(1) Barisic S (2) Brahmbhatt EM (3) Cherkasova E (4) Spear TT (5) Savani U (6) Pierre S (7) Scurti GM (8) Chen L (9) Igboko M (10) Nadal R (11) Zeng G (12) Parry G (13) Stroncek DF (14) Highfill S (15) Dalheim AV (16) Reger R (17) Nishimura MI (18) Childs RW

Journal for immunotherapy of cancer

Barisic et al. cloned the TCR of a CD8+ T cell clone from a patient with clear cell renal cell carcinoma (ccRCC) whose tumor regressed after allogeneic stem cell transplant. This TCR recognized an HLA-A11-restricted human endogenous retroviral E region-derived (HERV-E) peptide selectively expressed by most ccRCCs. TCR-transduced T cells (HERV-E T cells) were generated and shown to predominantly express CD8+ TEM cell markers, lyse HLA-A11+ HERV-E+ ccRCCs in vitro, and induce regression of established ccRCC tumors in a xenograft model. A GMP method for large-scale HERV-E T cell production was developed.

Contributed by Paula Hochman

BACKGROUND: We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells). METHODS: We isolated a CD8(+) T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells. RESULTS: The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8(+) T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11(+) ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC. CONCLUSIONS: This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).

Author Info: (1) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Mar

Author Info: (1) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (2) Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA. (3) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (4) Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA. (5) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (6) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (7) Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA. (8) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (9) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (10) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (11) T-Cure BioScience, Sherman Oaks, California, USA. (12) T-Cure BioScience, Sherman Oaks, California, USA. (13) Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. (14) Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA. (15) Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA. (16) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA. (17) Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA. (18) Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA childsr@nhlbi.nih.gov.

Citation: J Immunother Cancer 2024 Sep 11 12: Epub09/11/2024

Link to PUBMED: http://www.ncbi.nlm.nih.gov/pubmed/39266213

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