Meeting News

CAR T-cell therapy holds promise for multiple myeloma

James N. Kochenderfer

NEW YORK — Cellular immunotherapies such as chimeric antigen receptor therapy are a promising approach for treatment of multiple myeloma, according to a presenter at HemOnc Today New York.

CAR T cells have impressive activity against leukemia and lymphoma, and this has encouraged development of these therapies for myeloma, James N. Kochenderfer, MD, physician-scientist at Center for Cancer Research at NCI, said during his presentation.

“Persistence of multiple myeloma has been postulated to depend on a myeloma stem cell that has the phenotype of a mature B cell,” Kochenderfer said. “The phenotype of the myeloma stem cell is still under debate, but two groups have developed CAR T-cell approaches aimed at targeting B-cell antigens as a method of treating multiple myeloma.”

Researchers at University of Pennsylvania have strived to target CD19 with anti-CD19 CAR T-cell infusions after autologous stem cell transplant, whereas researchers at Baylor College of Medicine have targeted kappa light chain.

“I think it’s too early to determine the efficacy of this approach, but it definitely is very interesting and a good area for further study,” Kochenderfer said.

The largest area of study focuses on CAR T-cell therapy that targets B-cell maturation antigen (BCMA), a member of the tumor necrosis factor superfamily.

BCMA is uniformly expressed on 72% of cases of multiple myeloma when analyzed by the immunohistochemistry assay used at NCI, Kochenderfer said. Flow cytometry shows BCMA is expressed at least at low levels on myeloma cell surface in almost all cases.

Researchers with the NCI conducted a first-in-human, single-center study that assessed use of T cells genetically engineered to express an anti-BCMA chimeric antigen receptor.

The dose-escalation trial included 24 patients who had received a median 9.5 prior lines of therapy. Six of 15 (40%) evaluable patients had high-risk cytogenetics, five of 15 (33%) had deletion 17p, and 10 of 16 (63%) were refractory to their most recent treatment.

Results showed only two of 10 patients treated at the three lowest dose levels achieved objective response. However, 13 of 16 patients (81%) treated at the highest dose — 9 x 106 cells/kg — achieved objective response, including three who achieved stringent complete response.

Researchers reported median EFS of 31 weeks, with six patients continuing to experience ongoing response and three patients achieving EFS of more than 1 year.

“The anti-BCMA CAR T-cells do have potent activity,” Kochenderfer said. “This is a very heavily pretreated group, and some of these responses are very long-lasting. It is early, so it is very hard to draw firm conclusions, but certainly we’re seeing good activity.”

In the highest-dose cohort, two patients experienced grade 4 cytokine release syndrome (CRS) and four patients experienced grade 3 cytokine release syndrome. These cases occurred among patients with higher bone marrow plasma cell percentages, Kochenderfer said.

All other CRS cases were grade 1 or grade 2.

Five patients received tocilizumab (Actemra, Genentech) for cytokine release syndrome management, and four received corticosteroids for cytokine release syndrome management or adrenal insufficiency.

“Toxicity appeared substantial but reversible, and it was associated with myeloma burden,” Kochenderfer said.

Kochenderfer also provided an overview of the phase 1 CRB-401 study, which so far has included 21 patients with relapsed or refractory myeloma. The dose-escalation study, conducted at nine U.S. sites, was intended to determine the preliminary safety and efficacy and recommended phase 2 dose of bb2121 (bluebird bio), an anti-BCMA CAR T-cell therapy.

Results showed bb2121 at active doses ranging from 150 x 106cells/kg to 800 x 106 cells/kg has induced durable and deepening responses in heavily pretreated patients.

Researchers reported a 94% overall response rate, with 89% of patients achieving very good partial response or better, and 56% achieving complete response or better.

Median PFS had not been reached after 40 weeks of follow-up, and 90% of evaluable patient samples appeared negative for minimal residual disease.

The therapy also exhibited a manageable safety profile. Two patients experienced grade 3 cytokine release syndrome but both cases resolved within 24 hours. One patient — who had the highest tumor burden of all patients on the trial — experienced delayed-onset, reversible grade 4 neurotoxicity associated with tumor lysis syndrome and cytokine release syndrome.

The global, pivotal KarMMA trial, designed to evaluate bb2121 at a dose range of 150 x 106 cells/kg to 300 x 106 cells/kg, is now open for enrollment. – by Mark Leiser

 

Disclosure: NCI has cooperative research and development agreements (CRDAs) with Kite Pharma and bluebird bio. Kochenderfer is principle investigator of these CRDAs. He also has patent applications for multiple chimeric antigen receptors.

James N. Kochenderfer

NEW YORK — Cellular immunotherapies such as chimeric antigen receptor therapy are a promising approach for treatment of multiple myeloma, according to a presenter at HemOnc Today New York.

CAR T cells have impressive activity against leukemia and lymphoma, and this has encouraged development of these therapies for myeloma, James N. Kochenderfer, MD, physician-scientist at Center for Cancer Research at NCI, said during his presentation.

“Persistence of multiple myeloma has been postulated to depend on a myeloma stem cell that has the phenotype of a mature B cell,” Kochenderfer said. “The phenotype of the myeloma stem cell is still under debate, but two groups have developed CAR T-cell approaches aimed at targeting B-cell antigens as a method of treating multiple myeloma.”

Researchers at University of Pennsylvania have strived to target CD19 with anti-CD19 CAR T-cell infusions after autologous stem cell transplant, whereas researchers at Baylor College of Medicine have targeted kappa light chain.

“I think it’s too early to determine the efficacy of this approach, but it definitely is very interesting and a good area for further study,” Kochenderfer said.

The largest area of study focuses on CAR T-cell therapy that targets B-cell maturation antigen (BCMA), a member of the tumor necrosis factor superfamily.

BCMA is uniformly expressed on 72% of cases of multiple myeloma when analyzed by the immunohistochemistry assay used at NCI, Kochenderfer said. Flow cytometry shows BCMA is expressed at least at low levels on myeloma cell surface in almost all cases.

Researchers with the NCI conducted a first-in-human, single-center study that assessed use of T cells genetically engineered to express an anti-BCMA chimeric antigen receptor.

The dose-escalation trial included 24 patients who had received a median 9.5 prior lines of therapy. Six of 15 (40%) evaluable patients had high-risk cytogenetics, five of 15 (33%) had deletion 17p, and 10 of 16 (63%) were refractory to their most recent treatment.

Results showed only two of 10 patients treated at the three lowest dose levels achieved objective response. However, 13 of 16 patients (81%) treated at the highest dose — 9 x 106 cells/kg — achieved objective response, including three who achieved stringent complete response.

Researchers reported median EFS of 31 weeks, with six patients continuing to experience ongoing response and three patients achieving EFS of more than 1 year.

“The anti-BCMA CAR T-cells do have potent activity,” Kochenderfer said. “This is a very heavily pretreated group, and some of these responses are very long-lasting. It is early, so it is very hard to draw firm conclusions, but certainly we’re seeing good activity.”

In the highest-dose cohort, two patients experienced grade 4 cytokine release syndrome (CRS) and four patients experienced grade 3 cytokine release syndrome. These cases occurred among patients with higher bone marrow plasma cell percentages, Kochenderfer said.

All other CRS cases were grade 1 or grade 2.

Five patients received tocilizumab (Actemra, Genentech) for cytokine release syndrome management, and four received corticosteroids for cytokine release syndrome management or adrenal insufficiency.

“Toxicity appeared substantial but reversible, and it was associated with myeloma burden,” Kochenderfer said.

Kochenderfer also provided an overview of the phase 1 CRB-401 study, which so far has included 21 patients with relapsed or refractory myeloma. The dose-escalation study, conducted at nine U.S. sites, was intended to determine the preliminary safety and efficacy and recommended phase 2 dose of bb2121 (bluebird bio), an anti-BCMA CAR T-cell therapy.

Results showed bb2121 at active doses ranging from 150 x 106cells/kg to 800 x 106 cells/kg has induced durable and deepening responses in heavily pretreated patients.

Researchers reported a 94% overall response rate, with 89% of patients achieving very good partial response or better, and 56% achieving complete response or better.

Median PFS had not been reached after 40 weeks of follow-up, and 90% of evaluable patient samples appeared negative for minimal residual disease.

The therapy also exhibited a manageable safety profile. Two patients experienced grade 3 cytokine release syndrome but both cases resolved within 24 hours. One patient — who had the highest tumor burden of all patients on the trial — experienced delayed-onset, reversible grade 4 neurotoxicity associated with tumor lysis syndrome and cytokine release syndrome.

The global, pivotal KarMMA trial, designed to evaluate bb2121 at a dose range of 150 x 106 cells/kg to 300 x 106 cells/kg, is now open for enrollment. – by Mark Leiser

 

Disclosure: NCI has cooperative research and development agreements (CRDAs) with Kite Pharma and bluebird bio. Kochenderfer is principle investigator of these CRDAs. He also has patent applications for multiple chimeric antigen receptors.

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