Harnessing the Potential of JCARH125: Advancing BCMA-Targeted CAR T-Cell Therapy for Multiple Myeloma

Multiple myeloma, the second leading blood cancer in the US, is marked by the excessive growth of identical plasma cells in bone marrow. Despite improved survival rates due to new treatments, a cure has not been found. B-cell maturation antigen (BCMA) has been identified as a potential target for therapy. BCMA is found on all malignant plasma cells, whether relapsed or newly diagnosed, and is scarcely present in normal tissues.

Clinical trials involving BCMA-targeted CAR T cells have shown positive outcomes without off-target effects. Juno Therapeutics is advancing a CAR T-cell therapy, which includes both CD4+ and CD8+ T-cells from the same patient, modified to express a BCMA-specific CAR. This therapy utilizes a BCMA-specific single chain variable fragment (scFv) with human variable regions, a CD137 [4 1BB] co-stimulatory domain, and a CD3ζ signaling domain. The binding domain has been shown to bind BCMA specifically and with high affinity, without staining off-target cells.

When the CAR was expressed in primary T cells, they became activated, multiplied, and displayed potent lytic activity against BCMA-positive targets, while BCMA-negative targets were unaffected. The specific combination of the CAR's components was found to be advantageous. The CAR-transduced primary cells exhibited robust lytic activity and produced high levels of effector cytokines when in contact with target cells.

The CAR-expressing primary T cells demonstrated similar activity against both BCMA+ cell lines and primary CD138+ myeloma cells. They also showed comparable activity in the presence or absence of soluble BCMA. T cells engineered with the CAR from MM patients showed similar characteristics and antigen-specific activities as those from healthy donors.

In vitro assays showed no tonic signaling without antigen, but efficient signaling through the CAR was observed with increasing antigen levels. In vivo testing in NSG mouse models with MM cells showed enhanced survival and reduced tumor growth in mice treated with anti-BCMA CAR+ cells. In one model, complete tumor regression was observed by day 20 post CAR T-cell transfer, lasting up to day 60.

The circulating BCMA CAR T cells peaked on day 14 post transfer, with more CD8+ CAR+ T cells observed than CD4+ CAR+ T cells. These findings support the development of a fully human BCMA-specific CAR T cell product that targets myeloma cells across a range of antigen densities, unaffected by soluble BCMA levels. Phase 1 clinical trials for JCARH125, a BCMA CAR T cell candidate, are anticipated for early 2018.