CAR T-Cell Therapy Emerging in Numerous Myeloma
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For patients with numerous myeloma, chimeric antigen receptor (CAR) T-cell therapy is gaining ground in pilot studies. At the two thousand sixteen American Society of Hematology (ASH) Annual Meeting & Exposition, researchers introduced their latest findings for this innovative therapy, which has proven beneficial in other hematologic malignancies.
A leading researcher in the field, James Kochenderfer, MD, of the Experimental Transplantation and Immunology Branch of the National Cancer Institute, explained the difficulties that must be overcome for CAR T-cell therapy to work in numerous myeloma.
Target Antigen Is Critical
“Probably the most critical factor for any CAR T-cell therapy is the choice of target antigen. Adequate target antigens for myeloma are not abundant. Common numerous myeloma antigens such as CD38, CD56, and CD138 are all voiced on essential normal cells as well,” he said. “Another complicating factor is that the myeloma cells of any particular patient are clearly made up of many subclones, so heterogeneity of antigen expression is probable.”
It is thought that the persistence of myeloma depends on a myeloma stem cell that has the phenotype of a mature B cell. Two CAR T-cell approaches in development are targeting B-cell antigens: In research spearheaded by the University of Pennsylvania, anti-CD19 CAR T cells (CTL019) are infused after autologous stem cell transplantation, whereas Baylor College of Medicine researchers are targeting kappa light chains, Dr. Kochenderfer said.
“Targeting myeloma stem cells is an interesting and promising treatment, but the results so far are early,” he said. “Also, we need to better define the phenotype of the myeloma stem cell.”
CAR T-Cell Therapy in Myeloma
- Early-phase studies are underway for CAR T-cell therapy in numerous myeloma. Most available data are for anti-CD19 and anti–B-cell maturation antigen approaches.
- In a examine of the anti–B-cell maturation antigen product 11D5-3-CD828Z, responses were consistently observed in the six patients treated at the highest dose level.
- Another anti–B-cell maturation antigen product, bb2121, downright eradicated tumors in mice and produced sturdy responses in early
human trials.
Dr. Kochenderfer and his colleagues have taken a somewhat different treatment, developing CARs that target B-cell maturation antigen—“B-cell maturation antigen is the target that is voiced most uniformly on myeloma cells and not normal cells. In my opinion, it’s the best known target for CARs in the myeloma field,” he said in an interview with The ASCO Post.
Targeting B-Cell Maturation Antigen
B-cell maturation antigen, a tumor-specific antigen and a receptor for both a proliferation-inducing ligand and B-cell–activating factor, is a member of the tumor necrosis factor receptor superfamily and plays a key role in plasma cell survival. B-cell maturation antigen is voiced in most, if not all, myeloma cells but not in epithelial tissues. B-cell maturation antigen–specific CAR-expressing T lymphocytes specifically recognize and kill B-cell maturation antigen–expressing tumor cells.
At the two thousand fifteen ASH Annual Meeting, Dr. Kochenderfer introduced a late-breaking abstract on his work with the anti–B-cell maturation antigen CAR T-cell construct, 11D5-3-CD828Z. He reported the very first evidence of elimination of measurable numerous myeloma by CAR T cells. The antimyeloma activity of the CAR T cells targeting B-cell maturation antigen enlargened as the dose of the CAR T cells enhanced. 1
At the two thousand sixteen ASH Annual Meeting, he reported that responses were observed in five of six patients treated at the highest dose level, including a stringent finish response in one patient, a very good partial response in three patients (1 with 52+ weeks duration), and a partial response in one patient. Two These responses occurred, however, at the price of cytokine-release syndrome (which was reversible) and prolonged cytopenias in some patients. Elevations in a diversity of serum cytokines, he said, represent “both a major limitation and an chance for improvement.”
Patients who obtained significant antimyeloma responses had the highest blood levels of anti–B-cell maturation antigen CAR T cells. This association is similar to what is seen with anti-CD19 CAR T cells, he said. Patients experienced toxicities including fever and low blood pressure, which were also similar to those after infusions of anti-CD19 CAR T cells.
Dr. Kochenderfer also described his work with a 2nd anti–B-cell maturation antigen CAR T-cell product, bb2121. This product contains 4-1bb as a costimulatory domain, designed to better promote proliferation and persistence of the CARs, he said.
In an animal model, he said, “The bb2121 construct eliminated tumors in every mouse. The CAR T-cell–treated mice were all essentially cured. The bortezomib (Velcade)-treated mice had extended survival, but eventually all died. The control group (untreated) all died rapidly.”
In a multicenter phase I dose-escalation investigate of nine patients with relapsed/refractory myeloma (three per arm), infusions of the lowest dose resulted in one partial response, one disease stabilization, and one disease progression. At the second-highest dose, one very good partial response and two stringent responses were observed, all ongoing. At the highest dose, three partial responses emerged (which could deepen). Cytokine-release syndrome was limited to grade one to two (no grade Trio), and no significant grade three neurotoxicity was observed.
“We have found that anti–B-cell maturation antigen CAR T cells have powerful antimyeloma activity against measurable numerous myeloma, including in patients resistant to chemotherapy, tho’ toxicity has been substantial but reversible and similar to that seen on previous CAR T-cell trials in leukemia,” he said. “We are continuing to do preclinical work to come up with CAR T-cell therapies that will have improved efficacy and less toxicity.”
While maintaining that numerous myeloma “is one of the malignancies for which CAR T-cell therapy holds fine promise,” Dr. Kochenderfer acknowledged, “We still have a way to go to find the right antigens.”
An update on a pilot probe of an anti-CD19 CAR T-cell treatment was introduced by Alfred Garfall, MD, of Abramson Cancer Center at the University of Pennsylvania. Three However CD19 is voiced only infrequently on numerous myeloma plasma cells, infrequent CD19-positive B cells that are clonally related to the myeloma plasma cells can be identified, he said.
“Minor CD19-positive components of the myeloma clone can be identified in patients, and these CD19-positive subsets may have cancer stem cell properties,” Dr. Garfall explained. “Our hypothesis was that CTL019 would prolong response to standard therapy by depleting a minor CD19-positive population of numerous myeloma cells with cancer stem cell properties.”
The treatment involved administration of CTL019 after high-dose melphalan and autologous stem cell transplantation in ten myeloma patients who had disease progression within one year of prior first-line stem cell transplant. Patients had received a median of six prior lines of therapy. Poor-prognosis features were present in eight (eg, poor-prognosis cytogenetics, BRAF V600E mutation, secondary plasma cell leukemia). Baseline CD19 expression on myeloma plasma cells displayed the superior population to be CD19-negative in all cases, by flow cytometry, but minor CD19-positive subsets were seen in seven of nine evaluable cases.
“This was a safe and feasible treatment,” Dr. Garfall reported. All treated patients received the maximum target dose of five × ten 7 CTL019 cells. One patient experienced grade one cytokine-release syndrome, one developed autologous graft-vs-host disease (which resolved), and the other adverse events were as expected posttransplant.
After infusion, CTL019 cells were detectable in the peripheral blood of all subjects and persisted for a median of forty four days (range = 14–156). The presence of CTL019 cells was associated with an absence of peripheral blood B cells. Notably, CTL019 cells were detected in the bone marrow in nine of ten subjects at day forty two and/or day one hundred post–stem cell transplant.
Of the ten patients treated, six achieved very good partial responses by day 100, two had partial responses, and two continued to have progressive disease. The median progression-free survival after treatment with autologous stem cell transplantation plus CTL019 was one hundred eighty five days (range = 42–479).
“As expected, most patients had progression early after the 2nd transplant and at a shorter time than after their first-line transplant, but two patients had substantial prolongation of progression-free survival, despite having received a lower dose of melphalan,” he reported. “This compares favorably with our historical cohort of eighteen salvage transplants in the ‘modern era,’ where no subjects exhibited longer progression-free survival compared to their prior autologous transplant.”
Also of interest, patients with prolonged remission who eventually had progression exhibited indolent clinical features, ie, “a switch in the rhythm of their disease,” Dr. Garfall said. For example, one patient had undergone an [autologous stem cell transplantation] plus an extra nine lines of treatment. The patient had a 16-month response to [transplant] plus CTL019 and eventually became negative for minimal residual disease. When progression ultimately was observed, it was in the form of extramedullary plasmacytosis, which responded to radiation therapy and daratumumab (Darzalex). The patient has been on daratumumab for more than one year now, with no evidence of disease by serum biomarkers.
“What seemed to be a clinical slowing of this patient’s disease was observed despite very brief activity of CTL019,” he added. “CTL019 peaks very early and at a relatively low level, then dissipates by day 100.”
Interestingly, peak bone marrow CTL019 frequency correlated significantly with favorable time to progression (P = .009), but no such associations were observed for CTL019 in the peripheral blood. Also of interest, antibodies emerged against the stem cell antigen Sox2 in subjects with the best clinical outcomes.
The investigators believe that a higher CTL019 dose may increase the proportion of patients who benefit from this treatment. Therefore, they are conducting a phase II trial of CTL019 using a 10-fold higher dose after first-line autologous stem cell transplantation in high-risk myeloma patients. ■
CAR T-Cell Therapy Emerging in Numerous Myeloma – The ASCO Post
CAR T-Cell Therapy Emerging in Numerous Myeloma
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For patients with numerous myeloma, chimeric antigen receptor (CAR) T-cell therapy is gaining ground in pilot studies. At the two thousand sixteen American Society of Hematology (ASH) Annual Meeting & Exposition, researchers introduced their latest findings for this innovative therapy, which has proven beneficial in other hematologic malignancies.
A leading researcher in the field, James Kochenderfer, MD, of the Experimental Transplantation and Immunology Branch of the National Cancer Institute, explained the difficulties that must be overcome for CAR T-cell therapy to work in numerous myeloma.
Target Antigen Is Critical
“Probably the most critical factor for any CAR T-cell therapy is the choice of target antigen. Suitable target antigens for myeloma are not abundant. Common numerous myeloma antigens such as CD38, CD56, and CD138 are all voiced on essential normal cells as well,” he said. “Another complicating factor is that the myeloma cells of any particular patient are clearly made up of many subclones, so heterogeneity of antigen expression is probable.”
It is thought that the persistence of myeloma depends on a myeloma stem cell that has the phenotype of a mature B cell. Two CAR T-cell approaches in development are targeting B-cell antigens: In research spearheaded by the University of Pennsylvania, anti-CD19 CAR T cells (CTL019) are infused after autologous stem cell transplantation, whereas Baylor College of Medicine researchers are targeting kappa light chains, Dr. Kochenderfer said.
“Targeting myeloma stem cells is an interesting and promising treatment, but the results so far are early,” he said. “Also, we need to better define the phenotype of the myeloma stem cell.”
CAR T-Cell Therapy in Myeloma
- Early-phase studies are underway for CAR T-cell therapy in numerous myeloma. Most available data are for anti-CD19 and anti–B-cell maturation antigen approaches.
- In a probe of the anti–B-cell maturation antigen product 11D5-3-CD828Z, responses were consistently observed in the six patients treated at the highest dose level.
- Another anti–B-cell maturation antigen product, bb2121, fully eradicated tumors in mice and produced sturdy responses in early
human trials.
Dr. Kochenderfer and his colleagues have taken a somewhat different treatment, developing CARs that target B-cell maturation antigen—“B-cell maturation antigen is the target that is voiced most uniformly on myeloma cells and not normal cells. In my opinion, it’s the best known target for CARs in the myeloma field,” he said in an interview with The ASCO Post.
Targeting B-Cell Maturation Antigen
B-cell maturation antigen, a tumor-specific antigen and a receptor for both a proliferation-inducing ligand and B-cell–activating factor, is a member of the tumor necrosis factor receptor superfamily and plays a key role in plasma cell survival. B-cell maturation antigen is voiced in most, if not all, myeloma cells but not in epithelial tissues. B-cell maturation antigen–specific CAR-expressing T lymphocytes specifically recognize and kill B-cell maturation antigen–expressing tumor cells.
At the two thousand fifteen ASH Annual Meeting, Dr. Kochenderfer introduced a late-breaking abstract on his work with the anti–B-cell maturation antigen CAR T-cell construct, 11D5-3-CD828Z. He reported the very first evidence of elimination of measurable numerous myeloma by CAR T cells. The antimyeloma activity of the CAR T cells targeting B-cell maturation antigen enlargened as the dose of the CAR T cells enlargened. 1
At the two thousand sixteen ASH Annual Meeting, he reported that responses were observed in five of six patients treated at the highest dose level, including a stringent finish response in one patient, a very good partial response in three patients (1 with 52+ weeks duration), and a partial response in one patient. Two These responses occurred, however, at the price of cytokine-release syndrome (which was reversible) and prolonged cytopenias in some patients. Elevations in a multitude of serum cytokines, he said, represent “both a major limitation and an chance for improvement.”
Patients who obtained significant antimyeloma responses had the highest blood levels of anti–B-cell maturation antigen CAR T cells. This association is similar to what is seen with anti-CD19 CAR T cells, he said. Patients experienced toxicities including fever and low blood pressure, which were also similar to those after infusions of anti-CD19 CAR T cells.
Dr. Kochenderfer also described his work with a 2nd anti–B-cell maturation antigen CAR T-cell product, bb2121. This product contains 4-1bb as a costimulatory domain, designed to better promote proliferation and persistence of the CARs, he said.
In an animal model, he said, “The bb2121 construct eliminated tumors in every mouse. The CAR T-cell–treated mice were all essentially cured. The bortezomib (Velcade)-treated mice had extended survival, but eventually all died. The control group (untreated) all died rapidly.”
In a multicenter phase I dose-escalation probe of nine patients with relapsed/refractory myeloma (three per arm), infusions of the lowest dose resulted in one partial response, one disease stabilization, and one disease progression. At the second-highest dose, one very good partial response and two stringent responses were observed, all ongoing. At the highest dose, three partial responses emerged (which could deepen). Cytokine-release syndrome was limited to grade one to two (no grade Three), and no significant grade three neurotoxicity was observed.
“We have found that anti–B-cell maturation antigen CAR T cells have powerful antimyeloma activity against measurable numerous myeloma, including in patients resistant to chemotherapy, however toxicity has been substantial but reversible and similar to that seen on previous CAR T-cell trials in leukemia,” he said. “We are continuing to do preclinical work to come up with CAR T-cell therapies that will have improved efficacy and less toxicity.”
While maintaining that numerous myeloma “is one of the malignancies for which CAR T-cell therapy holds good promise,” Dr. Kochenderfer acknowledged, “We still have a way to go to find the right antigens.”
An update on a pilot explore of an anti-CD19 CAR T-cell treatment was introduced by Alfred Garfall, MD, of Abramson Cancer Center at the University of Pennsylvania. Three Tho’ CD19 is voiced only infrequently on numerous myeloma plasma cells, uncommon CD19-positive B cells that are clonally related to the myeloma plasma cells can be identified, he said.
“Minor CD19-positive components of the myeloma clone can be identified in patients, and these CD19-positive subsets may have cancer stem cell properties,” Dr. Garfall explained. “Our hypothesis was that CTL019 would prolong response to standard therapy by depleting a minor CD19-positive population of numerous myeloma cells with cancer stem cell properties.”
The treatment involved administration of CTL019 after high-dose melphalan and autologous stem cell transplantation in ten myeloma patients who had disease progression within one year of prior first-line stem cell transplant. Patients had received a median of six prior lines of therapy. Poor-prognosis features were present in eight (eg, poor-prognosis cytogenetics, BRAF V600E mutation, secondary plasma cell leukemia). Baseline CD19 expression on myeloma plasma cells demonstrated the superior population to be CD19-negative in all cases, by flow cytometry, but minor CD19-positive subsets were seen in seven of nine evaluable cases.
“This was a safe and feasible treatment,” Dr. Garfall reported. All treated patients received the maximum target dose of five × ten 7 CTL019 cells. One patient experienced grade one cytokine-release syndrome, one developed autologous graft-vs-host disease (which resolved), and the other adverse events were as expected posttransplant.
After infusion, CTL019 cells were detectable in the peripheral blood of all subjects and persisted for a median of forty four days (range = 14–156). The presence of CTL019 cells was associated with an absence of peripheral blood B cells. Notably, CTL019 cells were detected in the bone marrow in nine of ten subjects at day forty two and/or day one hundred post–stem cell transplant.
Of the ten patients treated, six achieved very good partial responses by day 100, two had partial responses, and two continued to have progressive disease. The median progression-free survival after treatment with autologous stem cell transplantation plus CTL019 was one hundred eighty five days (range = 42–479).
“As expected, most patients had progression early after the 2nd transplant and at a shorter time than after their first-line transplant, but two patients had substantial prolongation of progression-free survival, despite having received a lower dose of melphalan,” he reported. “This compares favorably with our historical cohort of eighteen salvage transplants in the ‘modern era,’ where no subjects exhibited longer progression-free survival compared to their prior autologous transplant.”
Also of interest, patients with prolonged remission who eventually had progression exhibited indolent clinical features, ie, “a switch in the rhythm of their disease,” Dr. Garfall said. For example, one patient had undergone an [autologous stem cell transplantation] plus an extra nine lines of treatment. The patient had a 16-month response to [transplant] plus CTL019 and eventually became negative for minimal residual disease. When progression ultimately was observed, it was in the form of extramedullary plasmacytosis, which responded to radiation therapy and daratumumab (Darzalex). The patient has been on daratumumab for more than one year now, with no evidence of disease by serum biomarkers.
“What seemed to be a clinical slowing of this patient’s disease was observed despite very brief activity of CTL019,” he added. “CTL019 peaks very early and at a relatively low level, then dissipates by day 100.”
Interestingly, peak bone marrow CTL019 frequency correlated significantly with favorable time to progression (P = .009), but no such associations were observed for CTL019 in the peripheral blood. Also of interest, antibodies emerged against the stem cell antigen Sox2 in subjects with the best clinical outcomes.
The investigators believe that a higher CTL019 dose may increase the proportion of patients who benefit from this treatment. Therefore, they are conducting a phase II trial of CTL019 using a 10-fold higher dose after first-line autologous stem cell transplantation in high-risk myeloma patients. ■