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All-in-one for myeloma: a single therapy to combine CAR T cells and bispecific antibodies to engage both innate and adaptive immune responses

Jianhua Yu

Jianhua Yu

PhD

Beckman Research Institute of the City of Hope

Project Term: July 1, 2018 - June 30, 2023

This project is designed to develop a novel cell therapy to treat relapse/refractory multiple myeloma (MM), an incurable cancer. We target BCMA, a protein highly expressed on MM compared to normal cells, with CAR T cells that also secrete a bispecific antibody that can engage all cytolytic cells, including various endogenous T cells, natural killer (NK) cells, and NKT cells to kill MM cells. We aim to complete all preclinical studies so that the therapy is ready for future clinical studies.

Lay Abstract

Immunotherapy is emerging as an exciting approach to cancer therapy. My research involves the immunotherapeutic approaches using chimeric antigen receptor (CAR) T cells and bispecific antibodies. CAR T cells are engineered killer T cells imprinted with synthetic receptors that can specifically bind to tumor cells and kill them. Bispecific antibodies are engineered to target two distinct markers, one on immune cells and the other on tumor cells, attracting immune killer cells to the tumor. Both approaches have revolutionized cancer treatment. However, some patients still relapse after treatment with either of these therapies. This may be attributed to the loss of targets on tumor cells and/or the short lifespan of bispecific antibodies after infusion into patients, resulting in lack of continuous tumor eradication and emergence of therapy resistance. In addition, bispecific antibody manufacturing is costly and time-consuming. To overcome the challenges associated with CAR T cell and bispecific antibody therapies, we have created a novel and unique platform to generate CAR T cells that also secrete a soluble bispecific antibody. In this platform, CAR T cells not only attack tumor cells directly but also work as a factory to continuously produce a bispecific antibody in patients. The bispecific antibody manufactured by CAR T cells can engage all immune killer cells in our body with tumor cells so that the former can spot and specifically attack the latter. Our bispecific antibody approach also attracts all killer immune cells, not just the killer T cells, which should greatly enhance the effective immune response against the tumor. One half of the bispecific antibody binds to NKG2D, a surface protein expressed on all immune killer cells while the other half is designed to bind directly to tumor cells. We tested our platform for the treatment of multiple myeloma (MM), where CAR T cells can see a surface protein on the tumor called BCMA, and the secreted bispecific antibody can see another MM surface protein called CS1. This triggers dual targeting of MM by CAR T cells and immune cells that already exist in our body. Therefore, our platform can simultaneously provide two living drugs for patients, CAR T cells and bispecific antibody, each of which can independently launch strong and persistent immune responses against tumor cells. This novel strategy will most likely reduce relapse and avoid the cost and complexities of traditional bispecific antibody manufacturing. With minor modifications, our platform can be used to treat other blood cancers. This strategy may provide better outcomes for patients with myeloma and possibly other blood cancers.

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