PBCAR269A + nirogacestat

PBCAR269A + nirogacestat is an investigational combination therapy for relapsed or refractory multiple myeloma, consisting of PBCAR269A, an allogeneic CAR T cell product targeting B-cell maturation antigen (BCMA), and nirogacestat, an oral, selective small molecule gamma secretase inhibitor. PBCAR269A is engineered from healthy donor T cells using ARCUS genome editing to knock out the native T cell receptor (TCR) and insert an anti-BCMA CAR, producing an “off-the-shelf” immunotherapy product designed for improved immune cell persistence. Nirogacestat blocks gamma secretase, preventing cleavage and shedding of BCMA from tumor cell surfaces, thereby increasing BCMA density on cells and reducing soluble BCMA levels, which preclinically enhances the efficacy of BCMA-directed cell therapies. The combination is currently being assessed in clinical trials to evaluate synergistic anti-myeloma effects. Precision BioSciences is developing PBCAR269A and SpringWorks Therapeutics is developing nirogacestat[1][2][5].