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Bispecific CAR T-cells yield high response rate in relapsed/refractory myeloma
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
ORLANDO – A dual-targeted chimeric antigen receptor (CAR) T-cell therapy has demonstrated a high overall response rate, a long response duration, and manageable safety in patients with relapsed or refractory multiple myeloma, according to an investigator in a phase 1 study.
The overall response rate exceeded 90%, and about three-quarters of patients remained progression-free at 9 months after treatment with the CAR T-cell therapy, which targets both B-cell maturation antigen (BCMA) and CD38, the study investigator reported.
Grade 3 or greater cytokine release syndrome (CRS) occurred in about one-quarter of the patients, and no neurotoxicity was observed, according to investigator Yu Hu, MD, of Tongji Medical College in Hubei, China.
“,” Dr. Hu said in a press conference.
Short-term relapse has been a “major challenge” with current CAR T-cell therapies currently under investigation for myeloma, most of which target BCMA, according to Dr. Hu.
He said the bispecific CAR T-cell therapy under investigation, known as BM38, was designed to target antigen loss and increase persistence of effector cells. According to the investigator, this was the first study to focus on an anti-BCMA and CD38 dual-targeted CAR T-cell therapy for patients with relapsed or refractory multiple myeloma.
Gary J. Schiller, MD, of UCLA Health, who moderated the press conference, said that while dual-targeting is a potentially “attractive” approach in these hard-to-treat patients, further follow-up is needed to see duration of response and to see if antigen escape re-emerges.
“Cellular therapy is costly, in terms of toxicity as well as financial costs, so you would like to see what the durability of responses is before engaging in that as a late-stage therapy, not to mention moving it up front,” Dr. Schiller said in an interview.
The median progression-free survival (PFS) duration had not been reached at the time of this report, though the 9-month PFS rate was 78.87%, according to the data presented by Dr. Hu.
In the phase 1 study, 22 patients received BM38 CAR T-cell infusions following a fludarabine and cyclophosphamide preconditioning regimen. The median patient age was 59 years, and 50% were male. Nearly three-quarters (72%) had a cytogenetic abnormality, and the median number of prior therapies approached four (range, two to nine prior therapies).
Twenty of the patients (90.9%) had a response: 12 who achieved stringent complete remission, 2 with very good partial response, 5 with partial responses, and 1 with a minimal response.
Of 9 patients with extramedullary disease, 8 achieved partial or complete elimination of tumors, Dr. Hu said in his presentation.
Cytokine release syndrome occurred in 20 patients (90.91%), 5 of whom experienced severe cases (22.73%), according to the reported data. There was no observed neurotoxicity, according to the report, while almost all had hematologic toxicities. Three experienced hepatotoxicity and one had nephrotoxicity, according to Dr. Hu.
The phase 1 study was supported by the National Natural Science Foundation of China, the Major Technological Innovation Special Project Fund of Hubei Province of China, and Cellyan Therapeutics. The senior author of the study was affiliated with Cellyan Therapeutics. Dr. Hu and coauthors reported that they had no relevant conflicts of interest to declare.
SOURCE: Li C et al. ASH 2019. Abstract 930.
REPORTING FROM ASH 2019
High complete response rate seen with novel CAR-T for myeloma
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
ORLANDO – A novel chimeric antigen receptor T (CAR T) cell construct is associated with deep clinical responses in patients with multiple myeloma for whom prior lines of therapy – some numbering in the double digits – have failed.
Among 29 patients with multiple myeloma enrolled in a phase 1b/2 trial of JNJ-4528, the overall response rate (ORR) at 6 months median follow-up was 100%, including 69% complete responses, with 27 patients remaining free of disease progression at a median of 6 months, reported Deepu Madduri, MD, of Icahn School of Medicine at Mount Sinai, New York.
“These are very heavily pretreated patients, and so getting early and deep responses is quite amazing,” she said at a briefing prior to presentation of the data at the annual meeting of the American Society of Hematology.
JNJ-4528 is a second-generation CAR T containing two single-domain antibodies targeted against B-cell maturation protein (BCMA). As previously reported, an identical CAR T cell construct showed a high overall response with manageable toxicities in 74 patients with relapsed/refractory multiple myeloma. JNJ-4528 was granted a breakthrough therapy designation for relapsed/refractory multiple myeloma by the Food and Drug Administration on Dec. 6, 2019, and a priority medicines (PRIME) designation by the European Medicines Agency in April 2019.
BCMA was first described in myeloma in 2004 as a mechanism for the growth and survival of malignant plasma cells. Several research groups are currently investigating CAR T cells or monoclonal antibodies targeted to BCMA. The product closest to receiving FDA approval is likely BB2121.
At ASH 2019, Dr. Madduri presented results from the phase 1b portion of the CARTITUDE-1 trial. The investigators enrolled patients with multiple myeloma with measurable diseases as assessed by M-protein or serum free light chain levels who had experienced disease progression on at least 3 prior lines of therapy, or whose disease was refractory to at least two lines of therapy with a proteasome inhibitor, immunomodulatory drug (IMiD), and an anti-CD38 antibody.
Patients underwent apheresis for T-cell collection, with bridging therapy allowed until the expanded T cells could be delivered.
Following T-cell depletion with cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 over 3 days, patients received a single weight-based infusion (compared with fixed-dose infusions used with other CAR T cell constructs).
The dose was targeted at 0.75x106 CAR-positive cells/kg, with a target range of 0.5–1.0x106, administered 5-7 days after the start of the conditioning regimen.
A total of 29 patients, median age 60, were evaluable for the safety and efficacy endpoints. One-fourth of the patients had a high-risk cytogenetic profile. The patients had received a median of 5 prior lines of therapy, with one patient receiving 18 prior lines. Of the 29 patients, 25 (86%) had previously undergone autologous transplantation.
As noted before, the ORR after a median follow-up of 6 months was 100%, with 69% completer responses, 17% very good partial responses, and 14% partial responses. The median time to complete response was 1 month (range 1 to 9 months). All but two patients remained free of disease progression at the median 6-month follow-up.
Nearly all patients (27) developed cytokine release syndrome (CRS), and one patient with prolonged grade 4 CRS died from related complications 99 days after infusion.
The median time to onset of CRS was 7 days with more than 90% of cases occurring between days 5 and 9.
Neurotoxicities, specifically immune effector cell–associated neurotoxicity syndrome (ICANS), were infrequent in CRS, and when they did occur were generally low grade, with only 1 grade 3 ICANS event.
Asked in an interview whether the impressive response rates seen with JNJ-4528 might persist over time, Dr. Madduri acknowledged that follow-up is still relatively short.
“This product is unique in that has a CD8 central memory phenotype preferentially, and we’re hoping that this would play a central role in the durability of response because they’re memory cells, but I think at this time we don’t know,” she said.
The CARTITUDE-1 trial is funded by Janssen Research & Development. Dr. Madduri disclosed serving as a consultant to Janssen and to Takeda, Foundation Medicine, AbbVie, and Celgene.
SOURCE: Madduri D et al. ASH 2019. Abstract 577.
REPORTING FROM ASH 2019
ASH preview: Key themes include tackling CAR T obstacles, sickle cell advances, VTE
Chimeric antigen receptor (CAR) T-cell therapies have garnered a great deal of attention given their “incredible efficacy” in treating B-cell malignancies, and new findings are taking aim at the drawbacks of therapy, such as the time, expense, and toxicity involved, according to Robert A. Brodsky, MD.
One example, from a study slated for presentation during a plenary session at the upcoming annual meeting of the American Society of Hematology involves the investigational T-cell bispecific antibody mosunetuzumab, which targets both CD20 on the surface of malignant B cells, and CD3 on cytotoxic T cells, engaging the T cells and directing their cytotoxicity against B cells.
In a study (Abstract 6) of 218 non-Hodgkin lymphoma patients, including 23 who had already received CAR T-cell therapy and had relapsed or were refractory to the treatment, 64% responded, 42% had a complete response, and the median duration of response is now out to 9 months, Dr. Brodsky, ASH secretary and director of the division of hematology at Johns Hopkins University, Baltimore, said during a premeeting press conference.
“It’s basically an antibody using the patient’s own T cell to do what a CAR-T cell would do – [a] very exciting study and large study,” he said. “It is an off-the-shelf product, it completely gets around the problem of the time to generate the CAR T-cell product, and because it’s going to be much simpler and faster to produce, it’s likely going to be much cheaper than CAR T cells.”
The preliminary results also suggest it is less toxic than CAR T-cell therapy, he added.
Two other CAR T-cell therapy–related studies highlighted during the press conference address its use for multiple myeloma. One, the phase 1b/2 CARTITUDE study (Abstract 577) uses CAR T cells against the B-cell maturation antigen (BCMA) in the relapsed/refractory setting.
Of 25 patients treated with chemotherapy followed by CAR T-cell infusion and followed for a median of 3 months, 91% responded, two achieved a complete remission, and “many other responses were very deep responses,” Dr. Brodsky said, noting that the second featured multiple myeloma trial (Abstract 930) looked at bispecific CAR T-cell therapy targeting BCMA and CD38 in an effort to reduce resistance to the therapy.
“Again, very interesting preliminary results,” he said, noting that of 16 patients followed for a median of 36 weeks, 87.5% responded, the treatment was well tolerated, and progression-free survival at 9 months was 75%.
In addition to the “key theme” of overcoming CAR T-cell therapy obstacles, three other themes have emerged from among the thousands of abstracts submitted for presentation at ASH. These, as presented during the press conference, include new venous thromboembolism (VTE) therapies and approaches to research; inclusive medicine, with abstracts focused on age- and race-related issues in clinical trials; and new advances in the treatment of sickle cell disease. All of these have potentially practice-changing implications, as do the six late-breaking abstracts selected from 93 abstracts submitted for consideration for oral presentation at ASH, Dr. Brodsky said.
One of the “truly practice-changing” late-breakers is a randomized phase 3 trial (Abstract LBA-1) comparing the bispecific antibody blinatumomab to chemotherapy for post-re-induction therapy in high- and intermediate-risk acute lymphoblastic leukemia (ALL) at first relapse in children, adolescents and young adults.
The study demonstrated the superiority of blinatumomab for efficacy and tolerability, which is particularly encouraging given the challenges in getting relapsed ALL patients back into remission so they can undergo bone marrow transplant, Dr. Brodsky said.
Of 208 patients randomized, 73% vs. 45% in the blinatumomab vs. chemotherapy arms were able to get to transplant – and therefore to potential cure, he said.
“Of note, the blinatumomab arm was less toxic and there was marked improvement in disease-free and overall survival, so this is clearly going to become a new standard of care for relapsed and refractory ALL,” he added.
Chimeric antigen receptor (CAR) T-cell therapies have garnered a great deal of attention given their “incredible efficacy” in treating B-cell malignancies, and new findings are taking aim at the drawbacks of therapy, such as the time, expense, and toxicity involved, according to Robert A. Brodsky, MD.
One example, from a study slated for presentation during a plenary session at the upcoming annual meeting of the American Society of Hematology involves the investigational T-cell bispecific antibody mosunetuzumab, which targets both CD20 on the surface of malignant B cells, and CD3 on cytotoxic T cells, engaging the T cells and directing their cytotoxicity against B cells.
In a study (Abstract 6) of 218 non-Hodgkin lymphoma patients, including 23 who had already received CAR T-cell therapy and had relapsed or were refractory to the treatment, 64% responded, 42% had a complete response, and the median duration of response is now out to 9 months, Dr. Brodsky, ASH secretary and director of the division of hematology at Johns Hopkins University, Baltimore, said during a premeeting press conference.
“It’s basically an antibody using the patient’s own T cell to do what a CAR-T cell would do – [a] very exciting study and large study,” he said. “It is an off-the-shelf product, it completely gets around the problem of the time to generate the CAR T-cell product, and because it’s going to be much simpler and faster to produce, it’s likely going to be much cheaper than CAR T cells.”
The preliminary results also suggest it is less toxic than CAR T-cell therapy, he added.
Two other CAR T-cell therapy–related studies highlighted during the press conference address its use for multiple myeloma. One, the phase 1b/2 CARTITUDE study (Abstract 577) uses CAR T cells against the B-cell maturation antigen (BCMA) in the relapsed/refractory setting.
Of 25 patients treated with chemotherapy followed by CAR T-cell infusion and followed for a median of 3 months, 91% responded, two achieved a complete remission, and “many other responses were very deep responses,” Dr. Brodsky said, noting that the second featured multiple myeloma trial (Abstract 930) looked at bispecific CAR T-cell therapy targeting BCMA and CD38 in an effort to reduce resistance to the therapy.
“Again, very interesting preliminary results,” he said, noting that of 16 patients followed for a median of 36 weeks, 87.5% responded, the treatment was well tolerated, and progression-free survival at 9 months was 75%.
In addition to the “key theme” of overcoming CAR T-cell therapy obstacles, three other themes have emerged from among the thousands of abstracts submitted for presentation at ASH. These, as presented during the press conference, include new venous thromboembolism (VTE) therapies and approaches to research; inclusive medicine, with abstracts focused on age- and race-related issues in clinical trials; and new advances in the treatment of sickle cell disease. All of these have potentially practice-changing implications, as do the six late-breaking abstracts selected from 93 abstracts submitted for consideration for oral presentation at ASH, Dr. Brodsky said.
One of the “truly practice-changing” late-breakers is a randomized phase 3 trial (Abstract LBA-1) comparing the bispecific antibody blinatumomab to chemotherapy for post-re-induction therapy in high- and intermediate-risk acute lymphoblastic leukemia (ALL) at first relapse in children, adolescents and young adults.
The study demonstrated the superiority of blinatumomab for efficacy and tolerability, which is particularly encouraging given the challenges in getting relapsed ALL patients back into remission so they can undergo bone marrow transplant, Dr. Brodsky said.
Of 208 patients randomized, 73% vs. 45% in the blinatumomab vs. chemotherapy arms were able to get to transplant – and therefore to potential cure, he said.
“Of note, the blinatumomab arm was less toxic and there was marked improvement in disease-free and overall survival, so this is clearly going to become a new standard of care for relapsed and refractory ALL,” he added.
Chimeric antigen receptor (CAR) T-cell therapies have garnered a great deal of attention given their “incredible efficacy” in treating B-cell malignancies, and new findings are taking aim at the drawbacks of therapy, such as the time, expense, and toxicity involved, according to Robert A. Brodsky, MD.
One example, from a study slated for presentation during a plenary session at the upcoming annual meeting of the American Society of Hematology involves the investigational T-cell bispecific antibody mosunetuzumab, which targets both CD20 on the surface of malignant B cells, and CD3 on cytotoxic T cells, engaging the T cells and directing their cytotoxicity against B cells.
In a study (Abstract 6) of 218 non-Hodgkin lymphoma patients, including 23 who had already received CAR T-cell therapy and had relapsed or were refractory to the treatment, 64% responded, 42% had a complete response, and the median duration of response is now out to 9 months, Dr. Brodsky, ASH secretary and director of the division of hematology at Johns Hopkins University, Baltimore, said during a premeeting press conference.
“It’s basically an antibody using the patient’s own T cell to do what a CAR-T cell would do – [a] very exciting study and large study,” he said. “It is an off-the-shelf product, it completely gets around the problem of the time to generate the CAR T-cell product, and because it’s going to be much simpler and faster to produce, it’s likely going to be much cheaper than CAR T cells.”
The preliminary results also suggest it is less toxic than CAR T-cell therapy, he added.
Two other CAR T-cell therapy–related studies highlighted during the press conference address its use for multiple myeloma. One, the phase 1b/2 CARTITUDE study (Abstract 577) uses CAR T cells against the B-cell maturation antigen (BCMA) in the relapsed/refractory setting.
Of 25 patients treated with chemotherapy followed by CAR T-cell infusion and followed for a median of 3 months, 91% responded, two achieved a complete remission, and “many other responses were very deep responses,” Dr. Brodsky said, noting that the second featured multiple myeloma trial (Abstract 930) looked at bispecific CAR T-cell therapy targeting BCMA and CD38 in an effort to reduce resistance to the therapy.
“Again, very interesting preliminary results,” he said, noting that of 16 patients followed for a median of 36 weeks, 87.5% responded, the treatment was well tolerated, and progression-free survival at 9 months was 75%.
In addition to the “key theme” of overcoming CAR T-cell therapy obstacles, three other themes have emerged from among the thousands of abstracts submitted for presentation at ASH. These, as presented during the press conference, include new venous thromboembolism (VTE) therapies and approaches to research; inclusive medicine, with abstracts focused on age- and race-related issues in clinical trials; and new advances in the treatment of sickle cell disease. All of these have potentially practice-changing implications, as do the six late-breaking abstracts selected from 93 abstracts submitted for consideration for oral presentation at ASH, Dr. Brodsky said.
One of the “truly practice-changing” late-breakers is a randomized phase 3 trial (Abstract LBA-1) comparing the bispecific antibody blinatumomab to chemotherapy for post-re-induction therapy in high- and intermediate-risk acute lymphoblastic leukemia (ALL) at first relapse in children, adolescents and young adults.
The study demonstrated the superiority of blinatumomab for efficacy and tolerability, which is particularly encouraging given the challenges in getting relapsed ALL patients back into remission so they can undergo bone marrow transplant, Dr. Brodsky said.
Of 208 patients randomized, 73% vs. 45% in the blinatumomab vs. chemotherapy arms were able to get to transplant – and therefore to potential cure, he said.
“Of note, the blinatumomab arm was less toxic and there was marked improvement in disease-free and overall survival, so this is clearly going to become a new standard of care for relapsed and refractory ALL,” he added.
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
CAR T-cell ‘cocktail’ may overcome antigen escape relapse
A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.
This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.
The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.
Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.
After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.
With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.
Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.
“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”
The investigators reported having no conflicts of interest.
SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.
A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.
This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.
The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.
Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.
After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.
With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.
Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.
“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”
The investigators reported having no conflicts of interest.
SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.
A chimeric antigen receptor (CAR) T-cell “cocktail” targeting both CD19 and CD22 could improve outcomes for patients with refractory or relapsed B-cell malignancies, according to investigators.
This dual approach, which appeared safe and effective, may be able to overcome antigen escape relapse, reported Na Wang, MD, of Huazhong University of Science and Technology in China, and colleagues.
The investigators tested this method in an open-label, single-arm pilot study involving 89 patients with refractory/relapsed B cell malignancies. Of these, 51 patients had B-cell acute lymphoblastic leukemia (B-ALL), while the remaining 38 had non-Hodgkin lymphoma (NHL). All patients had dual expression of CD19 and CD22 on malignant B cells, good performance status, and “essentially” normal organ function, the investigators reported in Blood.
Following lymphodepletion, patients were infused with CAR19 and CAR22 T cells, then evaluated for responses with imaging or bone marrow aspiration on a monthly basis for 6 months, then every 3 months thereafter.
After 30 days, most patients with ALL (96%) achieved a minimal residual disease-negative complete response or complete response with incomplete count recovery. After a median follow-up of 16.7 months, almost half of these responders relapsed (49%), median progression-free survival was 13.6 months, and overall survival was 31 months.
With a minimum follow-up of 3 months, half of the patients with NHL (50%) achieved complete responses, with the caveat that two patients who died of septic shock and severe cytokine release syndrome were excluded from this efficacy analysis. After a median follow-up of 14.4 months, in the NHL group, median progression-free survival was 9.9 months and overall survival was 18 months.
Across disease types, almost all patients (95.5%) experienced cytokine release syndrome, with more than three-quarters (77.6%) categorized as grade 1 or 2. CAR T cell-related encephalopathy syndrome (CRES) occurred in 13.5% of patients; most were low grade, apart from one case that was grade 4. In total, 12 patients died due to adverse events.
“The severe [adverse events] were mostly cytopenias and the most frequent fatal [adverse event] was lung infection, which was attributable in part to the high disease burden and heavy pretreatment of the enrolled patients,” the investigators wrote. “Nearly all the high-grade CRS and CRES were reversible and occurred in similar incidences as previously reported. Thus, the sequential infusion of CAR19/22 T-cell “cocktail” was an efficient and well-tolerated approach to circumvent antigen loss of CD19 or CD22.”
The investigators reported having no conflicts of interest.
SOURCE: Wang N et al. 2019 Oct 29. doi: 10.1182/blood.2019000017.
FROM BLOOD
Armored CAR T cells elicit responses in NHL patients
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
NATIONAL HARBOR, MD – An armored chimeric antigen receptor (CAR) T-cell therapy has demonstrated efficacy in vitro and in patients with relapsed or refractory non-Hodgkin lymphoma (NHL), according to findings presented at the annual meeting of the Society for Immunotherapy of Cancer.
ICTCAR014, a dominant negative PD-1 armored CAR T-cell therapy, proved more cytotoxic than traditional CAR T-cell therapy in vitro and produced responses in 12 of 13 NHL patients who received it.
Xiaobin Victor Lu, PhD, of Innovative Cellular Therapeutics, Shanghai, China, presented results with ICTCAR014 at the meeting.
Dr. Lu explained that ICTCAR014 consists of CD19-targeted CAR T cells genetically engineered to overexpress a PD-1 dominant negative protein with an altered intracellular signaling domain. The dominant negative protein can act as a “decoy receptor” to bind and block the PD-L1/2 inhibitory signal, thereby enhancing the efficacy of CAR T cells.
Innovative Cellular Therapeutics is developing ICTCAR014 because there is “some room to improve” with commercially available CAR T-cell products, Dr. Lu said. Specifically, tisagenlecleucel produced a 52% response rate in the JULIET trial (N Engl J Med. 2019;380:45-56), and axicabtagene ciloleucel produced an 82% response rate in the ZUMA-1 trial (N Engl J Med. 2017;377:2531-44).
There is also evidence to suggest that PD-1 blockade can modulate and “refuel” CAR T cells in relapsed/refractory NHL patients who fail or relapse after traditional anti-CD19 CAR T-cell therapy (Blood. 2017 Feb 23;129[8]:1039-41). This finding has prompted researchers to conduct trials of PD-1 inhibitors in combination with CAR T-cell therapies. But this combination approach may be expensive and cause more side effects than the armored CAR T-cell approach, Dr. Lu said.
In preclinical studies, Dr. Lu and colleagues found that ICTCAR014 was more effective than traditional anti-CD19 CAR T cells in killing Nalm6-PDL1 cells. In addition, the PD-1 dominant negative protein protected CAR T cells from exhaustion.
Dr. Lu also presented results in 13 NHL patients who have received ICTCAR014 in a phase 1 trial in China. Eleven patients had diffuse large B-cell lymphoma (DLBCL), and two had follicular lymphoma.
The objective response rate was 92.3% (12/13), which included five partial responses (38.5%) and seven complete responses (53.8%). Both follicular lymphoma patients and five DLBCL patients achieved a complete response. Five DLBCL patients achieved a partial response, and the remaining DLBCL patient did not respond.
Dr. Lu did not present safety data. However, he reported that there was no increased incidence of cytokine release syndrome or neurotoxicity in these patients, compared with patients receiving traditional CAR T-cell therapy.
Dr. Lu is employed by Innovative Cellular Therapeutics, which funded the research and is developing ICTCAR014.
SOURCE: Lu V et al. SITC 2019, Abstract O25.
REPORTING FROM SITC 2019
Immunotherapies under investigation in newly diagnosed B-ALL
SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.
“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”
Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Blinatumomab
Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).
The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).
Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).
The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.
In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).
Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
Inotuzumab ozogamicin
Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.
The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.
The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).
Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.
Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.
SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.
“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”
Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Blinatumomab
Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).
The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).
Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).
The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.
In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).
Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
Inotuzumab ozogamicin
Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.
The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.
The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).
Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.
Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.
SAN FRANCISCO – Positive results with blinatumomab and inotuzumab ozogamicin in the relapsed/refractory setting have prompted trials of these immunotherapies in newly diagnosed B-cell acute lymphoblastic leukemia (B-ALL).
Blinatumomab and inotuzumab have been shown to improve overall survival, compared with chemotherapy, in patients with relapsed/refractory B-ALL. However, most adults with relapsed/refractory B-ALL still die, so the initial therapy patients receive is “critical,” according to Jae Park, MD, of Memorial Sloan Kettering Cancer Center in New York.
“Ideally, we do not want to deal with the relapse,” Dr. Park said. “It’s better to cure the disease the first time ... which is the reason clinical trials are incorporating these agents earlier.”
Dr. Park discussed these points at the National Comprehensive Cancer Network Hematologic Malignancies Annual Congress.
Blinatumomab
Dr. Park cited the phase 3 TOWER trial, which showed that blinatumomab produced better response rates and overall survival compared with standard chemotherapy. The trial enrolled 405 patients with Ph-negative relapsed/refractory B-ALL who were randomized to blinatumomab (n = 271) or chemotherapy (n = 134).
The rate of complete response (CR) with full, partial, or incomplete hematologic recovery was 44% with blinatumomab and 25% with chemotherapy (P less than .001). The median overall survival was 7.7 months and 4.0 months, respectively (P = .01; N Engl J Med 2017; 376:836-47).
Based on these data, researchers decided to test blinatumomab in newly diagnosed, elderly patients (65 years and older) with Ph-negative B-ALL in the phase 2 SWOG 1318 study. The study enrolled 31 patients, and 29 were eligible. Their median age at baseline was 75 years (range 66‐84 years).
The patients received blinatumomab for two to five cycles, followed by 18 months of maintenance with prednisone, vincristine, 6-mercaptopurine, and methotrexate. One patient went on to transplant.
In all, 66% of patients achieved a CR or CR with incomplete count recovery. The estimated overall survival was 79% at 6 months and 65% at 1 year. These results were presented at the 2018 annual meeting of the American Society of Hematology (Blood. 2018;132:33).
Another study of blinatumomab as frontline treatment is the ECOG-E1910 trial. In this phase 3 study, researchers are testing chemotherapy, with or without blinatumomab, in adults (aged 30-70 years) with newly diagnosed, BCR-ABL-negative B-ALL. Results from this study are not yet available.
Inotuzumab ozogamicin
Dr. Park also discussed the INOVATE trial, in which inotuzumab ozogamicin bested standard chemotherapy. The trial enrolled patients with Ph-positive or negative, relapsed/refractory B-ALL.
The patients were randomized to inotuzumab (n = 141) or investigator’s choice of chemotherapy (n = 138). Some patients, 41% in the inotuzumab arm and 11% in the chemotherapy arm, went on to transplant.
The CR rate was 80.7% in the inotuzumab arm and 29.4% in the chemotherapy arm (P less than .001). The median progression-free survival was 5 months and 1.8 months, respectively (P less than .001). The median overall survival was 7.7 months and 6.7 months, respectively (P = .04; N Engl J Med 2016; 375:740-53).
Based on these results, researchers are testing inotuzumab as frontline therapy in young adults (aged 18-39 years) with CD22-positive, Ph-negative B-ALL. In the phase 3 A041501 trial, patients are receiving inotuzumab after the first and second courses of treatment with the CALGB 10403 chemotherapy regimen. Results from this trial are not yet available.
Dr. Park reported relationships with Allogene Therapeutics, Amgen, AstraZeneca, Incyte, Kite Pharma, Novartis, and Takeda.
EXPERT ANALYSIS FROM NCCN HEMATOLOGIC MALIGNANCIES
CAR T-cell therapy found safe, effective for HIV-associated lymphoma
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
HIV positivity does not preclude chimeric antigen receptor (CAR) T-cell therapy for patients with aggressive lymphoma, a report of two cases suggests. Both of the HIV-positive patients, one of whom had long-term psychiatric comorbidity, achieved durable remission on axicabtagene ciloleucel (Yescarta) without undue toxicity.
“To our knowledge, these are the first reported cases of CAR T-cell therapy administered to HIV-infected patients with lymphoma,” Jeremy S. Abramson, MD, of Massachusetts General Hospital, Boston and his colleagues wrote in Cancer. “Patients with HIV and AIDS, as well as those with preexisting mental illness, should not be considered disqualified from CAR T-cell therapy and deserve ongoing studies to optimize efficacy and safety in this population.”
The Food and Drug Administration has approved two CAR T-cell products that target the B-cell antigen CD19 for the treatment of refractory lymphoma. But their efficacy and safety in HIV-positive patients are unknown because this group has been excluded from pivotal clinical trials.
Dr. Abramson and coauthors detail the two cases of successful anti-CD19 CAR T-cell therapy with axicabtagene ciloleucel in patients with HIV-associated, refractory, high-grade B-cell lymphoma.
The first patient was an HIV-positive man with diffuse large B-cell lymphoma (DLBCL) of germinal center B-cell subtype who was intermittently adherent to antiretroviral therapy. His comorbidities included posttraumatic stress disorder and schizoaffective disorder.
Previous treatments for DLBCL included dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R), and rituximab, ifosfamide, carboplatin, and etoposide (RICE). A recurrence precluded high-dose chemotherapy with autologous stem cell support.
With close multidisciplinary management, including psychiatric consultation, the patient became a candidate for CAR T-cell therapy and received axicabtagene ciloleucel. He experienced grade 2 cytokine release syndrome and grade 3 neurologic toxicity, both of which resolved with treatment. Imaging showed complete remission at approximately 3 months that was sustained at 1 year. Additionally, he had an undetectable HIV viral load and was psychiatrically stable.
The second patient was a man with AIDS-associated, non–germinal center B-cell, Epstein-Barr virus–positive DLBCL who was adherent to antiretroviral therapy. His lymphoma had recurred rapidly after initially responding to dose-adjusted EPOCH-R and then was refractory to combination rituximab and lenalidomide. He previously had hepatitis B virus, cytomegalovirus, and Mycobacterium avium complex infections.
Because of prolonged cytopenias and infectious complications after the previous lymphoma treatments, the patient was considered a poor candidate for high-dose chemotherapy. He underwent CAR T-cell therapy with axicabtagene ciloleucel and had a complete remission on day 28. Additionally, his HIV infection remained well controlled.
“Although much remains to be learned regarding CAR T-cell therapy in patients with refractory hematologic malignancies, with or without HIV infection, the cases presented herein demonstrate that patients with chemotherapy-refractory, high-grade B-cell lymphoma can successfully undergo autologous CAR T-cell manufacturing, and subsequently can safely tolerate CAR T-cell therapy and achieve a durable complete remission,” the researchers wrote. “These cases have further demonstrated the proactive, multidisciplinary care required to navigate a patient with high-risk lymphoma through CAR T-cell therapy with attention to significant medical and psychiatric comorbidities.”
Dr. Abramson reported that he has acted as a paid member of the scientific advisory board and as a paid consultant for Kite Pharma, which markets Yescarta, and several other companies.
SOURCE: Abramson JS et al. Cancer. 2019 Sep 10. doi: 10.1002/cncr.32411.
FROM CANCER
CT103A elicits responses after prior CAR T-cell relapse
BOSTON – CT103A, a chimeric antigen receptor (CAR) T-cell therapy, is “active and effective” in patients with relapsed/refractory multiple myeloma, according to a speaker at the International Myeloma Workshop, held by the International Myeloma Society.
The anti–B-cell maturation antigen (BCMA) CAR T-cell therapy produced a 100% response rate in patients with heavily pretreated multiple myeloma, and three of four patients who had failed a prior CAR T-cell therapy achieved a stringent complete response after CT103A.
Chunrui Li, MD, PhD, of Tongji Hospital and Tongji Medical College, Huazhong University of Science, Wuhan, China, presented these results at the workshop.
Dr. Li noted that anti-BCMA CAR T-cell therapy has produced responses in myeloma patients, but approximately half of patients typically relapse in about a year. CAR T-cell infusions after relapse have not been effective in these patients.
In an effort to change that, Dr. Li and his colleagues developed CT103A, a lentiviral vector containing a CAR structure with a fully human single-chain fragment variant; CD8a hinger; and transmembrane, 4-1BB co-stimulatory, and CD3z activation domains.
Dr. Li and his colleagues evaluated CT103A in a phase 0 trial (ChiCTR1800018137) of 18 patients who had received at least three prior lines of therapy and had disease refractory to a proteasome inhibitor and an immunomodulatory agent.
The patients’ median age was 53.3 years (range, 38-66 years), and their median time since diagnosis was 32 months (range, 8-92 months). They had received a median of 4 (range, 3-6) prior therapies. All had received prior bortezomib and lenalidomide, seven had undergone a transplant, and four had been treated on a trial of murine anti-BCMA CAR T-cell therapy.
For the current trial, patients received lymphodepletion with cyclophosphamide and fludarabine, followed by CT103A at 1x106, 3x106, or 6x106 CAR T cells/kg.
There was one dose-limiting toxicity at the highest dose level – grade 4 cytokine release syndrome (CRS) in a patient who died at day 19 after CT103A infusion.
In all, 17 patients developed CRS, four with grade 1, eight with grade 2, four with grade 3, and one with grade 4 CRS. None of the patients developed neurologic toxicity.
Serious adverse events related to lymphodepletion and/or CT103A included prolonged cytopenia (n = 3), pulmonary infection (n = 2), herpes zoster (n = 1), pleuritis (n = 1), and hypoxemia (n = 1).
There were 17 patients evaluable for efficacy, and all of them achieved a response at some point. In eight patients, responses have lasted more than 200 days.
At the data cutoff, there were 10 stringent complete responses, two complete responses, and three very good partial responses. One patient progressed after achieving a very good partial response, and one patient achieved a partial response but ultimately died (likely of respiratory failure attributable to a lung infection).
Of the four patients who had previously received murine CAR T-cell therapy, one progressed, and three achieved a stringent complete response.
This study was funded by Nanjing Iaso Biotherapeutics. Dr. Li did not disclose any conflicts of interest.
SOURCE: Li C et al. IMW 2019, Abstract OAB-033.
BOSTON – CT103A, a chimeric antigen receptor (CAR) T-cell therapy, is “active and effective” in patients with relapsed/refractory multiple myeloma, according to a speaker at the International Myeloma Workshop, held by the International Myeloma Society.
The anti–B-cell maturation antigen (BCMA) CAR T-cell therapy produced a 100% response rate in patients with heavily pretreated multiple myeloma, and three of four patients who had failed a prior CAR T-cell therapy achieved a stringent complete response after CT103A.
Chunrui Li, MD, PhD, of Tongji Hospital and Tongji Medical College, Huazhong University of Science, Wuhan, China, presented these results at the workshop.
Dr. Li noted that anti-BCMA CAR T-cell therapy has produced responses in myeloma patients, but approximately half of patients typically relapse in about a year. CAR T-cell infusions after relapse have not been effective in these patients.
In an effort to change that, Dr. Li and his colleagues developed CT103A, a lentiviral vector containing a CAR structure with a fully human single-chain fragment variant; CD8a hinger; and transmembrane, 4-1BB co-stimulatory, and CD3z activation domains.
Dr. Li and his colleagues evaluated CT103A in a phase 0 trial (ChiCTR1800018137) of 18 patients who had received at least three prior lines of therapy and had disease refractory to a proteasome inhibitor and an immunomodulatory agent.
The patients’ median age was 53.3 years (range, 38-66 years), and their median time since diagnosis was 32 months (range, 8-92 months). They had received a median of 4 (range, 3-6) prior therapies. All had received prior bortezomib and lenalidomide, seven had undergone a transplant, and four had been treated on a trial of murine anti-BCMA CAR T-cell therapy.
For the current trial, patients received lymphodepletion with cyclophosphamide and fludarabine, followed by CT103A at 1x106, 3x106, or 6x106 CAR T cells/kg.
There was one dose-limiting toxicity at the highest dose level – grade 4 cytokine release syndrome (CRS) in a patient who died at day 19 after CT103A infusion.
In all, 17 patients developed CRS, four with grade 1, eight with grade 2, four with grade 3, and one with grade 4 CRS. None of the patients developed neurologic toxicity.
Serious adverse events related to lymphodepletion and/or CT103A included prolonged cytopenia (n = 3), pulmonary infection (n = 2), herpes zoster (n = 1), pleuritis (n = 1), and hypoxemia (n = 1).
There were 17 patients evaluable for efficacy, and all of them achieved a response at some point. In eight patients, responses have lasted more than 200 days.
At the data cutoff, there were 10 stringent complete responses, two complete responses, and three very good partial responses. One patient progressed after achieving a very good partial response, and one patient achieved a partial response but ultimately died (likely of respiratory failure attributable to a lung infection).
Of the four patients who had previously received murine CAR T-cell therapy, one progressed, and three achieved a stringent complete response.
This study was funded by Nanjing Iaso Biotherapeutics. Dr. Li did not disclose any conflicts of interest.
SOURCE: Li C et al. IMW 2019, Abstract OAB-033.
BOSTON – CT103A, a chimeric antigen receptor (CAR) T-cell therapy, is “active and effective” in patients with relapsed/refractory multiple myeloma, according to a speaker at the International Myeloma Workshop, held by the International Myeloma Society.
The anti–B-cell maturation antigen (BCMA) CAR T-cell therapy produced a 100% response rate in patients with heavily pretreated multiple myeloma, and three of four patients who had failed a prior CAR T-cell therapy achieved a stringent complete response after CT103A.
Chunrui Li, MD, PhD, of Tongji Hospital and Tongji Medical College, Huazhong University of Science, Wuhan, China, presented these results at the workshop.
Dr. Li noted that anti-BCMA CAR T-cell therapy has produced responses in myeloma patients, but approximately half of patients typically relapse in about a year. CAR T-cell infusions after relapse have not been effective in these patients.
In an effort to change that, Dr. Li and his colleagues developed CT103A, a lentiviral vector containing a CAR structure with a fully human single-chain fragment variant; CD8a hinger; and transmembrane, 4-1BB co-stimulatory, and CD3z activation domains.
Dr. Li and his colleagues evaluated CT103A in a phase 0 trial (ChiCTR1800018137) of 18 patients who had received at least three prior lines of therapy and had disease refractory to a proteasome inhibitor and an immunomodulatory agent.
The patients’ median age was 53.3 years (range, 38-66 years), and their median time since diagnosis was 32 months (range, 8-92 months). They had received a median of 4 (range, 3-6) prior therapies. All had received prior bortezomib and lenalidomide, seven had undergone a transplant, and four had been treated on a trial of murine anti-BCMA CAR T-cell therapy.
For the current trial, patients received lymphodepletion with cyclophosphamide and fludarabine, followed by CT103A at 1x106, 3x106, or 6x106 CAR T cells/kg.
There was one dose-limiting toxicity at the highest dose level – grade 4 cytokine release syndrome (CRS) in a patient who died at day 19 after CT103A infusion.
In all, 17 patients developed CRS, four with grade 1, eight with grade 2, four with grade 3, and one with grade 4 CRS. None of the patients developed neurologic toxicity.
Serious adverse events related to lymphodepletion and/or CT103A included prolonged cytopenia (n = 3), pulmonary infection (n = 2), herpes zoster (n = 1), pleuritis (n = 1), and hypoxemia (n = 1).
There were 17 patients evaluable for efficacy, and all of them achieved a response at some point. In eight patients, responses have lasted more than 200 days.
At the data cutoff, there were 10 stringent complete responses, two complete responses, and three very good partial responses. One patient progressed after achieving a very good partial response, and one patient achieved a partial response but ultimately died (likely of respiratory failure attributable to a lung infection).
Of the four patients who had previously received murine CAR T-cell therapy, one progressed, and three achieved a stringent complete response.
This study was funded by Nanjing Iaso Biotherapeutics. Dr. Li did not disclose any conflicts of interest.
SOURCE: Li C et al. IMW 2019, Abstract OAB-033.
REPORTING FROM IMW 2019
CAR T-cell therapy less effective in transformed follicular lymphoma
All complete responders with FL were still in remission at a median follow-up of 24 months, but the median duration of response was 10.2 months for patients with tFL.
Alexandre V. Hirayama, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues reported these results in Blood.
The trial enrolled 21 adults with relapsed/refractory CD19+ B-cell malignancies, including 8 patients with FL and 13 with tFL. At baseline, the FL/tFL patients had a median age of 56 years (range, 51-62), and 67% were male. Most patients (n = 19) had stage III/IV disease, 17 had extranodal disease, 8 had bulky disease, and 6 had bone marrow involvement. The patients had received a median of 5 prior therapies (range, 2-8), and 13 had received a transplant.
In this study, patients received a lymphodepleting regimen of cyclophosphamide and fludarabine, followed by 2 x 106 CD19 CAR T cells/kg. Five patients (one with FL and four with tFL) also received bridging chemotherapy between leukapheresis and lymphodepletion.
Grade 1-2 cytokine release syndrome occurred in 50% of FL patients and 39% of tFL patients (P = .35). Grade 1-2 neurotoxicity occurred in 50% and 23%, respectively (P = .67). There were no cases of grade 3 or higher cytokine release syndrome or neurotoxicity.
Most FL patients (7 of 8; 88%) achieved a complete response (CR) to treatment, and all of these patients were still in CR at a median follow-up of 24 months (range, 5-37 months). One FL patient received a transplant while in CR.
Six of 13 tFL patients (46%) achieved a CR. At a median follow-up of 38 months (range, 3-39 months), the median duration of response was 10.2 months. The median progression-free survival was 11.2 months in patients who achieved a CR and 1.4 months in all tFL patients.
The researchers noted that peak CAR T-cell counts and the duration of CAR T-cell detection were similar between FL and tFL patients. However, tFL patients had higher serum interleukin-8 concentrations and higher lactate dehydrogenase levels before treatment.
Past research suggested that IL-8 mediates the recruitment of tumor-associated neutrophils, promotes diffuse large B-cell lymphoma progression, and can contribute to local immune suppression. Other studies have linked elevated lactate dehydrogenase to aggressive disease and a more immunosuppressive tumor microenvironment.
“Although these data raise the possibility that differences in the tumor microenvironment may, in part, contribute to differences in outcomes after CAR T-cell immunotherapy in FL and tFL patients, additional studies are required,” the researchers wrote.
This research was supported by the National Institutes of Health, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinician Investigator Program, the Fred Hutchinson Cancer Research Center’s Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene.
The researchers disclosed relationships with Celgene, Juno Therapeutics, Lyell Immunopharma, Adaptive Biotechnologies, Nohla, Kite Pharma, Gilead, Genentech, Novartis, Eureka Therapeutics, Nektar Therapeutics, Caribou Biosciences, Precision Biosciences, Aptevo, Humanigen, and Allogene.
SOURCE: Hirayama AV et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000905
All complete responders with FL were still in remission at a median follow-up of 24 months, but the median duration of response was 10.2 months for patients with tFL.
Alexandre V. Hirayama, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues reported these results in Blood.
The trial enrolled 21 adults with relapsed/refractory CD19+ B-cell malignancies, including 8 patients with FL and 13 with tFL. At baseline, the FL/tFL patients had a median age of 56 years (range, 51-62), and 67% were male. Most patients (n = 19) had stage III/IV disease, 17 had extranodal disease, 8 had bulky disease, and 6 had bone marrow involvement. The patients had received a median of 5 prior therapies (range, 2-8), and 13 had received a transplant.
In this study, patients received a lymphodepleting regimen of cyclophosphamide and fludarabine, followed by 2 x 106 CD19 CAR T cells/kg. Five patients (one with FL and four with tFL) also received bridging chemotherapy between leukapheresis and lymphodepletion.
Grade 1-2 cytokine release syndrome occurred in 50% of FL patients and 39% of tFL patients (P = .35). Grade 1-2 neurotoxicity occurred in 50% and 23%, respectively (P = .67). There were no cases of grade 3 or higher cytokine release syndrome or neurotoxicity.
Most FL patients (7 of 8; 88%) achieved a complete response (CR) to treatment, and all of these patients were still in CR at a median follow-up of 24 months (range, 5-37 months). One FL patient received a transplant while in CR.
Six of 13 tFL patients (46%) achieved a CR. At a median follow-up of 38 months (range, 3-39 months), the median duration of response was 10.2 months. The median progression-free survival was 11.2 months in patients who achieved a CR and 1.4 months in all tFL patients.
The researchers noted that peak CAR T-cell counts and the duration of CAR T-cell detection were similar between FL and tFL patients. However, tFL patients had higher serum interleukin-8 concentrations and higher lactate dehydrogenase levels before treatment.
Past research suggested that IL-8 mediates the recruitment of tumor-associated neutrophils, promotes diffuse large B-cell lymphoma progression, and can contribute to local immune suppression. Other studies have linked elevated lactate dehydrogenase to aggressive disease and a more immunosuppressive tumor microenvironment.
“Although these data raise the possibility that differences in the tumor microenvironment may, in part, contribute to differences in outcomes after CAR T-cell immunotherapy in FL and tFL patients, additional studies are required,” the researchers wrote.
This research was supported by the National Institutes of Health, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinician Investigator Program, the Fred Hutchinson Cancer Research Center’s Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene.
The researchers disclosed relationships with Celgene, Juno Therapeutics, Lyell Immunopharma, Adaptive Biotechnologies, Nohla, Kite Pharma, Gilead, Genentech, Novartis, Eureka Therapeutics, Nektar Therapeutics, Caribou Biosciences, Precision Biosciences, Aptevo, Humanigen, and Allogene.
SOURCE: Hirayama AV et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000905
All complete responders with FL were still in remission at a median follow-up of 24 months, but the median duration of response was 10.2 months for patients with tFL.
Alexandre V. Hirayama, MD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues reported these results in Blood.
The trial enrolled 21 adults with relapsed/refractory CD19+ B-cell malignancies, including 8 patients with FL and 13 with tFL. At baseline, the FL/tFL patients had a median age of 56 years (range, 51-62), and 67% were male. Most patients (n = 19) had stage III/IV disease, 17 had extranodal disease, 8 had bulky disease, and 6 had bone marrow involvement. The patients had received a median of 5 prior therapies (range, 2-8), and 13 had received a transplant.
In this study, patients received a lymphodepleting regimen of cyclophosphamide and fludarabine, followed by 2 x 106 CD19 CAR T cells/kg. Five patients (one with FL and four with tFL) also received bridging chemotherapy between leukapheresis and lymphodepletion.
Grade 1-2 cytokine release syndrome occurred in 50% of FL patients and 39% of tFL patients (P = .35). Grade 1-2 neurotoxicity occurred in 50% and 23%, respectively (P = .67). There were no cases of grade 3 or higher cytokine release syndrome or neurotoxicity.
Most FL patients (7 of 8; 88%) achieved a complete response (CR) to treatment, and all of these patients were still in CR at a median follow-up of 24 months (range, 5-37 months). One FL patient received a transplant while in CR.
Six of 13 tFL patients (46%) achieved a CR. At a median follow-up of 38 months (range, 3-39 months), the median duration of response was 10.2 months. The median progression-free survival was 11.2 months in patients who achieved a CR and 1.4 months in all tFL patients.
The researchers noted that peak CAR T-cell counts and the duration of CAR T-cell detection were similar between FL and tFL patients. However, tFL patients had higher serum interleukin-8 concentrations and higher lactate dehydrogenase levels before treatment.
Past research suggested that IL-8 mediates the recruitment of tumor-associated neutrophils, promotes diffuse large B-cell lymphoma progression, and can contribute to local immune suppression. Other studies have linked elevated lactate dehydrogenase to aggressive disease and a more immunosuppressive tumor microenvironment.
“Although these data raise the possibility that differences in the tumor microenvironment may, in part, contribute to differences in outcomes after CAR T-cell immunotherapy in FL and tFL patients, additional studies are required,” the researchers wrote.
This research was supported by the National Institutes of Health, the Life Science Discovery Fund, the Bezos family, the University of British Columbia Clinician Investigator Program, the Fred Hutchinson Cancer Research Center’s Immunotherapy Integrated Research Center, and Juno Therapeutics/Celgene.
The researchers disclosed relationships with Celgene, Juno Therapeutics, Lyell Immunopharma, Adaptive Biotechnologies, Nohla, Kite Pharma, Gilead, Genentech, Novartis, Eureka Therapeutics, Nektar Therapeutics, Caribou Biosciences, Precision Biosciences, Aptevo, Humanigen, and Allogene.
SOURCE: Hirayama AV et al. Blood. 2019 Jun 26. doi: 10.1182/blood.2019000905
FROM BLOOD