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TCR targeting of KRAS G12V/C neoantigens is enhanced by lymphodepleting chemotherapy

ABSTRACT: Lung cancer remains the leading cause of cancer-related deaths worldwide. Immunotherapy agents have doubled treatment response rates in non-small cell lung cancer (NSCLC). However, these responses are neither universal nor consistently durable, underscoring the need for innovative therapeutic strategies. Using a data-driven approach, we identified and characterized an immunogenic neopeptide derived from the KRAS.G12V mutation, prevalent in lung, colon, and pancreatic cancers. We isolated a cognate TCR, T104, which targets and kills cancer cells expressing KRAS G12V. Moreover, TCR-T104 proved to cross-react with the KRAS.G12C neoantigen via a hydrophobic pocket and kill cancer cells expressing this prevalent KRAS mutant. Combining TCR therapy with lymphodepleting chemotherapy using fludarabine and cyclophosphamide resulted in synergistic antitumor effects against multiple neoantigens. HLA-immunopeptidomics revealed that chemotherapy modulates the cell immunopeptidome and enhances target peptide presentation, likely through immunoproteasome activation and HLA-I elevation. These findings suggest a new mechanism explaining the combined efficacy of chemotherapy and immunotherapy.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): B Cell, Melanocyte, Epithelial Cell, Cell Culture, Blood

DISEASE(S): Colon Cancer,Lung Non-squamous Non-small Cell Carcinoma,Pancreatic Ductal Adenocarcinoma,Skin Melanoma

SUBMITTER: Shira Sagie

LAB HEAD: Yardena Samuels

PROVIDER: PXD061178 | Pride | 2025-10-03

REPOSITORIES: Pride

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			Action	DRS
	QEP2_12889_YSA_895_1_101220.raw	Raw
	QEP2_13617_YSA_952_1_180421.raw	Raw
	QEP2_13770_YSA_1005_1_250421.raw	Raw
	TTU_YS_21571_1928_418p_PRM_6-9-2024_482.d.zip	Other
	TTU_YS_21571_1929_418p_PRM_6-9-2024_483.d.zip	Other

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Project description:Background Clinical success of T cell receptor (TCR) gene therapy has previously been demonstrated for NY-ESO-1 TCR gene therapy. To increase numbers of cancer patients that can be treated with TCR gene therapy we aimed to identify a novel set of high-affinity cancer specific TCRs targeting different cancer testis (CT) antigens in prevalent HLA class I alleles. Methods In this study, we selected based on publicly available gene expression databases the most promising CT genes to target. From these selected genes we identified by HLA peptidomics the naturally processed and presented HLA class I peptides. With these peptide-HLA tetramers were generated, and by single cell sorting CT specific CD8+ T cells were selected, and expanded from the allo-HLA repertoire of healthy donors. By several functional assays high avidity CT-specific T cell clones with safe recognition pattern were selected. To evaluate the potential for clinical application in TCR gene therapy, TCRs were sequenced and transferred into peripheral blood derived CD8+ T cells. Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 in the context of human leukocyte antigen(HLA) -A1, -A2, -A3, -B7, -B35 and -C7. TCR gene transfer into CD8⁺ T cells resulted in efficient cytokine production and cytotoxicity of variety of different tumor types without detectable cross-reactivity. In addition, major in vivo antitumor effects of MAGE-A1 specific TCR engineered CD8⁺ T cells was observed in an orthotopic xenograft model for established multiple myeloma, in which bone marrow located tumor cells were completely eradicated after T cell injection. Conclusion The identification of 7 novel CT-specific TCRs, reactive against CT antigens presented in a variety of different HLA class I alleles, allows selection of therapeutic TCRs for an increased number of cancer patients, and will improve development of personalized TCR gene therapy.

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TCR targeting of KRAS G12V/C neoantigens is enhanced by lymphodepleting chemotherapy

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