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Re: FACT-MASTER post# 72

Friday, 11/18/2022 9:11:01 PM

Friday, November 18, 2022 9:11:01 PM

Post# of 92
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COL-ing out TCR-Ts
Adoptive T cell therapy targeting neoantigens is a promising new therapeutic technique; however, the lack of shared neoantigens across patients limits the use of this technique. To overcome this, Kim et al. identified a shared pan-cancer collagen type VI a-3 (COL6A3) epitope that was presented on tumor stroma and was the result of an alternative splicing event. They created affinity-enhanced T cell receptor T (TCR-T) cells and treated mice in vivo to show regression in tumors that expressed physiological levels of the targeted pHLA without toxicity to normal cells. This method represents a promising treatment to target multiple cancer types and warrants further clinical investigation.
T cell receptor (TCR)–based immunotherapy has emerged as a promising therapeutic approach for the treatment of patients with solid cancers. Identifying peptide–human leukocyte antigen (pHLA) complexes highly presented on tumors and rarely expressed on healthy tissue in combination with high-affinity TCRs that when introduced into T cells can redirect T cells to eliminate tumor but not healthy tissue is a key requirement for safe and efficacious TCR-based therapies. To discover promising shared tumor antigens that could be targeted via TCR-based adoptive T cell therapy, we employed population-scale immunopeptidomics using quantitative mass spectrometry across ~1500 tumor and normal tissue samples. We identified an HLA-A*02:01-restricted pan-cancer epitope within the collagen type VI a-3 (COL6A3) gene that is highly presented on tumor stroma across multiple solid cancers due to a tumor-specific alternative splicing event that rarely occurs outside the tumor microenvironment. T cells expressing natural COL6A3-specific TCRs demonstrated only modest activity against cells presenting high copy numbers of COL6A3 pHLAs. One of these TCRs was affinity-enhanced, enabling transduced T cells to specifically eliminate tumors in vivo that expressed similar copy numbers of pHLAs as primary tumor specimens. The enhanced TCR variants exhibited a favorable safety profile with no detectable off-target reactivity, paving the way to initiate clinical trials using COL6A3-specific TCRs to target an array of solid tumors.

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