Safety and Efficacy of Fully Human BCMA CAR T Cells in Combination with a Gamma Secretase Inhibitor

Chimeric antigen receptor T cells (CAR T cells) targeting B cell maturation antigen (BCMA) have demonstrated rapid and deep responses among patients with multi-agent refractory multiple myeloma (MM). BCMA is shed from tumor cells mediated through enzymatic cleavage by the gamma secretase complex, and tumor cells with low levels of BCMA could potentially escape CAR T recognition. We showed previously that gamma secretase inhibitors (GSI) increase BCMA surface density on tumor cells, decrease soluble BCMA levels, and enhance efficacy of BCMA CAR T cells in an immunodeficient mouse model. We have completed accrual to a phase 1 first-in-human trial of escalating doses of BCMA targeted CAR T cells in combination with a GSI (JSMD194) for patients with relapsed or refractory multiple myeloma, and herein report results on the 18 patients accrued to this trial.

Discussion:

In this study combining a GSI with BCMA CAR T cells, we have demonstrated that the combination is safe and tolerable. GSI administration routinely increased BCMA surface density on plasma cells. Further, we have observed durable, rapid responses in a heavily pretreated refractory population of MM patients, of whom a significant proportion had prior treatment with BCMA targeted therapy and CAR T therapy. The combination of BCMA CAR T and GSI may augment anti-tumor activity, even when very low doses of BCMA CAR T cells are administered.

ASH 2021: Abstract 551

 

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