Harnessing the Potential of ALLO-715: Advancing Allogeneic BCMA CAR T Therapy with an Off-Switch for Multiple Myeloma

The study focuses on the development of an allogeneic CAR T cell therapy, ALLO-715, targeting the B-Cell Maturation Antigen (BCMA) for treating relapsed/refractory multiple myeloma (MM). Unlike autologous CAR T cells, which are patient-specific and time-consuming to produce, allogeneic CAR T cells are derived from healthy donors and can be readily available, potentially broadening patient access to such treatments.

The ALLO-715 CAR T cells were engineered using a second-generation CAR construct with a novel single chain variable fragment (scFv) that has a high affinity for BCMA. The cells were modified to reduce the risk of graft-versus-host disease and to make them resistant to a lymphodepleting agent. In vitro tests showed that these cells expanded robustly and maintained a phenotype that is associated with a high proliferative potential.

In long-term killing assays, ALLO-715 cells demonstrated significant expansion and potent cytotoxic activity against target cell lines, without showing signs of exhaustion or reduced activity over an extended period. The efficacy of these cells was also not compromised by high concentrations of soluble BCMA, which can affect other BCMA-specific CARs.

When tested in MM xenograft mouse models, ALLO-715 showed high efficacy at a single dose. The administration of adeno-associated viruses (AAV) to express human IL-7 and IL-15 further enhanced the expansion and antitumor activity of the CAR T cells.

Tissue cross-reactivity studies revealed that ALLO-715 had a limited expression pattern, with reactivity observed in lymphoid tissues and BCMA-expressing cell lines, but not in other tissues.

Manufacturing of BCMA CAR T cells was conducted using a proprietary process that preserved cell expansion, viability, phenotype, and in vivo antitumor efficacy.

The findings suggest that ALLO-715 could be a promising novel therapy for MM and other BCMA-positive cancers. The disclosures indicate that several authors are affiliated with companies involved in the development and production of CAR T cell therapies.