CAR T-cell therapy dubbed ‘promising’ for MM

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”

James Kochenderfer, MD

Photo courtesy of ASH

ORLANDO, FL—Chimeric antigen receptor (CAR) T cells can have “powerful activity” in patients with multiple myeloma (MM), according to a speaker at the 2015 ASH Annual Meeting.

The CAR T cells in question are directed against the B-cell maturation antigen (BCMA), a protein expressed by normal and malignant plasma cells.

In a phase 1 study of patients with previously treated MM, CAR-BCMA T cells eliminated plasma cells without causing direct damage to essential organs.

The therapy did produce “substantial” toxicity similar to that observed in previous CAR T-cell trials, but this was reversible, said James N. Kochenderfer, MD, of the National Cancer Institute in Bethesda, Maryland.

Dr Kochenderfer presented these results as a late-breaking abstract at the meeting (LBA-1). He received research funding from bluebird bio, the company developing CAR-BCMA T-cell therapy along with Celgene and Baylor College of Medicine.

The researchers enrolled 12 patients on this study. The patients had received at least 3 prior lines of therapy, had “essentially normal” major organ function, and had clear, uniform expression of BCMA on myeloma cells by flow cytometry or immunohistochemistry.

The patients’ own T cells were genetically modified to express the CAR with a gamma-retroviral vector. The CAR-BCMA incorporates an anti-BCMA

single-chain variable fragment, a CD28 domain, and a CD3-zeta T-cell activation domain. It was previously described in Clinical Cancer Research in 2013.

Before receiving CAR-BCMA T-cell infusions, patients received chemotherapy—cyclophosphamide at 300 mg/m² daily for 3 days and fludarabine at 30 mg/m² daily for 3 days.

Two days later, patients received a single infusion of CAR-BCMA T cells. The doses were escalated based on the number of CAR-positive T cells/kg. The doses were 0.3 x 10⁶, 1 x 10⁶, 3 x 10⁶, and 9 x 10⁶ CAR-positive T cells/kg.

Response and toxicity

“[O]n the lower 2 dose levels, toxicity was minimal—just a couple of fevers,” Dr Kochenderfer noted. “When we got to the higher dose levels, patients started to have more significant toxicity, along with more impressive responses.”

One patient, Patient 10, had a stringent complete response to the highest dose of CAR-BCMA T cells (9 x 10⁶). This response is ongoing and has lasted longer than 12 weeks.

Patient 8, who received a CAR-BCMA T-cell dose of 3 x 10⁶, achieved a very good partial response that lasted 8 weeks. A PET scan showed complete clearance of myeloma in this patient.

Two patients achieved partial responses. One response occurred on the lowest dose of CAR-BCMA T cells (0.3 x 10⁶) and lasted 2 weeks.

The other partial response occurred in Patient 11, who received the highest dose of CAR-BCMA T cells. This response is ongoing and has lasted more than 6 weeks.

The remaining 8 patients had stable disease that lasted anywhere from 2 weeks to 16 weeks.

Best responders

Patient 10, who achieved a stringent complete response, had chemotherapy-resistant IgA MM at baseline. He had received 3 prior lines of therapy and had relapsed with 90% bone marrow plasma cells 3 months after autologous transplant.

“BCMA expression was uniform but dim on his myeloma cells,” Dr Kochenderfer noted.

Within 4 hours of receiving CAR-BCMA T cells, Patient 10 became febrile. He showed other signs of cytokine release syndrome as well, including tachycardia, hypotension, elevated liver enzymes, and elevated creatinine kinase. But all of these symptoms resolved within 2 weeks.

Patient 10’s absolute neutrophil count was less than 500/µL at the time of CAR-BCMA T-cell infusion and remained less than 500/µL for 40 days after infusion. The patient was platelet-transfusion-dependent for 9 weeks after infusion.

Patient 11, who achieved the ongoing partial response, had received 5 prior lines of therapy. MM made up 80% of his bone marrow cells at baseline.

The patient experienced a rapid decrease in markers of MM after CAR-BCMA T-cell infusion, and his M protein levels continue to decrease.

Patient 11 also experienced fever, tachycardia, hypotension, acute kidney injury, dyspnea, delirium, and prolonged thrombocytopenia, but all of these toxicities have resolved completely.

Dr Kochenderfer noted that patients who had significant responses (Patients 8, 10, and 11) had the highest blood levels of CAR-BCMA T cells. They also had the most severe clinical signs of cytokine release syndrome and much higher serum levels of IL-6 than the other patients.

“We have demonstrated, for the first time, that CAR T cells can have powerful activity against measurable myeloma,” Dr Kochenderfer said in closing. “Anti-BCMA CAR T cells are a promising therapy for multiple myeloma.”