B-cell maturation antigen most promising myeloma target for CAR T-cell therapy

Immunotherapies are becoming the next-generation therapies for multiple myeloma.

The immune microenvironment is immunosuppressive, which makes this disease susceptible to cellular therapy with chimeric antigen receptor (CAR) T-cell therapy. CD-19 targeted CAR T-cell therapy has shown activity in acute lymphoblastic leukemia, chronic lymphocytic leukemia, and non-Hodgkin lymphoma. The most promising target in multiple myeloma is B-cell maturation antigen (BCMA).

“BCMA is a good target because it is expressed on normal and malignant plasma cells and promotes multiple myeloma cell survival,” said Adam D. Cohen, MD, director of myeloma immunotherapy at the University of Pennsylvania Abramson Cancer Center in Philadelphia.

In a presentation at the American Society of Hematology annual meeting, he explained that BCMA-targeted therapies, including CAR T cells, show preclinical and early clinical activity in myeloma. The BCMA CAR T-cell trial he reported divided multiple myeloma patients into three cohorts, including CAR alone with no lymphodepletion, with cyclophosphamide first, and with lower and higher doses of CAR cells. The patients had a median of seven prior lines of therapy, and almost all (95%) had high-risk genetics.

At the time of the analysis, 24 patients, mean age of 58, had been treated (nine in cohort 1, five in cohort 2, and 10 in cohort 3). All have successfully manufactured at least minimum target dose.

A total of 11 of 24 patients (46%) achieved an objective response, and median duration of response is 4 months. Two patients had a complete response (CR) — one in cohort 1 for 24 months, and one in cohort 3 for 6 months.

Toxicities remain cytokine release syndrome (CRS) in six patients and neurotoxicity in six, but there was no increased toxicity with cyclophosphamide, Cohen reported.

“CAR T-BCMA has activity in heavily pretreated multiple myeloma. Lymphodepletion is not required for robust expansion and response. Cyclophosphamide may increase the frequency of patients with strong expansion.”

Two other multicenter trials of CAR T-cell therapy in multiple myeloma also show durable responses, with some approaching 1 year, he noted.

At the 2017 American Society of Clinical Oncology annual meeting, Chinese researchers presented the results of treatment with a novel, proprietary CAR T-cell product, LCAR-B38M, targeting BCMA. All 19 patients with relapsed/refractory multiple myeloma responded, and 14 of 19 (74%) followed for a median of 4 months achieved a stringent CR and have not recurred. The majority (14 patients) experienced mild or manageable CRS, and five patients were even free of diagnosable CRS.

In another presentation at ASH17, durable clinical responses in heavily pretreated patients with relapsed/refractory multiple myeloma were reported with bb2121 anti-BCMA CAR T-cell therapy.

BB2121 is a second-generation CAR construct targeting BCMA, consisting of autologous T cells transduced with a lentiviral vector encoding a novel CAR incorporating an anti-BCMA scFv, a 4-1BB co-stimulatory motif to promote proliferation and persistence, and a CD3-zeta T cell activation domain.

The phase I study, conducted at nine sites in the United States, is the first U.S.-based multicenter study of a CAR T-cell therapy engineered to target BCMA. The study included 21 evaluable patients, median age of 58, who were enrolled in the dose-escalation phase. All had relapsed/refractory disease after a median of seven prior treatments, including a stem cell transplant. The patients had received three or more prior regimens, including a proteasome inhibitor and an immunomodulatory agent, or were double-refractory, and had at least 50% BCMA expression on malignant cells.

A one-time infusion of this investigational CAR T-cell therapy elicited an 86% overall response rate. Among 18 patients who received higher, active doses of infused CAR T cells, the response rate increased to 94%, with manageable adverse effects, reported researchers led by James Kochenderfer, MD, of the National Cancer Institute’s Center for Cancer Research.

Among these 18 patients, 10 (56%) had a CR, and nine of 10 evaluated for minimal residual disease (MRD) using sensitive genetic tests achieved an MRD-negative response. After a median follow-up of 40 weeks, the median progression-free survival had not been reached; four patients have progressed.

The duration of ongoing response is more than 1 year with no additional myeloma therapy, the researchers reported, noting that responses deepened over time — PFS at 6 months was 81% and at 9 months, 71% — and responses continued to improve as late as month 15, from a very good partial response to CR.

The CAR T-cell therapy was generally well-tolerated, and no dose-limiting toxicities were observed in dose escalation, the team noted. Cytopenias were mostly related to cyclophosphamide/fludarabine lymphodepletion. Patients recovered to less than Grade 3 cytopenias by month 2.

Five patients died, three due to disease progression. Two patients were being treated at active doses in CR at the time of death. Fourteen patients had one or more serious adverse events. Four patients had CRS grade 1-2 that required hospitalization, and two patients developed pyrexia.

Kochenderfer et al said they believe that specific targeting with this CAR T-cell therapy is safe and a logical way to attack multiple myeloma.

Cohen summed up: “BCMA is the most promising target for immunotherapy in multiple myeloma. CAR T-cell therapy leads to high response rates. We are in the early days for CAR T-cell therapy for multiple myeloma, but the future is bright.”

Still, he added, many questions and challenges remain, including determining optimal patient populations, how to manage toxicities, and assessing sequencing or combining immunotherapies with current therapies.