Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCR /CD28 receptor
John Maher, Renier J. Brentjens, Gertrude Gunset, Isabelle Rivière
& Michel Sadelain
Department of Human Genetics/Medicine, Gene Transfer and Somatic Cell Engineering Laboratory, and Immunology Program, Memorial Sloan−Kettering Cancer Center, New York, NY 10021.
Artificial receptors provide a promising approach to target T lymphocytes to tumor antigens. However, the receptors described thus far produce either an activation or a co-stimulatory signal alone, thus limiting the spectrum of functions accomplished by the genetically modified cells. Here we show that human primary T lymphocytes expressing fusion receptors directed to prostate-specific membrane antigen (PSMA) and containing combined T-cell receptor- (TCR), and CD28 signaling elements, effectively lyse tumor cells expressing PSMA. When stimulated by cell-surface PSMA, retrovirally transduced lymphocytes undergo robust proliferation, expanding by more than 2 logs in three weeks, and produce large amounts of interleukin-2 (IL-2). Importantly, the amplified cell populations retain their antigen-specific cytolytic activity. These data demonstrate that fusion receptors containing both TCR and CD28 signaling moieties are potent molecules able to redirect and amplify human T-cell responses. These findings have important implications for adoptive immunotherapy of cancer, especially in the context of tumor cells that fail to express major histocompatibility complex antigens and co-stimulatory molecules.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
/CD28 receptor
(TCR
