{ "abstract": "Background Our research identified ERVE-4, an endogenous retrovirus (ERV) with tumor-restricted expression in the majority of clear cell RCC (ccRCC). 1 ERVE-4 is regulated by hypoxia inducible factor (HIF) and encodes antigens including the HLA A11 restricted peptide CT-RCC-1.2 3 We cloned a T-cell receptor (TCR) targeting CT-RCC-1, demonstrating that transduced human T-cells (ERVE-4 T-cells) can kill ccRCC cells in vitro and in a murine xenograft model.4 This led to the design of a phase I clinical trial to evaluate the safety of adoptive autologous ERVE-4 T-cell therapy in patients with metastatic ccRCC.Methods Fifteen patients received escalating doses of ERVE-4 T-cells (1, 5, 10, and 50 x 10^6 cells/kg) in a 3+3 design. TCR cell products were derived from 15-liter apheresis collections, from which PBMCs were stimulated with cytokines, CD4-depleted, and transduced using a retroviral construct encoding ERVE-4 TCR α/β chains and truncated CD34 for purification. ERVE-4 T-cells underwent CD34 immunomagnetic bead selection and were expanded ex vivo over 21 days with allogeneic feeders and rhIL-2/rhIL-15. Multiparameter flow cytometry was used to profile ERVE-4 T-cell products, focusing on stem cell memory (Tscm), central memory (Tcm), effector memory (Tem), and effector (Teff) populations, along with markers of T cell activation and exhaustion such as PD-1, TIM-3, CTLA-4, LAG-3, CD39, CD25, CD69, IL-7R, and CD57.Results Of the 15 patients treated, no grade 3 or 4 toxicities were observed. Disease control was achieved in 33% of patients, with one partial remission and four cases of stable disease lasting at least eight weeks. Phenotypic analysis of ERVE-4 T-cell products showed a predominance of CD8 + T cells (mean 97%, range 87.3-99.7) and a limited presence of CD4+ T cells (mean 0.45%, range 0.01-1.7). The proportion of TCR-transduced T cells (CD34+) varied from 25% to 80%. Within the CD8+CD34+ compartment, most cells exhibited a Tem phenotype (mean 67.2%, range 29.6-91.6), with lower Tcm (mean 9.2%, range 2.5-15.6) and minimal Tscm (mean 3.7%, range 0.3-13.9) (Figures 1 and 2).Conclusions This first-in-human phase I trial targeting an ERV-derived tumor antigen in ccRCC demonstrated the safety and preliminary efficacy of adoptively infused ERVE-4 T-cells. The low clinical response rate and limited persistence of ERVE-4 T-cells in vivo may be due to low Tscm and Tcm frequencies in the T-cell product. To increase these phenotypes, we are evaluating multiple modifications to the ERVE-4 TCR manufacturing process, including the incorporation of IL-7 and reducing the overall culture duration.References Takahashi Y, Harashima N, Kajigaya S, et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest. Mar 2008;118(3):1099-109.Cherkasova E, Malinzak E, Rao S, et al. Inactivation of the von hippel-lindau tumor suppressor leads to selective expression of a human endogenous retrovirus in kidney cancer. Oncogene. Nov 24 2011;30(47):4697–706. doi:10.1038/onc.2011.179Jiang Q, Braun DA, Clauser KR, et al. HIF regulates multiple translated endogenous retroviruses: Implications for cancer immunotherapy. Cell. Apr 3 2025;188(7):1807–1827 e34. doi:10.1016/j.cell.2025.01.046Barisic S, Brahmbhatt EM, Cherkasova E, et al. Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus. J Immunother Cancer. Sep 11 2024;12(9)doi:10.1136/jitc-2024–009147Abstract 506 Figure 1Flow cytometric analysis of ERVE-4 T cells showed that transduced T cells (CD8+/CD34+) were predominantly effector memory (Tem) cells, with low levels of central memory (Tcm) cells and minimal to no stem cell memory (Tscm) cellsAbstract 506 Figure 2Expression of multiple exhaustion markers in CD3+ T cells within ERVE-4 T-cell products", "authors": [ { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA", "University of Washington/Fred Hutchinson Cancer Center, Seattle, WA, USA" ], "name": "Rosa Nadal Rios" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Lipei Shao" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA", "Duke University, Durham, NC, USA" ], "name": "Stefan Barisic" }, { "affiliations": [ "Loyola University Medical Center, Maywood, IL, USA" ], "name": "Gina Scurti" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Elena Cherkasova" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Long Chen" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Steven Highfill" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Yihua Cai" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Michaela Prochazkova" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Kyu Lee Han" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Ping Jin" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "David F Stroncek" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Xin Tian" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Robert Reger" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Jamie L Diemer" }, { "affiliations": [ "Loyola University Medical Center, Maywood, IL, USA" ], "name": "Michael Nishimura" }, { "affiliations": [ "National Institutes of Health, Bethesda, MD, USA" ], "name": "Richard W Childs" } ], "title": "506 Immune cell composition analysis of ERVE-4 T-Cell receptor gene therapy infusion products in metastatic ccRCC: insights from a first-in-human trial", "uid": "3533f854-21dc-5a81-83d1-31c17686f34c" }