Harnessing the Power of BCMA-Targeted CAR T Cell Therapy: A Breakthrough for Hematological Malignancies

Recent studies have highlighted the potential of B cell maturation antigen (BCMA) as a biomarker for detecting malignant plasma cells in individuals with multiple myeloma (MM). BCMA is predominantly found in MM and certain lymphoma cells, with limited expression in normal tissues such as plasma cells and mature B cells. This has prompted the exploration of BCMA as a therapeutic target for MM and some lymphomas.

Our research is focused on developing a chimeric antigen receptor (CAR) therapy aimed at BCMA-expressing MM. The therapy utilizes an anti-BCMA CAR that combines a single chain variable fragment (scFv) derived from a BCMA-specific antibody with CD137 (4-1BB) and CD3zeta signaling domains. The selection process for our lead candidate involved evaluating four distinct CARs, each with unique scFv fragments. The candidate, identified as BCMA02 or bb2121, was chosen for its high CAR-positive cell frequency, enhanced CAR molecule surface expression, and superior cytokine release and cytolytic activity against MM cell lines.

Bb2121 has shown activity against various MM and plasmacytoma cell lines and has also demonstrated a response to lymphoma cell lines, including those from Burkitt's, chronic lymphocytic leukemia, diffuse large B cell, and Mantle cell lymphoma. The therapy can identify tumor cells with BCMA molecule counts as low as 1000 per cell.

In vivo pharmacology studies using NSG mouse models of human MM and Burkitt's lymphoma were conducted. Mice were treated with either vehicle, anti-CD19Δ CAR T cells, anti-BCMA CAR T cells, or bortezomib, a standard MM treatment known for inducing tumor size reduction but also associated with toxicity. Bortezomib showed only temporary effects, whereas bb2121 led to a rapid and sustained tumor elimination, weight gain, and full survival rates.

Further analysis revealed that bb2121 CAR+ T cells migrated to the tumors and expanded significantly within the tumor and peripheral blood, correlating with tumor clearance and a subsequent decrease in circulating CAR+ T cell numbers. In additional tests using the CD19+ Daudi cell line, which has low BCMA expression, bb2121 demonstrated effective tumor clearance.

The findings suggest that adoptive T cell immunotherapy targeting BCMA could be a viable treatment for MM and potentially other B-cell malignancies resistant to chemotherapy. Following these promising results, a phase I clinical trial for bb2121 is planned for MM patients.