Cell therapies for cancer: CAR-Ts in development
Chimeric Antigen Receptor (CAR) T-cell therapy has hit the headlines with impressive clinical responses in hematologic B-cell malignancies that have led to the successful licensing of two products that both target CD19. Anti-BCMA CAR T-cell therapies for myeloma might come next but there is a dearth of targets outside of the B-cell malignancy space.
Celyad has been exploring the potential of Natural Killer cell receptors to target cancer. Specifically, the company is conducting a series of clinical trials testing the safety and efficacy of CAR-T cells bearing the Natural Killer Group 2D (NKG2D) receptor that has the ability to specifically bind eight stressed induced ligands found on a broad range of cancers, yet largely absent from the surface of non-malignant, healthy cells.
The first trial involved giving multiple infusions of autologous NKG2D-based CAR-T cells without pre-conditioning chemotherapy and provided some initial evidence of clinical activity with a good safety profile. Further clinical activity has tested this CAR-T approach with pre-conditioning and standard of care chemotherapy in hematological and solid tumors. Results of these trials and of the company’s trial of allogeneic NKG2D-based CAR T cell therapy will be reviewed; the latter being thought to be the first allogeneic CAR-T approach to be tested in the solid cancers.
Aside from NKG2D focused studies, the company is also embarking on a broader allogeneic CAR T cell platform technology exploiting interfering RNA to control graft versus host disease, the primary limitation of using allogeneic cells for therapy.
Taken together, these early clinical studies suggest that the NKG2D receptor in both autologous and allogeneic approaches could provide the potential to target a broad range of tumor targeting that could follow the success of CD19 and BCMA CAR T cell therapy. The challenges ahead relate to how to exploit the targeting ability of NKG2D. Some of the next steps including manipulating the memory phenotype of the CAR T cell product will be discussed.