UCLA researchers from the Department of Microbiology, Immunology, and Molecular Genetics and Stanford researchers from the Department of Molecular and Cellular Physiology have developed novel enhanced T cell receptors engineered to specifically recognize prostatic acid phosphatase, offering a powerful and precise immunotherapeutic strategy for prostate cancer.
BACKGROUND: Prostate cancer is a leading cause of cancer-related death among men, with limited effective treatment options for advanced or recurrent disease. Prostatic acid phosphatase (PAP) is a well-recognized prostate cancer antigen whose elevated serum levels correlate with disease progression and poor prognosis. Thus, PAP is an ideal target for cell-mediated immunotherapy. However, targeting PAP can be challenging because it is expressed in normal prostate tissue. As a result, high-affinity PAP-reactive T cells are likely eliminated during thymic negative selection. As a result, natural PAP-specific T cell receptors (TCRs) are generally of low potency and fail to mount strong cytotoxic responses against tumor cells. A potent cytotoxic PAP-specific TCR would thus provide a promising therapeutic path for prostate cancer.
INNOVATION: The lab of UCLA Professor Owen Witte and the lab of Stanford Professor Chris Garcia have utilized a novel “TCR turbo charging” platform to introduce a “catch bond” mechanism that prolongs the interaction between the TCR and major histocompatibility complex (pMHC). By prolonging TCR-pMHC interactions under force, T cell cytotoxicity is enhanced without compromising specificity. Researchers used this platform to build upon a naturally isolated, but weak PAP-specific TCR to develop two variants TCRs. These variants exhibit superior cytotoxicity in vitro and in vivo against prostate cancer cell lines, prolonged bond lifetimes, minimal structural alteration, and enhanced specificity. Thus, these enhanced TCRs represent a promising immunotherapy with the potential to selectively eliminate PAP-expressing cancer cells while minimizing off-target toxicity.
POTENTIAL APPLICATIONS:
- Adoptive T cell therapies for prostate cancer
- Development of PAP-specific immunotherapies with improved potency and safety profiles
- Utilization of the TCR turbo charging platform to engineer catch bond TCRs for other tumor antigens
ADVANTAGES:
- Novel catch bond TCR technology enhances TCR-pMHC bond lifetime
- Demonstrates superior tumor killing both in vitro and in vivo clinical models
- Specificity has been validated through multiple approaches
- Highly translatable – initial TCR derived from human donor, suggesting this can be optimized for clinical use
DEVELOPMENT-TO-DATE: UCLA and Stanford researchers have engineered two TCR variants that exhibit superior cytotoxicity against prostate cancer cells lines both in vitro and in vivo.
Related Papers (from the inventors only)
Mao Z, Nesterenko PA, McLaughlin J, Deng W, Burton Sojo G, Cheng D, Noguchi M, Chour W, DeLucia DC, Finton KA, Qin Y, Obusan MB, Tran W, Wang L, Bangayan NJ, Ta L, Chen CC, Seet CS, Crooks GM, Phillips JW, Heath JR, Strong RK, Lee JK, Wohlschlegel JA, Witte ON. Physical and in silico immunopeptidomic profiling of a cancer antigen prostatic acid phosphatase reveals targets enabling TCR isolation. Proc Natl Acad Sci U S A. 2022 Aug 2;119(31):e2203410119. doi: 10.1073/pnas.2203410119. Epub 2022 Jul 25. PMID: 35878026; PMCID: PMC9351518.
Keywords: immunotherapy, T cell receptor, MHC, TCR-MHC interaction, catch bond, cytotoxicity, specificity, prostate cancer, prostatic acid phosphatase, cell-mediated therapy, toxicity