25% vs. 15%).
The study was funded by the Dutch Cancer Society, and Novartis provided the mycophenolic acid used in the study. Dr. Broers reported having no conflicts of interest.
SOURCE: Broers AEC et al. ASH 2019, Abstract 1.
ORLANDO – Posttransplant cyclophosphamide may be superior to conventional immunosuppression as graft-versus-host disease prophylaxis, according to findings presented at the annual meeting of the American Society of Hematology.
A phase 3 trial showed that posttransplant cyclophosphamide (PT-Cy) reduced graft-versus-host disease (GVHD) without affecting relapse. Rates of acute and chronic GVHD were significantly lower among patients who received PT-Cy than among those who received conventional immunosuppression (CIS). Rates of progression/relapse, progression-free survival, and overall survival were similar between the PT-Cy and CIS arms.
These results suggest PT-Cy provides a “long-term benefit and positive impact on quality of life” for patients undergoing allogeneic hematopoietic stem cell transplant, according to Annoek E.C. Broers, MD, PhD, of Erasmus Medical Center Cancer Institute in Rotterdam, the Netherlands. Dr. Broers presented the results during the plenary session at ASH 2019.
The trial enrolled 160 patients with leukemias, lymphomas, myelomas, and other hematologic malignancies. All patients had a matched, related donor or an 8/8 or greater matched, unrelated donor.
The patients were randomized to receive CIS (n = 55) or PT-Cy (n = 105) as GVHD prophylaxis. The CIS regimen consisted of cyclosporine A (from day –3 to 180) and mycophenolic acid (from day 0 to 84). Patients in the PT-Cy arm received cyclophosphamide at 50 mg/kg (days 3 and 4) and cyclosporine A (from day 5 to 70).
Baseline characteristics were similar between the treatment arms. The median age was 58 years in the CIS arm and 57 years in the PT-Cy arm. A majority of patients were men – 63% and 67%, respectively.
Two patients in the CIS arm received myeloablative conditioning, but all other patients received reduced-intensity conditioning. Most patients in the CIS arm (67%) and the PT-Cy arm (70%) had a matched, unrelated donor. All patients in the CIS arm and 96% in the PT-Cy arm received peripheral blood cell grafts.
PT-Cy significantly reduced the cumulative incidence of acute and chronic GVHD. The incidence of grade 2-4 acute GVHD at 6 months was 48% in the CIS arm and 32% in the PT-Cy arm (P = .014). The incidence of chronic extensive GVHD at 24 months was 50% and 19%, respectively (P = .001).
There were no significant between-arm differences for any other individual endpoint assessed.
“With a median follow-up of 3.2 years, so far, there’s no difference in the cumulative incidence of progression or relapse, nor is there a difference in progression-free or overall survival,” Dr. Broers said.
At 60 months, the rate of relapse/progression was 32% in the PT-Cy arm and 26% in the CIS arm (P = .36). The rate of nonrelapse mortality was 11% and 14%, respectively (P = .53).
At 60 months, the progression-free survival was 60% in the CIS arm and 58% in the PT-Cy arm (P = .67). The overall survival was 69% and 63%, respectively (P = .63).
In addition to assessing endpoints that “determine the success of our transplant strategy,” Dr. Broers said she and her colleagues also looked at a combined endpoint to account for “the effect GVHD has on morbidity and quality of life.” That endpoint is GVHD- and relapse-free survival.
The researchers found that PT-Cy improved GVHD- and relapse-free survival at 12 months. It was 22% in the CIS arm and 45% in the PT-Cy arm (P = .001). PT-Cy conferred this benefit irrespective of donor type, Dr. Broers noted.
Overall, the incidence of adverse events was somewhat higher in the PT-Cy arm (60%) than in the CIS arm (42%). The incidence of infections also was higher in the PT-Cy arm (41%) than in the CIS arm (21%), and this was largely caused by a greater incidence of neutropenic fever with PT-Cy (25% vs. 15%).
The study was funded by the Dutch Cancer Society, and Novartis provided the mycophenolic acid used in the study. Dr. Broers reported having no conflicts of interest.
SOURCE: Broers AEC et al. ASH 2019, Abstract 1.
ORLANDO – Posttransplant cyclophosphamide may be superior to conventional immunosuppression as graft-versus-host disease prophylaxis, according to findings presented at the annual meeting of the American Society of Hematology.
A phase 3 trial showed that posttransplant cyclophosphamide (PT-Cy) reduced graft-versus-host disease (GVHD) without affecting relapse. Rates of acute and chronic GVHD were significantly lower among patients who received PT-Cy than among those who received conventional immunosuppression (CIS). Rates of progression/relapse, progression-free survival, and overall survival were similar between the PT-Cy and CIS arms.
These results suggest PT-Cy provides a “long-term benefit and positive impact on quality of life” for patients undergoing allogeneic hematopoietic stem cell transplant, according to Annoek E.C. Broers, MD, PhD, of Erasmus Medical Center Cancer Institute in Rotterdam, the Netherlands. Dr. Broers presented the results during the plenary session at ASH 2019.
The trial enrolled 160 patients with leukemias, lymphomas, myelomas, and other hematologic malignancies. All patients had a matched, related donor or an 8/8 or greater matched, unrelated donor.
The patients were randomized to receive CIS (n = 55) or PT-Cy (n = 105) as GVHD prophylaxis. The CIS regimen consisted of cyclosporine A (from day –3 to 180) and mycophenolic acid (from day 0 to 84). Patients in the PT-Cy arm received cyclophosphamide at 50 mg/kg (days 3 and 4) and cyclosporine A (from day 5 to 70).
Baseline characteristics were similar between the treatment arms. The median age was 58 years in the CIS arm and 57 years in the PT-Cy arm. A majority of patients were men – 63% and 67%, respectively.
Two patients in the CIS arm received myeloablative conditioning, but all other patients received reduced-intensity conditioning. Most patients in the CIS arm (67%) and the PT-Cy arm (70%) had a matched, unrelated donor. All patients in the CIS arm and 96% in the PT-Cy arm received peripheral blood cell grafts.
PT-Cy significantly reduced the cumulative incidence of acute and chronic GVHD. The incidence of grade 2-4 acute GVHD at 6 months was 48% in the CIS arm and 32% in the PT-Cy arm (P = .014). The incidence of chronic extensive GVHD at 24 months was 50% and 19%, respectively (P = .001).
There were no significant between-arm differences for any other individual endpoint assessed.
“With a median follow-up of 3.2 years, so far, there’s no difference in the cumulative incidence of progression or relapse, nor is there a difference in progression-free or overall survival,” Dr. Broers said.
At 60 months, the rate of relapse/progression was 32% in the PT-Cy arm and 26% in the CIS arm (P = .36). The rate of nonrelapse mortality was 11% and 14%, respectively (P = .53).
At 60 months, the progression-free survival was 60% in the CIS arm and 58% in the PT-Cy arm (P = .67). The overall survival was 69% and 63%, respectively (P = .63).
In addition to assessing endpoints that “determine the success of our transplant strategy,” Dr. Broers said she and her colleagues also looked at a combined endpoint to account for “the effect GVHD has on morbidity and quality of life.” That endpoint is GVHD- and relapse-free survival.
The researchers found that PT-Cy improved GVHD- and relapse-free survival at 12 months. It was 22% in the CIS arm and 45% in the PT-Cy arm (P = .001). PT-Cy conferred this benefit irrespective of donor type, Dr. Broers noted.
Overall, the incidence of adverse events was somewhat higher in the PT-Cy arm (60%) than in the CIS arm (42%). The incidence of infections also was higher in the PT-Cy arm (41%) than in the CIS arm (21%), and this was largely caused by a greater incidence of neutropenic fever with PT-Cy (25% vs. 15%).
The study was funded by the Dutch Cancer Society, and Novartis provided the mycophenolic acid used in the study. Dr. Broers reported having no conflicts of interest.
SOURCE: Broers AEC et al. ASH 2019, Abstract 1.
REPORTING FROM ASH 2019
NFIX could be a target for sickle cell therapy
ORLANDO – Preclinical research suggests nuclear factor I X is a fetal hemoglobin repressor, a finding that could have implications for the treatment of sickle cell disease.
Researchers found that knocking down nuclear factor I X (NFIX) in adult erythroblasts induced fetal hemoglobin expression in a vast majority of cells, and the total amount of fetal hemoglobin in those cells was about 40%. The target level of fetal hemoglobin for sickle cell patients to become asymptomatic is 30%, according to study investigator Jeffrey R. Shearstone, PhD, of Syros Pharmaceuticals in Cambridge, Mass. He made these remarks during a press conference at the annual meeting of the American Society of Hematology. Mudit Chaand, PhD, also of Syros, is scheduled to present the study at the meeting on Dec. 9, 2019.
“While this is obviously a preclinical, investigational study, to see levels of induction in primary cells and cell lines of 40% is very encouraging and shows that [NFIX] is a very potent fetal hemoglobin repressor,” Dr. Shearstone said. “We see this discovery as, potentially, a new avenue for therapeutic intervention in sickle cell disease, but there’s still a lot of work to be done.”
Syros researchers began this study by comparing erythroblasts derived from cord blood, which have high levels of fetal hemoglobin, and erythroblasts derived from bone marrow, which have low levels of fetal hemoglobin. The team’s goal was to identify transcription factors that might regulate the repression of fetal hemoglobin in adult cells.
Chromatin accessibility mapping pointed to NFIX as a hemoglobin repressor. The researchers observed increased accessibility at the NFIX promoter and elevated NFIX messenger RNA in adult cells.
To confirm NFIX’s role as a repressor of fetal hemoglobin, the researchers used short hairpin RNA to knock down NFIX in primary erythroblasts and cell lines.
“By knocking down NFIX, we saw a very robust induction of fetal hemoglobin,” Dr. Shearstone said. “We saw nearly 100% of cells in which NFIX was knocked down express fetal hemoglobin. This level of induction compared very favorably to probably the two most potent known repressors of fetal hemoglobin, ZBTB7A and BCL11A.”
Specifically, 86%-97% of cells with NFIX knockdown expressed fetal hemoglobin, compared with 16% of control cells, 88% of cells with BCL11A knockdown, and 91% of cells with ZBTB7A knockdown.
The total amount of fetal hemoglobin in erythroblasts with NFIX knockdown was 39%-40%.
The researchers plan to conduct additional studies to validate these results, examine how NFIX directly binds at the fetal globin promoter, determine if NFIX interacts with any previously identified fetal hemoglobin repressors, and investigate how NFIX can be shut down in patients with sickle cell disease. The researchers’ ultimate goal is to develop a small molecule that would target NFIX.
All researchers involved in this work are employees of Syros Pharmaceuticals.
SOURCE: Shearstone JR et al. ASH 2019, Abstract 821.
ORLANDO – Preclinical research suggests nuclear factor I X is a fetal hemoglobin repressor, a finding that could have implications for the treatment of sickle cell disease.
Researchers found that knocking down nuclear factor I X (NFIX) in adult erythroblasts induced fetal hemoglobin expression in a vast majority of cells, and the total amount of fetal hemoglobin in those cells was about 40%. The target level of fetal hemoglobin for sickle cell patients to become asymptomatic is 30%, according to study investigator Jeffrey R. Shearstone, PhD, of Syros Pharmaceuticals in Cambridge, Mass. He made these remarks during a press conference at the annual meeting of the American Society of Hematology. Mudit Chaand, PhD, also of Syros, is scheduled to present the study at the meeting on Dec. 9, 2019.
“While this is obviously a preclinical, investigational study, to see levels of induction in primary cells and cell lines of 40% is very encouraging and shows that [NFIX] is a very potent fetal hemoglobin repressor,” Dr. Shearstone said. “We see this discovery as, potentially, a new avenue for therapeutic intervention in sickle cell disease, but there’s still a lot of work to be done.”
Syros researchers began this study by comparing erythroblasts derived from cord blood, which have high levels of fetal hemoglobin, and erythroblasts derived from bone marrow, which have low levels of fetal hemoglobin. The team’s goal was to identify transcription factors that might regulate the repression of fetal hemoglobin in adult cells.
Chromatin accessibility mapping pointed to NFIX as a hemoglobin repressor. The researchers observed increased accessibility at the NFIX promoter and elevated NFIX messenger RNA in adult cells.
To confirm NFIX’s role as a repressor of fetal hemoglobin, the researchers used short hairpin RNA to knock down NFIX in primary erythroblasts and cell lines.
“By knocking down NFIX, we saw a very robust induction of fetal hemoglobin,” Dr. Shearstone said. “We saw nearly 100% of cells in which NFIX was knocked down express fetal hemoglobin. This level of induction compared very favorably to probably the two most potent known repressors of fetal hemoglobin, ZBTB7A and BCL11A.”
Specifically, 86%-97% of cells with NFIX knockdown expressed fetal hemoglobin, compared with 16% of control cells, 88% of cells with BCL11A knockdown, and 91% of cells with ZBTB7A knockdown.
The total amount of fetal hemoglobin in erythroblasts with NFIX knockdown was 39%-40%.
The researchers plan to conduct additional studies to validate these results, examine how NFIX directly binds at the fetal globin promoter, determine if NFIX interacts with any previously identified fetal hemoglobin repressors, and investigate how NFIX can be shut down in patients with sickle cell disease. The researchers’ ultimate goal is to develop a small molecule that would target NFIX.
All researchers involved in this work are employees of Syros Pharmaceuticals.
SOURCE: Shearstone JR et al. ASH 2019, Abstract 821.
ORLANDO – Preclinical research suggests nuclear factor I X is a fetal hemoglobin repressor, a finding that could have implications for the treatment of sickle cell disease.
Researchers found that knocking down nuclear factor I X (NFIX) in adult erythroblasts induced fetal hemoglobin expression in a vast majority of cells, and the total amount of fetal hemoglobin in those cells was about 40%. The target level of fetal hemoglobin for sickle cell patients to become asymptomatic is 30%, according to study investigator Jeffrey R. Shearstone, PhD, of Syros Pharmaceuticals in Cambridge, Mass. He made these remarks during a press conference at the annual meeting of the American Society of Hematology. Mudit Chaand, PhD, also of Syros, is scheduled to present the study at the meeting on Dec. 9, 2019.
“While this is obviously a preclinical, investigational study, to see levels of induction in primary cells and cell lines of 40% is very encouraging and shows that [NFIX] is a very potent fetal hemoglobin repressor,” Dr. Shearstone said. “We see this discovery as, potentially, a new avenue for therapeutic intervention in sickle cell disease, but there’s still a lot of work to be done.”
Syros researchers began this study by comparing erythroblasts derived from cord blood, which have high levels of fetal hemoglobin, and erythroblasts derived from bone marrow, which have low levels of fetal hemoglobin. The team’s goal was to identify transcription factors that might regulate the repression of fetal hemoglobin in adult cells.
Chromatin accessibility mapping pointed to NFIX as a hemoglobin repressor. The researchers observed increased accessibility at the NFIX promoter and elevated NFIX messenger RNA in adult cells.
To confirm NFIX’s role as a repressor of fetal hemoglobin, the researchers used short hairpin RNA to knock down NFIX in primary erythroblasts and cell lines.
“By knocking down NFIX, we saw a very robust induction of fetal hemoglobin,” Dr. Shearstone said. “We saw nearly 100% of cells in which NFIX was knocked down express fetal hemoglobin. This level of induction compared very favorably to probably the two most potent known repressors of fetal hemoglobin, ZBTB7A and BCL11A.”
Specifically, 86%-97% of cells with NFIX knockdown expressed fetal hemoglobin, compared with 16% of control cells, 88% of cells with BCL11A knockdown, and 91% of cells with ZBTB7A knockdown.
The total amount of fetal hemoglobin in erythroblasts with NFIX knockdown was 39%-40%.
The researchers plan to conduct additional studies to validate these results, examine how NFIX directly binds at the fetal globin promoter, determine if NFIX interacts with any previously identified fetal hemoglobin repressors, and investigate how NFIX can be shut down in patients with sickle cell disease. The researchers’ ultimate goal is to develop a small molecule that would target NFIX.
All researchers involved in this work are employees of Syros Pharmaceuticals.
SOURCE: Shearstone JR et al. ASH 2019, Abstract 821.
REPORTING FROM ASH 2019
Off-the-shelf cellular therapy shows promise in the lab
ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
Jode P. Goodridge, PhD, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. Abstract 301.
ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
Jode P. Goodridge, PhD, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. Abstract 301.
ORLANDO – A cellular therapy called FT596 is active against B-cell malignancies and, when combined with rituximab, can be more effective than traditional chimeric antigen receptor (CAR) T cells, preclinical research findings suggest.
FT596 is a universal, anti-CD19 CAR natural killer (NK) cell therapy derived from a master induced pluripotent stem cell (iPSC) line.
FT596 reduced tumor growth in mouse models of leukemia and lymphoma. When combined with rituximab, FT596 was able to overcome CD19 antigen escape.
Jode P. Goodridge, PhD, of Fate Therapeutics in San Diego, presented these results at the annual meeting of the American Society of Hematology.
Dr. Goodridge explained that FT596 begins with a source material, such as a fibroblast, that is reprogrammed into an iPSC progenitor cell. That cell is sorted and expanded into a renewable, homogeneous, pluripotent master iPSC line. The iPSCs are differentiated into CD34 cells, which are differentiated into NK cells. The iPSC-derived NK cells are then modified with the following:
- An anti-CD19 CAR that is optimized for NK-cell biology and contains an NKG2D transmembrane domain, a 2B4 costimulatory domain, and a CD3-zeta signaling domain.
- An interleukin-15 receptor fusion that promotes cell survival and reduces the need for cytokine support.
- A high-affinity 158V, noncleavable CD16 Fc receptor that enhances antibody-dependent cellular cytotoxicity when FT596 is combined with a monoclonal antibody such as rituximab.
Dr. Goodridge presented results with FT596, both alone and in combination with rituximab, in vitro and in vivo.
When compared with no treatment, three doses of FT596 monotherapy reduced tumor growth in a mouse model of leukemia (Nalm6). FT596 plus rituximab reduced tumor growth in a mouse model of lymphoma (Raji), when compared with no treatment or rituximab alone.
Three doses of FT596 proved more effective than a single dose of CD19 CAR T-cell therapy in a mouse model of lymphoma (Raji). FT596 both reduced tumor growth and prolonged survival in the mice.
Lastly, in vitro experiments in Raji cells showed that FT596 plus rituximab can produce deeper responses than primary CAR-T cells, and the combination can prevent antigen escape.
Dr. Goodridge said these results support the phase 1 study of FT596, given as monotherapy or in combination with rituximab or obinutuzumab, in patients with relapsed/refractory B-cell lymphomas or chronic lymphocytic leukemia.
Dr. Goodridge is employed by Fate Therapeutics, the company developing FT596.
SOURCE: Goodridge JP et al. ASH 2019. Abstract 301.
REPORTING FROM ASH 2019
ASH to recognize researchers at annual meeting
The American Society of Hematology (ASH) plans to honor 10 researchers with awards and lectures at this year’s annual meeting, scheduled to take place Dec. 7-10 in Orlando.
Richard Aster, MD, will receive the 2019 Wallace H. Coulter Award for Lifetime Achievement in Hematology. Dr. Aster, of the Medical College of Wisconsin and Versiti Blood Center of Wisconsin in Milwaukee, “will be honored for his significant contributions to hematology through research, mentorship, and education throughout his 62-year career,” according to ASH.
Dr. Aster is known for his research on immune diseases that affect blood cells, particularly platelets. His work has led to improvements in platelet preparation, storage, and matching. In addition, he and his team developed the standard techniques for diagnosing immune thrombocytopenia and heparin-induced thrombocytopenia-thrombosis.
Other ASH awardees include William Eaton, MD, PhD, and Richard A. Larson, MD, who will receive the 2019 Henry M. Stratton Medal “for their seminal contributions to basic and clinical/translational hematology research, respectively.”
Dr. Eaton, of the National Institute of Diabetes and Digestive and Kidney Diseases conducts research on sickle cell disease, and his work contributed to the development of hydroxyurea. Dr. Larson, of the University of Chicago is the namesake of the Larson regimen (CALGB 8811) for acute lymphoblastic leukemia, and he played a key role in research that led to the U.S. approval of midostaurin.
Philip Greenberg, MD, will deliver the 2019 E. Donnall Thomas Lecture in recognition of “his outstanding contributions to the field of immunotherapy.” Dr. Greenberg, of theFred Hutchinson Cancer Research Center and the University of Washington in Seattle, is known for contributing to the development of T-cell adoptive immune therapy. His lecture will focus on the engineering of T cells to target acute myeloid leukemia and other malignancies.
Sriram Krishnaswamy, PhD, and Jeffrey I. Weitz, MD, will deliver the 2019 Ernest Beutler Lecture in recognition of “their significant research contributions to the understanding and treatment of blood clots.” The researchers will each deliver one part of the lecture at the meeting, and both will discuss research related to novel anticoagulants.
Dr. Krishnaswamy, of the University of Pennsylvania and Children’s Hospital of Philadelphia, is considered an authority on the function of surface-dependent coagulation complexes. Dr. Weitz, of McMaster University in Hamilton, Ont., has conducted research that led to the development of novel anticoagulants.
Emmanuelle Passegué, PhD, will receive the 2019 William Dameshek Prize “for her outstanding contributions to the understanding of hematopoietic stem cells.” Dr. Passegué, of Columbia University Irving Medical Center in New York, conducts research focused on changes to hematopoietic stem cells in the contexts of myeloid malignancies and physiological aging.
Griffin Rodgers, MD, will receive the ASH Award for Leadership in Promoting Diversity “for his extraordinary commitment to diversity and inclusion in hematology.” As director of the National Institute of Diabetes and Digestive and Kidney Diseases, Dr. Rodgers has worked to promote diversity in the scientific workforce and in clinical trials.
Leonard Zon, MD, and Michael R. DeBaun, MD, will receive the 2019 ASH Mentor Award “for their sustained, outstanding commitment to the training and career development of early career hematologists.”
Dr. DeBaun, of Vanderbilt University School of Medicine in Nashville, Tenn., has mentees ranging from high school students with sickle cell disease to tenured faculty members at medical schools. Dr. Zon, of Harvard University and Boston Children’s Hospital, organizes mentoring events for postdocs, graduate students, and technicians.
The American Society of Hematology (ASH) plans to honor 10 researchers with awards and lectures at this year’s annual meeting, scheduled to take place Dec. 7-10 in Orlando.
Richard Aster, MD, will receive the 2019 Wallace H. Coulter Award for Lifetime Achievement in Hematology. Dr. Aster, of the Medical College of Wisconsin and Versiti Blood Center of Wisconsin in Milwaukee, “will be honored for his significant contributions to hematology through research, mentorship, and education throughout his 62-year career,” according to ASH.
Dr. Aster is known for his research on immune diseases that affect blood cells, particularly platelets. His work has led to improvements in platelet preparation, storage, and matching. In addition, he and his team developed the standard techniques for diagnosing immune thrombocytopenia and heparin-induced thrombocytopenia-thrombosis.
Other ASH awardees include William Eaton, MD, PhD, and Richard A. Larson, MD, who will receive the 2019 Henry M. Stratton Medal “for their seminal contributions to basic and clinical/translational hematology research, respectively.”
Dr. Eaton, of the National Institute of Diabetes and Digestive and Kidney Diseases conducts research on sickle cell disease, and his work contributed to the development of hydroxyurea. Dr. Larson, of the University of Chicago is the namesake of the Larson regimen (CALGB 8811) for acute lymphoblastic leukemia, and he played a key role in research that led to the U.S. approval of midostaurin.
Philip Greenberg, MD, will deliver the 2019 E. Donnall Thomas Lecture in recognition of “his outstanding contributions to the field of immunotherapy.” Dr. Greenberg, of theFred Hutchinson Cancer Research Center and the University of Washington in Seattle, is known for contributing to the development of T-cell adoptive immune therapy. His lecture will focus on the engineering of T cells to target acute myeloid leukemia and other malignancies.
Sriram Krishnaswamy, PhD, and Jeffrey I. Weitz, MD, will deliver the 2019 Ernest Beutler Lecture in recognition of “their significant research contributions to the understanding and treatment of blood clots.” The researchers will each deliver one part of the lecture at the meeting, and both will discuss research related to novel anticoagulants.
Dr. Krishnaswamy, of the University of Pennsylvania and Children’s Hospital of Philadelphia, is considered an authority on the function of surface-dependent coagulation complexes. Dr. Weitz, of McMaster University in Hamilton, Ont., has conducted research that led to the development of novel anticoagulants.
Emmanuelle Passegué, PhD, will receive the 2019 William Dameshek Prize “for her outstanding contributions to the understanding of hematopoietic stem cells.” Dr. Passegué, of Columbia University Irving Medical Center in New York, conducts research focused on changes to hematopoietic stem cells in the contexts of myeloid malignancies and physiological aging.
Griffin Rodgers, MD, will receive the ASH Award for Leadership in Promoting Diversity “for his extraordinary commitment to diversity and inclusion in hematology.” As director of the National Institute of Diabetes and Digestive and Kidney Diseases, Dr. Rodgers has worked to promote diversity in the scientific workforce and in clinical trials.
Leonard Zon, MD, and Michael R. DeBaun, MD, will receive the 2019 ASH Mentor Award “for their sustained, outstanding commitment to the training and career development of early career hematologists.”
Dr. DeBaun, of Vanderbilt University School of Medicine in Nashville, Tenn., has mentees ranging from high school students with sickle cell disease to tenured faculty members at medical schools. Dr. Zon, of Harvard University and Boston Children’s Hospital, organizes mentoring events for postdocs, graduate students, and technicians.
The American Society of Hematology (ASH) plans to honor 10 researchers with awards and lectures at this year’s annual meeting, scheduled to take place Dec. 7-10 in Orlando.
Richard Aster, MD, will receive the 2019 Wallace H. Coulter Award for Lifetime Achievement in Hematology. Dr. Aster, of the Medical College of Wisconsin and Versiti Blood Center of Wisconsin in Milwaukee, “will be honored for his significant contributions to hematology through research, mentorship, and education throughout his 62-year career,” according to ASH.
Dr. Aster is known for his research on immune diseases that affect blood cells, particularly platelets. His work has led to improvements in platelet preparation, storage, and matching. In addition, he and his team developed the standard techniques for diagnosing immune thrombocytopenia and heparin-induced thrombocytopenia-thrombosis.
Other ASH awardees include William Eaton, MD, PhD, and Richard A. Larson, MD, who will receive the 2019 Henry M. Stratton Medal “for their seminal contributions to basic and clinical/translational hematology research, respectively.”
Dr. Eaton, of the National Institute of Diabetes and Digestive and Kidney Diseases conducts research on sickle cell disease, and his work contributed to the development of hydroxyurea. Dr. Larson, of the University of Chicago is the namesake of the Larson regimen (CALGB 8811) for acute lymphoblastic leukemia, and he played a key role in research that led to the U.S. approval of midostaurin.
Philip Greenberg, MD, will deliver the 2019 E. Donnall Thomas Lecture in recognition of “his outstanding contributions to the field of immunotherapy.” Dr. Greenberg, of theFred Hutchinson Cancer Research Center and the University of Washington in Seattle, is known for contributing to the development of T-cell adoptive immune therapy. His lecture will focus on the engineering of T cells to target acute myeloid leukemia and other malignancies.
Sriram Krishnaswamy, PhD, and Jeffrey I. Weitz, MD, will deliver the 2019 Ernest Beutler Lecture in recognition of “their significant research contributions to the understanding and treatment of blood clots.” The researchers will each deliver one part of the lecture at the meeting, and both will discuss research related to novel anticoagulants.
Dr. Krishnaswamy, of the University of Pennsylvania and Children’s Hospital of Philadelphia, is considered an authority on the function of surface-dependent coagulation complexes. Dr. Weitz, of McMaster University in Hamilton, Ont., has conducted research that led to the development of novel anticoagulants.
Emmanuelle Passegué, PhD, will receive the 2019 William Dameshek Prize “for her outstanding contributions to the understanding of hematopoietic stem cells.” Dr. Passegué, of Columbia University Irving Medical Center in New York, conducts research focused on changes to hematopoietic stem cells in the contexts of myeloid malignancies and physiological aging.
Griffin Rodgers, MD, will receive the ASH Award for Leadership in Promoting Diversity “for his extraordinary commitment to diversity and inclusion in hematology.” As director of the National Institute of Diabetes and Digestive and Kidney Diseases, Dr. Rodgers has worked to promote diversity in the scientific workforce and in clinical trials.
Leonard Zon, MD, and Michael R. DeBaun, MD, will receive the 2019 ASH Mentor Award “for their sustained, outstanding commitment to the training and career development of early career hematologists.”
Dr. DeBaun, of Vanderbilt University School of Medicine in Nashville, Tenn., has mentees ranging from high school students with sickle cell disease to tenured faculty members at medical schools. Dr. Zon, of Harvard University and Boston Children’s Hospital, organizes mentoring events for postdocs, graduate students, and technicians.
Combo elicits lasting responses in metastatic melanoma
NATIONAL HARBOR, MD. – The combination of bempegaldesleukin and nivolumab produced durable responses in a phase 1/2 trial of patients with previously untreated metastatic melanoma.
The overall response rate was 53%, and most responders were still in response at a median follow-up of about 19 months. The median progression-free survival was not reached, and the combination was considered well tolerated.
Adi Diab, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented these results from the PIVOT-02 study at the annual meeting of the Society for Immunotherapy of Cancer.
Dr. Diab explained that bempegaldesleukin (bempeg) is a CD122-preferential interleukin-2 pathway agonist, and earlier results from the PIVOT-02 trial showed that adding bempeg to nivolumab can convert baseline tumors from programmed death–ligand 1 (PD-L1) negative to PD-L1 positive (SITC 2018, Abstract O4).
Dr. Diab presented updated results from PIVOT-02 (NCT02983045) in 41 patients with metastatic melanoma who received bempeg plus nivolumab as first-line treatment. The patients had a median age of 63 years (range, 22-80 years) at baseline, and 58.5% were male. Most patients (58.5%) were PD-L1 positive, although PD-L1 status was unknown in 7.3% of patients.
Patients received bempeg at 0.006 mg/kg and nivolumab at 360 mg every 3 weeks. They received a median of nine cycles (range, 1-34), and the median follow-up was 18.6 months.
Efficacy
In the 38 patients who were evaluable for efficacy, the overall response rate was 53% (n = 20), and the complete response rate was 34% (n = 13). The median time to response was 2.0 months, and the median time to complete response was 7.9 months.
Dr. Diab noted that responses were seen regardless of PD-L1 expression at baseline. The response rate was 39% among PD-L1-negative patients, 64% among PD-L1-positive patients, and 33% among patients whose PD-L1 status was unknown.
Dr. Diab also pointed out that responses were durable and deepened over time. The median duration of response was not reached, and 17 of the 20 responders had ongoing responses at last follow-up. The median progression-free survival has not been reached.
Safety
“This combination is safe and tolerable, there’s no overlapping immune-related adverse events, and the most common side effects are grade 1/2 flu-like symptoms,” Dr. Diab said.
The most common grade 1/2 treatment-related adverse events (AEs) were flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (46.3%), arthralgia (43.9%), decreased appetite (36.6%), and myalgia (36.6%).
Dr. Diab noted that cytokine-related AEs (flu-like symptoms, rash, and pruritus) were easily managed with NSAIDs; decreased with subsequent cycles of treatment; and did not necessitate dose delays, reductions, or discontinuations.
Grade 3/4 treatment-related AEs included two cases of acute kidney injury, two cases of atrial fibrillation, one case of dizziness, one case of dyspnea, one case of hypoxia, one case of hyperglycemia, and one case of hypernatremia.
Five patients discontinued treatment because of related AEs, including cerebrovascular accident, peripheral edema, blood creatinine increase, malaise, and pharyngitis. There were no treatment-related deaths.
Dr. Diab said these results were used to support the recent breakthrough therapy designation granted to bempeg in combination with nivolumab. The results have also prompted a phase 3 trial in which researchers are comparing the combination with nivolumab alone (NCT03635983).
The phase 1/2 trial is sponsored by Nektar Therapeutics in collaboration with Bristol-Myers Squibb. Dr. Diab reported relationships with Nektar, Celgene, CureVac, Idera, and Pfizer.
SOURCE: Diab A et al. SITC 2019, Abstract O35.
NATIONAL HARBOR, MD. – The combination of bempegaldesleukin and nivolumab produced durable responses in a phase 1/2 trial of patients with previously untreated metastatic melanoma.
The overall response rate was 53%, and most responders were still in response at a median follow-up of about 19 months. The median progression-free survival was not reached, and the combination was considered well tolerated.
Adi Diab, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented these results from the PIVOT-02 study at the annual meeting of the Society for Immunotherapy of Cancer.
Dr. Diab explained that bempegaldesleukin (bempeg) is a CD122-preferential interleukin-2 pathway agonist, and earlier results from the PIVOT-02 trial showed that adding bempeg to nivolumab can convert baseline tumors from programmed death–ligand 1 (PD-L1) negative to PD-L1 positive (SITC 2018, Abstract O4).
Dr. Diab presented updated results from PIVOT-02 (NCT02983045) in 41 patients with metastatic melanoma who received bempeg plus nivolumab as first-line treatment. The patients had a median age of 63 years (range, 22-80 years) at baseline, and 58.5% were male. Most patients (58.5%) were PD-L1 positive, although PD-L1 status was unknown in 7.3% of patients.
Patients received bempeg at 0.006 mg/kg and nivolumab at 360 mg every 3 weeks. They received a median of nine cycles (range, 1-34), and the median follow-up was 18.6 months.
Efficacy
In the 38 patients who were evaluable for efficacy, the overall response rate was 53% (n = 20), and the complete response rate was 34% (n = 13). The median time to response was 2.0 months, and the median time to complete response was 7.9 months.
Dr. Diab noted that responses were seen regardless of PD-L1 expression at baseline. The response rate was 39% among PD-L1-negative patients, 64% among PD-L1-positive patients, and 33% among patients whose PD-L1 status was unknown.
Dr. Diab also pointed out that responses were durable and deepened over time. The median duration of response was not reached, and 17 of the 20 responders had ongoing responses at last follow-up. The median progression-free survival has not been reached.
Safety
“This combination is safe and tolerable, there’s no overlapping immune-related adverse events, and the most common side effects are grade 1/2 flu-like symptoms,” Dr. Diab said.
The most common grade 1/2 treatment-related adverse events (AEs) were flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (46.3%), arthralgia (43.9%), decreased appetite (36.6%), and myalgia (36.6%).
Dr. Diab noted that cytokine-related AEs (flu-like symptoms, rash, and pruritus) were easily managed with NSAIDs; decreased with subsequent cycles of treatment; and did not necessitate dose delays, reductions, or discontinuations.
Grade 3/4 treatment-related AEs included two cases of acute kidney injury, two cases of atrial fibrillation, one case of dizziness, one case of dyspnea, one case of hypoxia, one case of hyperglycemia, and one case of hypernatremia.
Five patients discontinued treatment because of related AEs, including cerebrovascular accident, peripheral edema, blood creatinine increase, malaise, and pharyngitis. There were no treatment-related deaths.
Dr. Diab said these results were used to support the recent breakthrough therapy designation granted to bempeg in combination with nivolumab. The results have also prompted a phase 3 trial in which researchers are comparing the combination with nivolumab alone (NCT03635983).
The phase 1/2 trial is sponsored by Nektar Therapeutics in collaboration with Bristol-Myers Squibb. Dr. Diab reported relationships with Nektar, Celgene, CureVac, Idera, and Pfizer.
SOURCE: Diab A et al. SITC 2019, Abstract O35.
NATIONAL HARBOR, MD. – The combination of bempegaldesleukin and nivolumab produced durable responses in a phase 1/2 trial of patients with previously untreated metastatic melanoma.
The overall response rate was 53%, and most responders were still in response at a median follow-up of about 19 months. The median progression-free survival was not reached, and the combination was considered well tolerated.
Adi Diab, MD, of the University of Texas MD Anderson Cancer Center, Houston, presented these results from the PIVOT-02 study at the annual meeting of the Society for Immunotherapy of Cancer.
Dr. Diab explained that bempegaldesleukin (bempeg) is a CD122-preferential interleukin-2 pathway agonist, and earlier results from the PIVOT-02 trial showed that adding bempeg to nivolumab can convert baseline tumors from programmed death–ligand 1 (PD-L1) negative to PD-L1 positive (SITC 2018, Abstract O4).
Dr. Diab presented updated results from PIVOT-02 (NCT02983045) in 41 patients with metastatic melanoma who received bempeg plus nivolumab as first-line treatment. The patients had a median age of 63 years (range, 22-80 years) at baseline, and 58.5% were male. Most patients (58.5%) were PD-L1 positive, although PD-L1 status was unknown in 7.3% of patients.
Patients received bempeg at 0.006 mg/kg and nivolumab at 360 mg every 3 weeks. They received a median of nine cycles (range, 1-34), and the median follow-up was 18.6 months.
Efficacy
In the 38 patients who were evaluable for efficacy, the overall response rate was 53% (n = 20), and the complete response rate was 34% (n = 13). The median time to response was 2.0 months, and the median time to complete response was 7.9 months.
Dr. Diab noted that responses were seen regardless of PD-L1 expression at baseline. The response rate was 39% among PD-L1-negative patients, 64% among PD-L1-positive patients, and 33% among patients whose PD-L1 status was unknown.
Dr. Diab also pointed out that responses were durable and deepened over time. The median duration of response was not reached, and 17 of the 20 responders had ongoing responses at last follow-up. The median progression-free survival has not been reached.
Safety
“This combination is safe and tolerable, there’s no overlapping immune-related adverse events, and the most common side effects are grade 1/2 flu-like symptoms,” Dr. Diab said.
The most common grade 1/2 treatment-related adverse events (AEs) were flu-like symptoms (80.5%), rash (70.7%), fatigue (65.9%), pruritus (48.8%), nausea (46.3%), arthralgia (43.9%), decreased appetite (36.6%), and myalgia (36.6%).
Dr. Diab noted that cytokine-related AEs (flu-like symptoms, rash, and pruritus) were easily managed with NSAIDs; decreased with subsequent cycles of treatment; and did not necessitate dose delays, reductions, or discontinuations.
Grade 3/4 treatment-related AEs included two cases of acute kidney injury, two cases of atrial fibrillation, one case of dizziness, one case of dyspnea, one case of hypoxia, one case of hyperglycemia, and one case of hypernatremia.
Five patients discontinued treatment because of related AEs, including cerebrovascular accident, peripheral edema, blood creatinine increase, malaise, and pharyngitis. There were no treatment-related deaths.
Dr. Diab said these results were used to support the recent breakthrough therapy designation granted to bempeg in combination with nivolumab. The results have also prompted a phase 3 trial in which researchers are comparing the combination with nivolumab alone (NCT03635983).
The phase 1/2 trial is sponsored by Nektar Therapeutics in collaboration with Bristol-Myers Squibb. Dr. Diab reported relationships with Nektar, Celgene, CureVac, Idera, and Pfizer.
SOURCE: Diab A et al. SITC 2019, Abstract O35.
REPORTING FROM SITC 2019
Will TP53-mutated AML respond to immunotherapy?
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
NATIONAL HARBOR, MD. – New research has shown increased immune infiltration in patients with TP53-mutated acute myeloid leukemia (AML).
Patients with TP53-mutated AML had higher levels of T-cell infiltration, immune checkpoint molecules, and interferon (IFN)–gamma signaling than patients with wild-type TP53.
These findings may indicate that patients with TP53-mutated AML will respond to T-cell targeting immunotherapies, but more investigation is needed, according to Sergio Rutella, MD, PhD, of Nottingham (England) Trent University.
Dr. Rutella described the findings at the annual meeting of the Society for Immunotherapy of Cancer.
He and his colleagues recently identified subgroups of AML, called “immune infiltrated” and “immune depleted,” that can predict chemotherapy resistance and response to flotetuzumab (ASH 2019, Abstract 460). However, the team has not determined the genetic drivers of immune infiltration in AML.*
With the current study, Dr. Rutella and his colleagues wanted to determine if TP53 mutations are associated with the AML immune milieu and see if TP53-mutated patients might benefit from immunotherapy.
Discovery cohort
The researchers first analyzed 147 patients with non-promyelocytic AML from the Cancer Genome Atlas. In total, 9% of these patients (n = 13) had TP53-mutated AML. The researchers assessed how 45 immune gene and biological activity signatures correlated with prognostic molecular lesions (TP53 mutations, FLT3-ITD, etc.) and clinical outcomes in this cohort.
The data showed that immune subtypes were associated with overall survival (OS). The median OS was 11.8 months in patients with immune-infiltrated AML, 16.4 months in patients with intermediate AML, and 25.8 months in patients with immune-depleted AML.
The inflammatory chemokine score (P = .011), IDO1 score (P = .027), IFN-gamma score (P = .036), and B7H3 score (P = .045) were all significantly associated with OS. In fact, these factors were all better predictors of OS than cytogenetic risk score (P = .049).
The IFN-gamma score, inflammatory chemokine score, and lymphoid score were all significantly higher in TP53-mutated patients than in patients with RUNX1 mutations, NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .05).
Likewise, the tumor inflammation signature score was significantly higher among TP53-mutated patients than among patients with NPM1 mutations, FLT3-ITD (with or without NPM1 mutations), and TET2/DNMT3A/ASXL1 mutations (P values ranging from less than .0001 to .01).
Validation cohort and bone marrow samples
The researchers also looked at data from a validation cohort, which consisted of 140 patients with non-promyelocytic AML in the Beat AML Master Trial. Twelve percent of these patients (n = 17) had TP53 mutations.
Data in this cohort showed that CD3G messenger RNA (mRNA) was significantly higher in TP53-mutated AML than in TP53-wild-type AML (P = .04). The same was true for CD8A mRNA (P = .0002) and GZMB mRNA (P = .0005).
Likewise, IFN-gamma mRNA (P = .0052), IFIT2 mRNA (P = .0064), and IFIT3 mRNA (P = .003) were all significantly higher in patients with TP53-mutated AML.
Lastly, the researchers analyzed gene expression profiles of bone marrow samples from patients with AML, 36 with mutated TP53 and 24 with wild-type TP53.
The team found that IFN-gamma–induced genes (IFNG and IRF1), markers of T-cell infiltration (CD8A and CD3G) and senescence (EOMES, KLRD1, and HRAS), immune checkpoint molecules (IDO1, LAG3, PDL1, and VISTA), effector function molecules (GZMB, GZMK, and GZMM), and proinflammatory cytokines (IL17A and TNF) were all significantly overexpressed in TP53-mutated AML.
Among the top overexpressed genes in TP53-mutated AML were genes associated with IFN signaling and inflammation pathways – IL-33, IL-6, IFN-gamma, OASL, RIPK2, TNFAIP3, CSF1, and PTGER4. The IL-17 and TNF signaling pathways were the most enriched pathways in TP53-mutated AML.
“Our analysis of primary bone marrow samples showed that TP53-mutated samples are enriched in IL-17, TNF, and IFN signaling molecules, and show higher levels of T-cell infiltrations and immune checkpoints relative to their wild-type counterparts,” Dr. Rutella said.
“The in silico analysis indicated that TP53-mutated cases will show higher levels of T-cell infiltration, immune checkpoints, and IFN-gamma signaling, compared with AML subgroups without risk-defining molecular lesions,” he added. “This is speculative. Whether TP53-mutated AML can be amenable to respond to T-cell targeting immunotherapies is still to be determined.”
Dr. Rutella reported research support from NanoString Technologies, MacroGenics, and Kura Oncology.
SOURCE: Rutella S et al. SITC 2019. Abstract O3.
*This article was updated on 11/19/2019.
REPORTING FROM SITC 2019
Cleveland Clinic grants award, welcomes new talent
Brian Bolwell, MD, chairman of Cleveland Clinic Taussig Cancer Institute in Ohio, has received the 2019 Alfred and Norma Lerner Humanitarian Award.
Dr. Bolwell received the award “in honor of his 32 years of compassionate service as a physician leader and educator, along with his contributions to clinical and translational cancer research throughout the world,” according to a statement from Cleveland Clinic. The award recognizes “Cleveland Clinic physicians whose selfless dedication, boundless compassion, and tireless work have made the most profound and singular contribution to the good of humankind.”
In addition to serving as chairman of Taussig Cancer Institute, Dr. Bolwell is a professor of medicine for Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and deputy director of the Case Comprehensive Cancer Center. He was director of the Cleveland Clinic bone marrow transplant program for 24 years and chairman of the department of hematologic oncology & blood disorders from 2006 to 2011.
In other Cleveland Clinic news, Halle Moore, MD, has been named director of breast medical oncology and codirector for the comprehensive breast cancer program at the clinic. She will assume this role in January 2020.
Dr. Moore is currently a staff physician at Taussig Cancer Institute and an associate professor of medicine at Lerner College of Medicine. Her clinical expertise is the management of breast cancer, and her research is focused on breast cancer treatment and cancer survivorship.
Cleveland Clinic has also added four new staff physicians to the department of hematology and medical oncology.
Shilpa Gupta, MD, has joined the clinic’s genitourinary cancer program. Dr. Gupta previously worked in the division of hematology, oncology, and transplantation at the University of Minnesota in Minneapolis, where she led the interdisciplinary solid tumor phase 1 program .
Khaled Hassan, MD, has joined the thoracic cancer program at Cleveland Clinic. Dr. Hassan was previously an assistant professor in the department of internal medicine, division of hematology/oncology at the University of Michigan in Ann Arbor. Suneel Kamath, MD, has joined the gastrointestinal cancer program at the clinic. Dr. Kamath was previously the hematology and medical oncology chief fellow at Northwestern University in Evanston, Ill.
Brian Bolwell, MD, chairman of Cleveland Clinic Taussig Cancer Institute in Ohio, has received the 2019 Alfred and Norma Lerner Humanitarian Award.
Dr. Bolwell received the award “in honor of his 32 years of compassionate service as a physician leader and educator, along with his contributions to clinical and translational cancer research throughout the world,” according to a statement from Cleveland Clinic. The award recognizes “Cleveland Clinic physicians whose selfless dedication, boundless compassion, and tireless work have made the most profound and singular contribution to the good of humankind.”
In addition to serving as chairman of Taussig Cancer Institute, Dr. Bolwell is a professor of medicine for Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and deputy director of the Case Comprehensive Cancer Center. He was director of the Cleveland Clinic bone marrow transplant program for 24 years and chairman of the department of hematologic oncology & blood disorders from 2006 to 2011.
In other Cleveland Clinic news, Halle Moore, MD, has been named director of breast medical oncology and codirector for the comprehensive breast cancer program at the clinic. She will assume this role in January 2020.
Dr. Moore is currently a staff physician at Taussig Cancer Institute and an associate professor of medicine at Lerner College of Medicine. Her clinical expertise is the management of breast cancer, and her research is focused on breast cancer treatment and cancer survivorship.
Cleveland Clinic has also added four new staff physicians to the department of hematology and medical oncology.
Shilpa Gupta, MD, has joined the clinic’s genitourinary cancer program. Dr. Gupta previously worked in the division of hematology, oncology, and transplantation at the University of Minnesota in Minneapolis, where she led the interdisciplinary solid tumor phase 1 program .
Khaled Hassan, MD, has joined the thoracic cancer program at Cleveland Clinic. Dr. Hassan was previously an assistant professor in the department of internal medicine, division of hematology/oncology at the University of Michigan in Ann Arbor. Suneel Kamath, MD, has joined the gastrointestinal cancer program at the clinic. Dr. Kamath was previously the hematology and medical oncology chief fellow at Northwestern University in Evanston, Ill.
Brian Bolwell, MD, chairman of Cleveland Clinic Taussig Cancer Institute in Ohio, has received the 2019 Alfred and Norma Lerner Humanitarian Award.
Dr. Bolwell received the award “in honor of his 32 years of compassionate service as a physician leader and educator, along with his contributions to clinical and translational cancer research throughout the world,” according to a statement from Cleveland Clinic. The award recognizes “Cleveland Clinic physicians whose selfless dedication, boundless compassion, and tireless work have made the most profound and singular contribution to the good of humankind.”
In addition to serving as chairman of Taussig Cancer Institute, Dr. Bolwell is a professor of medicine for Cleveland Clinic Lerner College of Medicine at Case Western Reserve University and deputy director of the Case Comprehensive Cancer Center. He was director of the Cleveland Clinic bone marrow transplant program for 24 years and chairman of the department of hematologic oncology & blood disorders from 2006 to 2011.
In other Cleveland Clinic news, Halle Moore, MD, has been named director of breast medical oncology and codirector for the comprehensive breast cancer program at the clinic. She will assume this role in January 2020.
Dr. Moore is currently a staff physician at Taussig Cancer Institute and an associate professor of medicine at Lerner College of Medicine. Her clinical expertise is the management of breast cancer, and her research is focused on breast cancer treatment and cancer survivorship.
Cleveland Clinic has also added four new staff physicians to the department of hematology and medical oncology.
Shilpa Gupta, MD, has joined the clinic’s genitourinary cancer program. Dr. Gupta previously worked in the division of hematology, oncology, and transplantation at the University of Minnesota in Minneapolis, where she led the interdisciplinary solid tumor phase 1 program .
Khaled Hassan, MD, has joined the thoracic cancer program at Cleveland Clinic. Dr. Hassan was previously an assistant professor in the department of internal medicine, division of hematology/oncology at the University of Michigan in Ann Arbor. Suneel Kamath, MD, has joined the gastrointestinal cancer program at the clinic. Dr. Kamath was previously the hematology and medical oncology chief fellow at Northwestern University in Evanston, Ill.
Researchers seek a way to predict cognitive deficits in children treated for ALL
Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.
The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.
Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.
Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).
“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.
This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).
The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.
Cognitive testing
While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.
The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.
The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.
In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.
Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.
Preliminary results
This research is ongoing, so it’s too early to announce any discoveries, but the study is moving along as planned.
“The preliminary data we have so far are demonstrating the validity of the study,” Dr. Cole said. “Things are going well. We’re able to do the cognitive testing and collect the samples that we need and ship them without losing the integrity of the samples.”
Dr. Sands noted that enrollment has been encouraging. As this is a substudy of DFCI-16-001, the researchers must obtain consent separately from the main study. Dr. Sands said about 89% of parents involved in the main study have agreed to enroll their children in the substudy.
Dr. Sands also said that early results from Cogstate testing have revealed patients who are experiencing cognitive decline during treatment. The researchers still have to determine if these results correlate with any biomarkers or gene variants.
Potential interventions
If the researchers can pinpoint patients at risk for cognitive deficits, the next step will be to investigate pharmacologic and behavioral interventions.
Dr. Cole said he is particularly interested in treatments that reduce oxidative stress, such as dextromethorphan and memantine. Dextromethorphan has been shown to resolve symptoms of methotrexate-induced neurotoxicity in patients (Pediatr Hematol Oncol. 2002 Jul-Aug;19[5]:319-27), and memantine reduced memory deficits in animals treated with methotrexate (Clin Cancer Res. 2013 Aug 15;19[16]:4446-54).
“Memantine hasn’t been used in kids with leukemia yet, but it’s something that I’d like to see brought to a clinical trial,” Dr. Cole said.
Dr. Sands pointed to other potential pharmacologic interventions, including the stimulants methylphenidate and modafinil. Both drugs have been shown to improve cognitive deficits in cancer survivors (J Clin Oncol. 2001 Mar 15;19[6]:1802-8; Cancer. 2009 Jun 15; 115[12]: 2605-16).
Computer-based cognitive training tools may be another option. One such tool, Lumosity, improved executive functions in a study of breast cancer survivors (Clin Breast Cancer. 2013 Aug;13[4]:299-306). Another tool, CogMed, improved working memory in survivors of brain tumors and ALL (Psychooncology. 2013 Aug; 22[8]: 1856-65).
Other behavioral interventions might include sleep hygiene and exercise. Sleep hygiene has been shown to improve cognitive function in childhood cancer survivors (Cancer. 2011 Jun 1;117[11]:2559-68), and a recent study revealed an association between exercise intolerance and negative neurocognitive outcomes in ALL survivors (Cancer. 2019 Oct 21. doi: 10.1002/cncr.32510).
“What we need to figure out is which children will respond to which interventions,” Dr. Sands said, adding that interventions will likely need to be combined.
“It’s not going to be one thing that will work for everybody,” he said. “It’s going to be: What packages of things will work for different people?”
Dr. Sands and Dr. Cole reported having no relevant financial disclosures.
Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.
The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.
Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.
Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).
“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.
This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).
The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.
Cognitive testing
While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.
The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.
The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.
In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.
Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.
Preliminary results
This research is ongoing, so it’s too early to announce any discoveries, but the study is moving along as planned.
“The preliminary data we have so far are demonstrating the validity of the study,” Dr. Cole said. “Things are going well. We’re able to do the cognitive testing and collect the samples that we need and ship them without losing the integrity of the samples.”
Dr. Sands noted that enrollment has been encouraging. As this is a substudy of DFCI-16-001, the researchers must obtain consent separately from the main study. Dr. Sands said about 89% of parents involved in the main study have agreed to enroll their children in the substudy.
Dr. Sands also said that early results from Cogstate testing have revealed patients who are experiencing cognitive decline during treatment. The researchers still have to determine if these results correlate with any biomarkers or gene variants.
Potential interventions
If the researchers can pinpoint patients at risk for cognitive deficits, the next step will be to investigate pharmacologic and behavioral interventions.
Dr. Cole said he is particularly interested in treatments that reduce oxidative stress, such as dextromethorphan and memantine. Dextromethorphan has been shown to resolve symptoms of methotrexate-induced neurotoxicity in patients (Pediatr Hematol Oncol. 2002 Jul-Aug;19[5]:319-27), and memantine reduced memory deficits in animals treated with methotrexate (Clin Cancer Res. 2013 Aug 15;19[16]:4446-54).
“Memantine hasn’t been used in kids with leukemia yet, but it’s something that I’d like to see brought to a clinical trial,” Dr. Cole said.
Dr. Sands pointed to other potential pharmacologic interventions, including the stimulants methylphenidate and modafinil. Both drugs have been shown to improve cognitive deficits in cancer survivors (J Clin Oncol. 2001 Mar 15;19[6]:1802-8; Cancer. 2009 Jun 15; 115[12]: 2605-16).
Computer-based cognitive training tools may be another option. One such tool, Lumosity, improved executive functions in a study of breast cancer survivors (Clin Breast Cancer. 2013 Aug;13[4]:299-306). Another tool, CogMed, improved working memory in survivors of brain tumors and ALL (Psychooncology. 2013 Aug; 22[8]: 1856-65).
Other behavioral interventions might include sleep hygiene and exercise. Sleep hygiene has been shown to improve cognitive function in childhood cancer survivors (Cancer. 2011 Jun 1;117[11]:2559-68), and a recent study revealed an association between exercise intolerance and negative neurocognitive outcomes in ALL survivors (Cancer. 2019 Oct 21. doi: 10.1002/cncr.32510).
“What we need to figure out is which children will respond to which interventions,” Dr. Sands said, adding that interventions will likely need to be combined.
“It’s not going to be one thing that will work for everybody,” he said. “It’s going to be: What packages of things will work for different people?”
Dr. Sands and Dr. Cole reported having no relevant financial disclosures.
Researchers are attempting to determine, early in the treatment process, which children with acute lymphoblastic leukemia (ALL) have an increased risk of neurocognitive deficits after chemotherapy.
The goal of the researchers’ project (5R01CA220568-02) is to determine if gene variants and biomarkers associated with oxidative stress, neuroinflammation, and folate physiology correlate with cognitive decline during and after chemotherapy. Ideally, certain variants and biomarkers will reveal patients who might benefit from interventions to prevent or even reverse cognitive deficits.
Peter D. Cole, MD, of Rutgers Cancer Institute, New Brunswick, N.J., and colleagues are conducting this research in patients from the DFCI-16-001 trial (NCT03020030). This multicenter, phase 3 study is enrolling patients (aged 1-21 years) with B- or T-cell ALL who then receive a multidrug chemotherapy regimen.
Dr. Cole and colleagues are analyzing a subset of patients from the trial, looking for relationships between chemotherapy-induced neurocognitive changes, gene variants, and changes in biomarkers detected in cerebrospinal fluid (CSF).
“We’re looking at a broad panel of target gene variants that are associated with either drug metabolism, defenses against oxidative stress, neuroinflammation, or folate physiology,” Dr. Cole said in an interview.
This includes variants Dr. Cole and colleagues identified in a previous, retrospective study of ALL survivors. The researchers found that survivors who were homozygous for NOS3 894T, had a variant SLCO2A1 G allele, or had at least one GSTP1 T allele were more likely to exhibit cognitive deficits (J Clin Oncol. 2015 Jul 1;33[19]:2205-11).
The researchers are also analyzing CSF samples, looking for changes in tau protein, homocysteine, homocysteic acid, the adenosylmethionine to adenosylhomocysteine ratio, and other biomarkers of oxidative stress, neuroinflammation, and folate physiology. The CSF is collected at five time points: the start of chemotherapy, day 18, the start of first consolidation, the end of first consolidation, and 7 weeks later in second consolidation.
Cognitive testing
While Dr. Cole is leading the genetic and biomarker analyses, Stephen A. Sands, PsyD, of Memorial Sloan Kettering Cancer Center in New York, is leading the cognitive testing.
The researchers are evaluating patients for cognitive decline using computerized tests from a company called Cogstate. The tests are designed to assess functions such as processing speed, attention, visual learning, and working memory. The tests are administered on an iPad and involve tasks like identifying features of playing cards and finding the correct way through a maze.
The patients – aged 3 years and older – undergo cognitive testing at six time points: baseline, which is any time between days 8 and 32 of induction (except within 72 hours after sedation or anesthesia); at first consolidation; the end of central nervous system therapy; 1 year into chemotherapy; the end of chemotherapy; and 1 year after chemotherapy ends.
In a prior study, Cogstate testing proved reliable for detecting neurocognitive changes in patients undergoing treatment for ALL (Support Care Cancer. 2017;25[2]:449-57). In the current study, the researchers are supplementing Cogstate test results with Wechsler IQ tests administered 1 year after patients complete chemotherapy.
Dr. Sands noted that Cogstate tests provide benefits over the Wechsler “paper-and-pencil” tests. One benefit is that Cogstate tests can be given more often without inducing practice effects (J Clin Exp Neuropsychol. 2006 Oct;28[7]:1095-112). Another is that Cogstate tests can be administered by anyone with a bachelor’s degree who has undergone the appropriate training, while Wechsler IQ tests must be given by psychologists.
Preliminary results
This research is ongoing, so it’s too early to announce any discoveries, but the study is moving along as planned.
“The preliminary data we have so far are demonstrating the validity of the study,” Dr. Cole said. “Things are going well. We’re able to do the cognitive testing and collect the samples that we need and ship them without losing the integrity of the samples.”
Dr. Sands noted that enrollment has been encouraging. As this is a substudy of DFCI-16-001, the researchers must obtain consent separately from the main study. Dr. Sands said about 89% of parents involved in the main study have agreed to enroll their children in the substudy.
Dr. Sands also said that early results from Cogstate testing have revealed patients who are experiencing cognitive decline during treatment. The researchers still have to determine if these results correlate with any biomarkers or gene variants.
Potential interventions
If the researchers can pinpoint patients at risk for cognitive deficits, the next step will be to investigate pharmacologic and behavioral interventions.
Dr. Cole said he is particularly interested in treatments that reduce oxidative stress, such as dextromethorphan and memantine. Dextromethorphan has been shown to resolve symptoms of methotrexate-induced neurotoxicity in patients (Pediatr Hematol Oncol. 2002 Jul-Aug;19[5]:319-27), and memantine reduced memory deficits in animals treated with methotrexate (Clin Cancer Res. 2013 Aug 15;19[16]:4446-54).
“Memantine hasn’t been used in kids with leukemia yet, but it’s something that I’d like to see brought to a clinical trial,” Dr. Cole said.
Dr. Sands pointed to other potential pharmacologic interventions, including the stimulants methylphenidate and modafinil. Both drugs have been shown to improve cognitive deficits in cancer survivors (J Clin Oncol. 2001 Mar 15;19[6]:1802-8; Cancer. 2009 Jun 15; 115[12]: 2605-16).
Computer-based cognitive training tools may be another option. One such tool, Lumosity, improved executive functions in a study of breast cancer survivors (Clin Breast Cancer. 2013 Aug;13[4]:299-306). Another tool, CogMed, improved working memory in survivors of brain tumors and ALL (Psychooncology. 2013 Aug; 22[8]: 1856-65).
Other behavioral interventions might include sleep hygiene and exercise. Sleep hygiene has been shown to improve cognitive function in childhood cancer survivors (Cancer. 2011 Jun 1;117[11]:2559-68), and a recent study revealed an association between exercise intolerance and negative neurocognitive outcomes in ALL survivors (Cancer. 2019 Oct 21. doi: 10.1002/cncr.32510).
“What we need to figure out is which children will respond to which interventions,” Dr. Sands said, adding that interventions will likely need to be combined.
“It’s not going to be one thing that will work for everybody,” he said. “It’s going to be: What packages of things will work for different people?”
Dr. Sands and Dr. Cole reported having no relevant financial disclosures.
Neoantigen vaccine appears safe and active in NSCLC
NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).
The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.
“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.
The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.
To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).
In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.
Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.
Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
Results
Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).
Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.
The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).
Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.
The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.
“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”
This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.
SOURCE: Lizee G et al. SITC 2019. Abstract O18.
NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).
The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.
“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.
The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.
To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).
In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.
Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.
Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
Results
Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).
Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.
The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).
Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.
The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.
“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”
This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.
SOURCE: Lizee G et al. SITC 2019. Abstract O18.
NATIONAL HARBOR, MD. – Trial results suggest a personalized vaccination approach is feasible and safe, and the vaccine can produce clinical responses in patients with non–small cell lung cancer (NSCLC).
The neoantigen vaccine produced only grade 1 adverse events, yielded responses in patients with epidermal growth factor receptor (EGFR) mutations, and proved particularly effective in patients who were also receiving an EGFR inhibitor.
“EGFR inhibitors seemed to reduce tumor immunosuppression barriers and may enhance antitumor immune responses before and during immunization, suggesting there may be a potential synergy of EGFR with immunotherapies,” Gregory A. Lizee, PhD, of University of Texas MD Anderson Cancer Center, Houston, said at the annual meeting of the Society for Immunotherapy of Cancer.
The research began with an elderly patient who had heavily pretreated NSCLC (Oncoimmunology. 2016;5[12]:e1238539). Dr. Lizee and colleagues used tumor mutational profiling and human leukocyte antigen (HLA) typing to develop a personalized peptide vaccine for the patient. He received the vaccine along with topical imiquimod and had multiple lung tumor nodules regress. However, the patient also had liver metastasis that remained refractory to treatment, and he ultimately died.
To investigate this treatment approach in a larger group, Dr. Lizee and colleagues began a phase 1b trial of patients with advanced NSCLC (ChiCTR-IIR-16009867). As with the prior patient, the researchers designed personalized peptide vaccines for the trial subjects based on mutational profiling of 508 cancer-associated genes and high-resolution HLA typing. The peptides were selected based on nonsynonymous somatic tumor–associated mutations with variant allele frequency greater than 0.04 and the highest predicted neoantigen peptide binding to each patient’s HLA class I and II molecules. The vaccines targeted up to eight independent somatic mutations (mean, 3.75 mutations).
In all, 31 patients provided lung tumor biopsies and peripheral blood for mutational and HLA analyses. The researchers designed 27 personalized neoantigen vaccines, and 24 patients were ultimately vaccinated. This translates to a vaccination rate of 77%, which suggests this treatment approach is feasible, Dr. Lizee said.
Of the 24 vaccinated patients, 18 had adenocarcinoma, and 6 had squamous cell carcinoma. All patients had received multiple prior therapies, including surgery, chemotherapy, radiation, and EGFR inhibitors.
Each patient was vaccinated with a personalized mixture of short and long neoantigen peptides (mean, 9.4 peptides) dissolved in isotonic saline. Patients received at least 12 weekly immunizations and had topical imiquimod applied over the injection site for costimulation through toll-like receptor 7. The 16 patients with EGFR mutations were given the option of continuing on an EGFR inhibitor, and 9 patients elected to do so.
Results
Dr. Lizee said this treatment approach was “very safe,” with only grade 1 treatment-related adverse events. The events were fatigue (n = 2), rash (n = 1), and fever (n = 1).
Seven patients achieved a response after vaccination, and one patient achieved a complete response. All seven responders had EGFR mutations, and four of them were receiving an EGFR inhibitor.
The patients on an EGFR inhibitor had significantly better overall survival than that of EGFR-mutated patients who had stopped taking an EGFR inhibitor – 13.8 months and 7.6 months, respectively (P = .038).
Immune profiling revealed that neoantigen-specific T-cell reactivity was associated with clinical responses. The researchers observed EGFR neoantigen-specific T-cell responses in five responders. In three responders, the strongest response was against a peptide encompassing the L858R driver mutation.
The researchers also found evidence of synergy between EGFR inhibitor therapy and the peptide vaccine. EGFR inhibition caused immunomodulatory pathways in EGFR-mutated cancer cells to favor immune-cell infiltration and HLA-mediated antigen presentation.
“Our mechanistic working model is that, in the circulation, the personalized vaccine increased the T-cell frequency,” Dr. Lizee said. “The EGFR inhibitor increased chemokines and antigen presentation at the tumor site, which then attracted those T cells to migrate to the tumor. Then, recognition of the antigen caused interferon gamma [to increase], which caused, potentially, a feed-forward loop by increasing chemokines and antigen presentation further.”
This research is sponsored by Tianjin Beichen Hospital and funded by Tianjin HengJia Biotechnology Development Co. Ltd. Dr. Lizee disclosed a consulting relationship with Tianjin HengJia Biotechnology Development Co. Ltd.
SOURCE: Lizee G et al. SITC 2019. Abstract O18.
REPORTING FROM SITC 2019