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Back to the drawing board for MPN combo
NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).
The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”
However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.
Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.
The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.
Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.
Treatment and safety
For the first cycle, patients received decitabine at 20 mg/m2 per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.
“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.
Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.
Response and survival
Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.
Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.
Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.
The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.
The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.
Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.
“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”
Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).
The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”
However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.
Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.
The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.
Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.
Treatment and safety
For the first cycle, patients received decitabine at 20 mg/m2 per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.
“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.
Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.
Response and survival
Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.
Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.
Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.
The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.
The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.
Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.
“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”
Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – The combination of ruxolitinib and decitabine will not proceed to a phase 3 trial in patients with accelerated or blast phase myeloproliferative neoplasms (MPNs).
The combination demonstrated activity and tolerability in a phase 2 trial, but outcomes were not optimal, according to Raajit K. Rampal, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York.
“[P]erhaps the outcomes might be favorable compared to standard induction chemotherapy regimens,” Dr. Rampal said. “Nonetheless, it’s clear that we still have a lot of work to do, and the outcomes are not optimal in these patients.”
However, Dr. Rampal and his colleagues are investigating the possibility of combining ruxolitinib and decitabine with other agents to treat patients with accelerated or blast phase MPNs.
Dr. Rampal and his colleagues presented results from the phase 2 trial in a poster at the Acute Leukemia Forum of Hemedicus.
The trial (NCT02076191) enrolled 25 patients, 10 with accelerated phase MPN (10%-19% blasts) and 15 with blast phase MPN (at least 20% blasts). The patients’ median age was 71 years.
Patients had a median disease duration of 72.9 months. Six patients (25%) had received prior ruxolitinib, and two (8.3%) had received prior decitabine.
Treatment and safety
For the first cycle, patients received decitabine at 20 mg/m2 per day on days 8-12 and ruxolitinib at 25 mg twice a day on days 1-35. For subsequent cycles, patients received the same dose of decitabine on days 1-5 and ruxolitinib at 10 mg twice a day on days 6-28. Patients were treated until progression, withdrawal, or unacceptable toxicity.
“The adverse events we saw in this study were typical for this population, including fevers, mostly neutropenic fevers, as well as anemia and thrombocytopenia,” Dr. Rampal said.
Nonhematologic adverse events (AEs) included fatigue, abdominal pain, pneumonia, diarrhea, dizziness, and constipation. Hematologic AEs included anemia, neutropenia, febrile neutropenia, and thrombocytopenia.
Response and survival
Eighteen patients were evaluable for response. Four patients were not evaluable because they withdrew from the study due to secondary AEs and completed one cycle of therapy or less, two patients did not have circulating blasts at baseline, and one patient refused further treatment.
Among the evaluable patients, nine (50%) achieved a partial response, including four patients with accelerated phase MPN and five with blast phase MPN.
Two patients (11.1%), one with accelerated phase MPN and one with blast phase MPN, achieved a complete response with incomplete count recovery.
The remaining seven patients (38.9%), five with blast phase MPN and two with accelerated phase MPN, did not respond.
The median overall survival was 7.6 months for the entire cohort, 9.7 months for patients with blast phase MPN, and 5.8 months for patients with accelerated phase MPN.
Based on these results, Dr. Rampal and his colleagues theorized that ruxolitinib plus decitabine might be improved by the addition of other agents. The researchers are currently investigating this possibility.
“The work for this trial really came out of preclinical work in the laboratory where we combined these drugs and saw efficacy in murine models,” Dr. Rampal said. “So we’re going back to the drawing board and looking at those again to see, ‘Can we come up with new rational combinations?’ ”
Dr. Rampal and his colleagues reported having no conflicts of interest. Their study was supported by the National Institutes of Health, the National Cancer Institute, and Incyte Corporation.
The Acute Leukemia Forum is held by Hemedicus, which is owned by the same company as this news organization.
REPORTING FROM ALF 2019
Physicians discuss bringing cultural humility to medicine
PHILADELPHIA – during a panel discussion moderated by Sarah Candler, MD, an internist in Houston.
Dr. Candler, former chair, Council of Resident and Fellow Members, Board of Regents, American College of Physicians, began the discussion by asking Dr. DeLisser, to describe his role in teaching medical students about the social determinants of health, at the annual Internal Medicine meeting of the ACP.
Dr. DeLisser, associate dean for professionalism and humanism at the University of Pennsylvania, Philadelphia, said he focuses on a number of issues, including social medicine, cultural competency, and cultural humility.
“We look at health care disparities and try to do a lot of innovation around service learning that will bring our students into the community, one to learn about these determinants but more importantly to be able to see how these issues can be addressed both on a provider level but also on a more structural systemic level,” he noted.
Dr. Poorman, an internist at the University of Washington, later discussed the importance of practicing cultural humility as it related to her experience providing care to migrant workers while she was a medical school student.
Dr. Candler, an internist in Houston, concluded the discussion by describing some of the ACP’s newest resources designed to address the social determinants of health for specific groups of patients.
The full panel discussion was recorded as a video.
PHILADELPHIA – during a panel discussion moderated by Sarah Candler, MD, an internist in Houston.
Dr. Candler, former chair, Council of Resident and Fellow Members, Board of Regents, American College of Physicians, began the discussion by asking Dr. DeLisser, to describe his role in teaching medical students about the social determinants of health, at the annual Internal Medicine meeting of the ACP.
Dr. DeLisser, associate dean for professionalism and humanism at the University of Pennsylvania, Philadelphia, said he focuses on a number of issues, including social medicine, cultural competency, and cultural humility.
“We look at health care disparities and try to do a lot of innovation around service learning that will bring our students into the community, one to learn about these determinants but more importantly to be able to see how these issues can be addressed both on a provider level but also on a more structural systemic level,” he noted.
Dr. Poorman, an internist at the University of Washington, later discussed the importance of practicing cultural humility as it related to her experience providing care to migrant workers while she was a medical school student.
Dr. Candler, an internist in Houston, concluded the discussion by describing some of the ACP’s newest resources designed to address the social determinants of health for specific groups of patients.
The full panel discussion was recorded as a video.
PHILADELPHIA – during a panel discussion moderated by Sarah Candler, MD, an internist in Houston.
Dr. Candler, former chair, Council of Resident and Fellow Members, Board of Regents, American College of Physicians, began the discussion by asking Dr. DeLisser, to describe his role in teaching medical students about the social determinants of health, at the annual Internal Medicine meeting of the ACP.
Dr. DeLisser, associate dean for professionalism and humanism at the University of Pennsylvania, Philadelphia, said he focuses on a number of issues, including social medicine, cultural competency, and cultural humility.
“We look at health care disparities and try to do a lot of innovation around service learning that will bring our students into the community, one to learn about these determinants but more importantly to be able to see how these issues can be addressed both on a provider level but also on a more structural systemic level,” he noted.
Dr. Poorman, an internist at the University of Washington, later discussed the importance of practicing cultural humility as it related to her experience providing care to migrant workers while she was a medical school student.
Dr. Candler, an internist in Houston, concluded the discussion by describing some of the ACP’s newest resources designed to address the social determinants of health for specific groups of patients.
The full panel discussion was recorded as a video.
REPORTING FROM INTERNAL MEDICINE 2019
ACP governmental affairs leaders discuss ACA, Title X
PHILADELPHIA – in a video interview conducted during the annual meeting of the American College of Physicians.
Robert B. Doherty, the ACP’s senior vice president, governmental affairs and public policy, and Shari M. Erickson, the organization’s vice president of governmental affairs and medical practice, addressed the future of the Affordable Care Act (ACA), cuts to the funding of Title X clinics, and the National Rifle Association’s urging of Congress to vote against the Violence Against Women Reauthorization Act.
“We’re very, very concerned by a decision by a Texas judge that, if upheld on appeal, would gut the entire ACA and the decision by the administration not to defend any part of the ACA,” said Mr. Doherty.
Ms. Erikson later discussed a final rule released by the administration that she said “significantly impacts access to care for women,” particularly for those in low-income and underserved areas who may be seen by clinics that receive Title X funding.
She also addressed the rule’s effects on federally qualified health centers and other health clinics near Title X–funded clinics that are forced to close.
On a positive note, Mr. Doherty noted that the ACP is supporting legislation that has been introduced in the House to stabilize the current insurance markets.
Mr. Doherty and Ms. Erikson concluded by discussing an ACP initiative focused on reducing administrative burden for ACP members.
PHILADELPHIA – in a video interview conducted during the annual meeting of the American College of Physicians.
Robert B. Doherty, the ACP’s senior vice president, governmental affairs and public policy, and Shari M. Erickson, the organization’s vice president of governmental affairs and medical practice, addressed the future of the Affordable Care Act (ACA), cuts to the funding of Title X clinics, and the National Rifle Association’s urging of Congress to vote against the Violence Against Women Reauthorization Act.
“We’re very, very concerned by a decision by a Texas judge that, if upheld on appeal, would gut the entire ACA and the decision by the administration not to defend any part of the ACA,” said Mr. Doherty.
Ms. Erikson later discussed a final rule released by the administration that she said “significantly impacts access to care for women,” particularly for those in low-income and underserved areas who may be seen by clinics that receive Title X funding.
She also addressed the rule’s effects on federally qualified health centers and other health clinics near Title X–funded clinics that are forced to close.
On a positive note, Mr. Doherty noted that the ACP is supporting legislation that has been introduced in the House to stabilize the current insurance markets.
Mr. Doherty and Ms. Erikson concluded by discussing an ACP initiative focused on reducing administrative burden for ACP members.
PHILADELPHIA – in a video interview conducted during the annual meeting of the American College of Physicians.
Robert B. Doherty, the ACP’s senior vice president, governmental affairs and public policy, and Shari M. Erickson, the organization’s vice president of governmental affairs and medical practice, addressed the future of the Affordable Care Act (ACA), cuts to the funding of Title X clinics, and the National Rifle Association’s urging of Congress to vote against the Violence Against Women Reauthorization Act.
“We’re very, very concerned by a decision by a Texas judge that, if upheld on appeal, would gut the entire ACA and the decision by the administration not to defend any part of the ACA,” said Mr. Doherty.
Ms. Erikson later discussed a final rule released by the administration that she said “significantly impacts access to care for women,” particularly for those in low-income and underserved areas who may be seen by clinics that receive Title X funding.
She also addressed the rule’s effects on federally qualified health centers and other health clinics near Title X–funded clinics that are forced to close.
On a positive note, Mr. Doherty noted that the ACP is supporting legislation that has been introduced in the House to stabilize the current insurance markets.
Mr. Doherty and Ms. Erikson concluded by discussing an ACP initiative focused on reducing administrative burden for ACP members.
REPORTING FROM INTERNAL MEDICINE 2019
Role of Diet in Treating Skin Conditions
Volunteerism: How and why to do it, according to Dr. Eileen Barrett
PHILADELPHIA –
“I think what we get out of it is the feeling of our commitment to our sense of purpose and mission, and you just feel great when you’re giving, and then you meet these really remarkable people who do really, really remarkable things. ... It’s tremendously inspiring,” Dr. Barrett said in a video interview at the annual meeting of the American College of Physicians. She is a hospitalist at the University of New Mexico, Albuquerque, and serves on the ACP Board of Regents.
In addition, Dr. Barrett has done disaster relief work in West Africa, provided patient care to refugees in a hospital on the Thailand side of the Thailand-Myanmar border, and even helped bring organization to a public radio station in rural New Mexico.
She also described some opportunities available to internists who are trying to get their feet wet in volunteering that are available through the organizations, Health Volunteers Overseas and the Maven Project.
PHILADELPHIA –
“I think what we get out of it is the feeling of our commitment to our sense of purpose and mission, and you just feel great when you’re giving, and then you meet these really remarkable people who do really, really remarkable things. ... It’s tremendously inspiring,” Dr. Barrett said in a video interview at the annual meeting of the American College of Physicians. She is a hospitalist at the University of New Mexico, Albuquerque, and serves on the ACP Board of Regents.
In addition, Dr. Barrett has done disaster relief work in West Africa, provided patient care to refugees in a hospital on the Thailand side of the Thailand-Myanmar border, and even helped bring organization to a public radio station in rural New Mexico.
She also described some opportunities available to internists who are trying to get their feet wet in volunteering that are available through the organizations, Health Volunteers Overseas and the Maven Project.
PHILADELPHIA –
“I think what we get out of it is the feeling of our commitment to our sense of purpose and mission, and you just feel great when you’re giving, and then you meet these really remarkable people who do really, really remarkable things. ... It’s tremendously inspiring,” Dr. Barrett said in a video interview at the annual meeting of the American College of Physicians. She is a hospitalist at the University of New Mexico, Albuquerque, and serves on the ACP Board of Regents.
In addition, Dr. Barrett has done disaster relief work in West Africa, provided patient care to refugees in a hospital on the Thailand side of the Thailand-Myanmar border, and even helped bring organization to a public radio station in rural New Mexico.
She also described some opportunities available to internists who are trying to get their feet wet in volunteering that are available through the organizations, Health Volunteers Overseas and the Maven Project.
REPORTING FROM INTERNAL MEDICINE 2019
Creating CAR T-cell therapies for T-cell malignancies
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
NEWPORT BEACH, CALIF. – Preclinical research has revealed workarounds that may make chimeric antigen receptor (CAR) T-cell therapy feasible for patients with T-cell malignancies.
Researchers have found that using allogeneic cells for CAR T-cell therapy can eliminate contamination by malignant T cells, and editing those allogeneic T cells to delete the target antigen and the T-cell receptor alpha chain (TRAC) can prevent fratricide and graft-versus-host disease (GVHD).
Additionally, an interleukin-7 molecule called NT-I7 has been shown to enhance CAR T-cell proliferation, differentiation, and tumor killing in a mouse model of a T-cell malignancy.
John F. DiPersio, MD, PhD, of Washington University in St. Louis, described this work in a presentation at the Acute Leukemia Forum of Hemedicus.
Obstacles to development
“The primary obstacle for targeting T-cell malignancies with a T cell is that all of the targets that are on the [malignant] T cells are also expressed on the normal T cells,” Dr. DiPersio said. “So when you put a CAR into a normal T cell, it just kills itself. It’s called fratricide.”
A second issue that has limited development is that the phenotype of the malignant T cell in the blood is similar to a normal T cell, so they can’t be separated, he explained.
“So if you were to do anything to a normal T cell, you would also be doing it, in theory, to the malignant T cell – in theory, making it resistant to therapy,” he said.
A third obstacle, which has been seen in patients with B-cell malignancies as well, is the inability to harvest enough T cells to generate effective CAR T-cell therapy.
And a fourth obstacle is that T cells from patients with malignancies may not function normally because they have been exposed to prior therapies.
Dr. DiPersio and his colleagues believe these obstacles can be overcome by creating CAR T-cell therapies using T cells derived from healthy donors or cord blood, using gene editing to remove the target antigen and TRAC, and using NT-I7 to enhance the efficacy of these universal, “off-the-shelf” CAR T cells.
The researchers have tested these theories, and achieved successes, in preclinical models. The team is now planning a clinical trial in patients at Washington University. Dr. DiPersio and his colleagues also created a company called WUGEN that will develop the universal CAR T-cell therapies if the initial proof-of-principle trial proves successful.
UCART7
One of the universal CAR T-cell therapies Dr. DiPersio and his colleagues have tested is UCART7, which targets CD7. Dr. DiPersio noted that CD7 is expressed on 98% of T-cell acute lymphoblastic leukemias (T-ALLs), 24% of acute myeloid leukemias, natural killer (NK) cells, and T cells.
The researchers created UCART7 by using CRISPR/Cas9 to delete CD7 and TRAC from allogeneic T cells and following this with lentiviral transduction with a third-generation CD7-CAR. The team found a way to delete both TRAC and CD7 in a single day with 95% efficiency, Dr. DiPersio noted.
“Knocking out CD7 doesn’t seem to have any impact on the expansion or trafficking of these T cells in vivo,” Dr. DiPersio said. “So we think that deleting that target in a normal T cell will not affect its overall ability to kill a target when we put a CAR into those T cells.”
In fact, the researchers’ experiments showed that UCART7 can kill T-ALL cells in vitro and target primary T-ALL in vivo without inducing GVHD (Leukemia. 2018 Sep;32[9]:1970-83.)
UCART2 and NT-I7
Dr. DiPersio and his colleagues have also tested UCART2, an allogeneic CAR T-cell therapy in which CD2 and TRAC are deleted. The therapy targets CD2 because this antigen is expressed on T-ALL and other T-cell and NK-cell malignancies. Experiments showed that UCART2 targets T-cell malignancies, including T-ALL and cutaneous T-cell lymphoma, in vitro.
The researchers also tested UCART2 in a mouse model of Sézary syndrome. In these experiments, UCART2 was combined with NT-I7.
NT-I7 enhanced the proliferation, persistence, and tumor killing ability of UCART2. Sézary mice that received UCART2 and NT-I7 had “virtually no tumor burden,” according to researchers, and survived longer than mice treated with UCART2 alone (Blood. 2018;132:340).
Dr. DiPersio noted that there was no cytokine release syndrome because these were immunodeficient mice. However, cytokine release syndrome may be a side effect of NT-I7 in patients as NT-I7 induces rapid expansion of CAR T cells.
Dr. DiPersio reported ownership and investment in WUGEN and Magenta Therapeutics. He also has relationships with Cellworks Group, Tioma Therapeutics, RiverVest Venture Partners, Bioline, Asterias Biotherapeutics, Amphivena Therapeutics, Bluebird Bio, Celgene, Incyte, NeoImuneTech, and MacroGenics.
The Acute Leukemia Forum is organized by Hemedicus, which is owned by the same company as this news organization.
EXPERT ANALYSIS FROM ALF 2019
Atmospheric fluctuations tied to lupus flares
SAN FRANCISCO – , according to investigators from Johns Hopkins University, Baltimore.
The work helps solve a longstanding mystery in systemic lupus erythematosus (SLE): why symptoms seem to come and go with the seasons.
Johns Hopkins University research previously has shown that renal flares are more common in the winter; double-stranded DNA antibodies more common in late fall; and rashes more likely in late spring.
However, “the exact reasons of why the seasonality was there remained a big question,” said lead investigator George Stojan, MD, an assistant professor of rheumatology and the codirector of the Hopkins Lupus Center.
To get a handle on the matter, Dr. Stojan and his team reviewed 1,628 patients treated at the university during 1999-2017. Using Environmental Protection Agency data, they examined atmospheric conditions within 350 km of Baltimore in the 10 days leading up to lupus visits for flares; the researchers adjusted for age, sex, income, ethnicity, rural versus urban residence, and how close patients lived to highways and airports.
“We [found] specific, strong associations between atmospheric variables and fine particulate matter concentrations ... and organ-specific lupus flares,” Dr. Stojan said. He explained why that matters in a video interview at an international congress on SLE.
In short, rash was directly associated with concentrations of ozone and inhalable, fine particulate matter less than 2.5 mcm in diameter (PM 2.5). Joint flares were associated with PM 2.5, ozone, resultant wind, and humidity.
Renal flares were inversely associated with temperature, and directly associated with wind and humidity. Pulmonary flares and serositis were associated with PM 2.5, and both hematologic and neurologic flares with wind and temperature.
The analysis was based on a per-unit basis. For example, each mcg/m3 increase in PM 2.5 increased the odds of a pulmonary flare about 4% (odds ratio, 1.042, P = .026). The other findings were mostly of smaller magnitude, but still statistically significant.
The National Institutes of Health funded the research. Dr. Stojan had no disclosures.
SOURCE: Stojan G et al. LUPUS 2019, Abstract M31.
SAN FRANCISCO – , according to investigators from Johns Hopkins University, Baltimore.
The work helps solve a longstanding mystery in systemic lupus erythematosus (SLE): why symptoms seem to come and go with the seasons.
Johns Hopkins University research previously has shown that renal flares are more common in the winter; double-stranded DNA antibodies more common in late fall; and rashes more likely in late spring.
However, “the exact reasons of why the seasonality was there remained a big question,” said lead investigator George Stojan, MD, an assistant professor of rheumatology and the codirector of the Hopkins Lupus Center.
To get a handle on the matter, Dr. Stojan and his team reviewed 1,628 patients treated at the university during 1999-2017. Using Environmental Protection Agency data, they examined atmospheric conditions within 350 km of Baltimore in the 10 days leading up to lupus visits for flares; the researchers adjusted for age, sex, income, ethnicity, rural versus urban residence, and how close patients lived to highways and airports.
“We [found] specific, strong associations between atmospheric variables and fine particulate matter concentrations ... and organ-specific lupus flares,” Dr. Stojan said. He explained why that matters in a video interview at an international congress on SLE.
In short, rash was directly associated with concentrations of ozone and inhalable, fine particulate matter less than 2.5 mcm in diameter (PM 2.5). Joint flares were associated with PM 2.5, ozone, resultant wind, and humidity.
Renal flares were inversely associated with temperature, and directly associated with wind and humidity. Pulmonary flares and serositis were associated with PM 2.5, and both hematologic and neurologic flares with wind and temperature.
The analysis was based on a per-unit basis. For example, each mcg/m3 increase in PM 2.5 increased the odds of a pulmonary flare about 4% (odds ratio, 1.042, P = .026). The other findings were mostly of smaller magnitude, but still statistically significant.
The National Institutes of Health funded the research. Dr. Stojan had no disclosures.
SOURCE: Stojan G et al. LUPUS 2019, Abstract M31.
SAN FRANCISCO – , according to investigators from Johns Hopkins University, Baltimore.
The work helps solve a longstanding mystery in systemic lupus erythematosus (SLE): why symptoms seem to come and go with the seasons.
Johns Hopkins University research previously has shown that renal flares are more common in the winter; double-stranded DNA antibodies more common in late fall; and rashes more likely in late spring.
However, “the exact reasons of why the seasonality was there remained a big question,” said lead investigator George Stojan, MD, an assistant professor of rheumatology and the codirector of the Hopkins Lupus Center.
To get a handle on the matter, Dr. Stojan and his team reviewed 1,628 patients treated at the university during 1999-2017. Using Environmental Protection Agency data, they examined atmospheric conditions within 350 km of Baltimore in the 10 days leading up to lupus visits for flares; the researchers adjusted for age, sex, income, ethnicity, rural versus urban residence, and how close patients lived to highways and airports.
“We [found] specific, strong associations between atmospheric variables and fine particulate matter concentrations ... and organ-specific lupus flares,” Dr. Stojan said. He explained why that matters in a video interview at an international congress on SLE.
In short, rash was directly associated with concentrations of ozone and inhalable, fine particulate matter less than 2.5 mcm in diameter (PM 2.5). Joint flares were associated with PM 2.5, ozone, resultant wind, and humidity.
Renal flares were inversely associated with temperature, and directly associated with wind and humidity. Pulmonary flares and serositis were associated with PM 2.5, and both hematologic and neurologic flares with wind and temperature.
The analysis was based on a per-unit basis. For example, each mcg/m3 increase in PM 2.5 increased the odds of a pulmonary flare about 4% (odds ratio, 1.042, P = .026). The other findings were mostly of smaller magnitude, but still statistically significant.
The National Institutes of Health funded the research. Dr. Stojan had no disclosures.
SOURCE: Stojan G et al. LUPUS 2019, Abstract M31.
REPORTING FROM LUPUS 2019
ACP leaders explain why they value telehealth
PHILADELPHIA – according to the recently announced results of a questionnaire by the American College of Physicians.
The survey participants included 233 members of the ACP, who provided their responses between October 2018 and January 2019. ACP President Ana Maria Lopez, MD, as well as Tabassum Salam, MD, vice president for medical education, announced the survey’s results at a press briefing at the annual meeting of the American College of Physicians.
Dr. Lopez and Dr. Salam highlighted some of the findings and expressed their enthusiasm about the recent increases in the use of telemedicine in a video interview. They also explained how telehealth benefits patients and the barriers to more widespread use of telemedicine.
Dr. Lopez and Dr. Salam did not disclose any relevant conflicts of interest.
PHILADELPHIA – according to the recently announced results of a questionnaire by the American College of Physicians.
The survey participants included 233 members of the ACP, who provided their responses between October 2018 and January 2019. ACP President Ana Maria Lopez, MD, as well as Tabassum Salam, MD, vice president for medical education, announced the survey’s results at a press briefing at the annual meeting of the American College of Physicians.
Dr. Lopez and Dr. Salam highlighted some of the findings and expressed their enthusiasm about the recent increases in the use of telemedicine in a video interview. They also explained how telehealth benefits patients and the barriers to more widespread use of telemedicine.
Dr. Lopez and Dr. Salam did not disclose any relevant conflicts of interest.
PHILADELPHIA – according to the recently announced results of a questionnaire by the American College of Physicians.
The survey participants included 233 members of the ACP, who provided their responses between October 2018 and January 2019. ACP President Ana Maria Lopez, MD, as well as Tabassum Salam, MD, vice president for medical education, announced the survey’s results at a press briefing at the annual meeting of the American College of Physicians.
Dr. Lopez and Dr. Salam highlighted some of the findings and expressed their enthusiasm about the recent increases in the use of telemedicine in a video interview. They also explained how telehealth benefits patients and the barriers to more widespread use of telemedicine.
Dr. Lopez and Dr. Salam did not disclose any relevant conflicts of interest.
REPORTING FROM INTERNAL MEDICINE 2019
Gilteritinib prolonged survival in FLT3-mutated AML
ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).
In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.
In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.
The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.
ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).
In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.
In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.
The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.
ATLANTA – The FLT3 inhibitor gilteritinib (Xospata) significantly prolonged overall survival, compared with salvage chemotherapy, in patients with FLT3-mutated relapsed/refractory acute myeloid leukemia, Alexander E. Perl, MD, from the Abramson Cancer Center at the University of Pennsylvania in Philadelphia reported at the 2019 annual meeting of the American Association for Cancer Research (AACR).
In a video interview, Dr. Perl discussed the results of the ADMIRAL global phase 3 randomized trial and described the current state of therapy for patients with relapsed/refractory AML bearing FLT3 mutations. Up to 70% of patients with acute myeloid leukemia will experience a relapse, and up to 40% may have disease that is resistant to induction chemotherapy. Survival for these patients is generally poor.
In particular, patients with acute myeloid leukemia and FLT3-activating mutations are at increased risk for early relapse and poor overall survival.
The ADMIRAL trial is funded by Astellas Pharma. Dr. Perl disclosed advisory board participation, consulting fees, and institutional support from Astellas and others.
REPORTING FROM AACR 2019
Highlights from the ‘Updates in ACS’ session (VIDEO)
Hospital Medicine 2019 attendees outlined their key takeaways from the Updates in Acute Coronary Syndrome session, presented by Jeffrey Trost, MD, of Johns Hopkins University, Baltimore.
Dr. Trost’s discussion focused on the relationship between dual antiplatelet therapy, in-stent thrombosis, and in-stent restenosis. He also explored the diagnostic role of fractional flow reserve, and he outlined effective approaches to PCSK9 inhibitor use.
Hospital Medicine 2019 attendees outlined their key takeaways from the Updates in Acute Coronary Syndrome session, presented by Jeffrey Trost, MD, of Johns Hopkins University, Baltimore.
Dr. Trost’s discussion focused on the relationship between dual antiplatelet therapy, in-stent thrombosis, and in-stent restenosis. He also explored the diagnostic role of fractional flow reserve, and he outlined effective approaches to PCSK9 inhibitor use.
Hospital Medicine 2019 attendees outlined their key takeaways from the Updates in Acute Coronary Syndrome session, presented by Jeffrey Trost, MD, of Johns Hopkins University, Baltimore.
Dr. Trost’s discussion focused on the relationship between dual antiplatelet therapy, in-stent thrombosis, and in-stent restenosis. He also explored the diagnostic role of fractional flow reserve, and he outlined effective approaches to PCSK9 inhibitor use.
REPORTING FROM HM19
