Aiming to avoid allogeneic CAR-T rejection, Zhang and Li et al. found that a CD70 CAR depleted donor-mismatched, activated (CD70+) T and NK cells in coculture. Dual CD19/CD70 CAR T cells responded to CD19+ tumor cells comparably to single CD19 CAR-T, but also recognized CD70+ target cells and protected against allo-mediated killing. Dual CD19-CD70 CAR T cells transiently eliminated B cells in CD34-humanized mice, and depleted B cells and autoantibodies in lupus PBMC-humanized mice, with superior persistence of CD19 CAR-T cells, without lymphodepletion. CD70 CAR variants were optimized for expression and functionality.
Contributed by Alex Najibi
ABSTRACT: Chimeric antigen receptor (CAR) T cells can achieve sustained clinical benefit in B cell malignancies and autoimmune diseases. Despite the many potential advantages over autologous products, allogeneic CAR T cells carry a higher risk of rejection, which may limit persistence and therapeutic efficacy. We report the design and evaluation of an optimized CD70 CAR that prevents rejection of allogeneic CAR T cells by targeting activated alloreactive lymphocytes. Co-expression of this CD70 CAR with a CD19 CAR resulted in sustained CAR T cell persistence in the presence of alloreactive lymphocytes and prolonged antitumor activity in a CD19 antigen escape model. In vivo, CD19/CD70 dual CAR T cells eliminated B cells and CD70(+) T cells derived from patients with systemic lupus erythematosus in humanized mouse models, resulting in reduced immunoglobulin production. An allogeneic CD19/CD70 dual CAR T cell therapy may therefore broaden clinical applicability while enabling the use of less intensive lymphodepleting conditioning regimens prior to CAR T cell infusion.
Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA,
Author Info: (1) Allogene Therapeutics Inc., South San Francisco, CA, USA. (2) Allogene Therapeutics Inc., South San Francisco, CA, USA. (3) Allogene Therapeutics Inc., South San Francisco, CA, USA. (4) Allogene Therapeutics Inc., South San Francisco, CA, USA. (5) Allogene Therapeutics Inc., South San Francisco, CA, USA. (6) Allogene Therapeutics Inc., South San Francisco, CA, USA. (7) Allogene Therapeutics Inc., South San Francisco, CA, USA. (8) Allogene Therapeutics Inc., South San Francisco, CA, USA. (9) Allogene Therapeutics Inc., South San Francisco, CA, USA. (10) Allogene Therapeutics Inc., South San Francisco, CA, USA. (11) Allogene Therapeutics Inc., South San Francisco, CA, USA. cesar.sommer@allogene.com. (12) Allogene Therapeutics Inc., South San Francisco, CA, USA. elvin.lauron@allogene.com.
