Related Experiment Videos
Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor
John Maher1, Renier J Brentjens, Gertrude Gunset
1Department of Human Genetics/Medicine, Gene Transfer and Somatic Cell Engineering Laboratory, and Immunology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Abstract:
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-zeta (TCRzeta), 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.
Insights
Engineered T lymphocytes targeting prostate-specific membrane antigen (PSMA) with novel fusion receptors effectively kill cancer cells. These modified cells also proliferate and produce IL-2, enhancing adoptive immunotherapy potential.
Area of Science:
- Immunology
- Cancer Biology
- Biotechnology
Background:
- Current artificial receptors for T cell targeting have limitations.
- Existing receptors provide only activation or co-stimulatory signals, restricting cellular functions.
Purpose of the Study:
- To develop and evaluate fusion receptors for enhanced T cell-mediated cancer immunotherapy.
- To investigate the efficacy of T cells engineered with combined TCR-zeta and CD28 signaling elements against prostate-specific membrane antigen (PSMA)-expressing tumors.
Main Methods:
- Retroviral transduction of human primary T lymphocytes with fusion receptors targeting PSMA.
- Assessment of tumor cell lysis, T cell proliferation, and cytokine production (IL-2) upon stimulation.
Main Results:
- Engineered T cells effectively lysed PSMA-expressing tumor cells.
- Transduced lymphocytes exhibited robust proliferation (over 2 logs in 3 weeks) and significant IL-2 production.
- Amplified T cell populations maintained antigen-specific cytolytic activity.
Conclusions:
- Fusion receptors combining TCR-zeta and CD28 signaling moieties effectively redirect and amplify human T cell responses.
- This approach holds significant promise for adoptive immunotherapy, particularly for cancers with compromised antigen presentation or co-stimulatory molecule expression.