Larson et al. generated CAR T cells specific for TACI, which, unlike BCMA, showed negligible RNA expression in the basal ganglia. Anti-TACI-CAR T cells were cytotoxic against TACI+ targets in vitro and rejected xenografted TACI+ multiple myeloma cells, even if targets lacked BCMA expression due to gene deletion or prior anti-BCMA-CAR T cell therapy. Bispecific CAR T cells comprising tandem anti-BCMA–anti-TACI scFvs were generated, and exhibited antitumor activity against multiple myeloma cells – including cell lines lacking BCMA or TACI expression due to gene deletion – and a plasma cell tumor from a patient who relapsed after anti-BCMA-CAR T cell treatment.
Contributed by Paula Hochman
ABSTRACT: Chimeric Antigen Receptor (CAR) T cells directed to B cell maturation antigen (BCMA) mediate profound responses in patients with multiple myeloma, but most patients do not achieve long-term complete remissions. In addition, recent evidence suggests that high-affinity binding to BCMA can result in on-target, off-tumor activity in the basal ganglia and can lead to fatal Parkinsonian-like disease. Here we develop CAR T cells against multiple myeloma using a binder to targeting transmembrane activator and CAML interactor (TACI) in mono and dual-specific formats with anti-BCMA. These CARs have robust, antigen-specific activity in vitro and in vivo. We also show that TACI RNA expression is limited in the basal ganglia, which may circumvent some of the toxicities recently reported with BCMA CARs. Thus, single-targeting TACI CARs may have a safer toxicity profile, whereas dual-specific BCMA-TACI CAR T cells have potential to avoid the antigen escape that can occur with single-antigen targeting.
Author Info: (1) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston,
Author Info: (1) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (2) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (3) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (4) Department of Pathology and Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA. (5) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (6) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (7) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (8) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (9) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (10) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (11) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (12) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (13) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (14) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. Harvard Medical School, Boston, MA, USA. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. (15) Cellular Immunotherapy Program, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu. Harvard Medical School, Boston, MA, USA. mvmaus@mgh.harvard.edu. Cancer Center, Massachusetts General Hospital, Boston, MA, USA. mvmaus@mgh.harvard.edu.
