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Final results of a phase I trial of HERV-E TCR transduced T cells for the treatment of HLA-A*11 patients with metastatic clear cell renal cell carcinoma (mccRCC).

医学 肾细胞癌 T细胞受体 人类白细胞抗原 肿瘤科 癌症研究 内科学 细胞 T细胞 病理 免疫学 免疫系统 抗原 生物 遗传学
作者
Rosa Nadal,Stefan Barisic,Gina Scurti,Elena Cherkasova,Guolin Chen,Katherine Wood,Steven L. Highfill,Brian Wells,Georg Aue,Reem Shalabi,Thomas E. Hughes,Xin Tian,Yifei Xu,Ashkan A. Malayeri,Robert Reger,Michael I. Nishimura,Richard W. Childs
出处
期刊:Journal of Clinical Oncology [American Society of Clinical Oncology]
卷期号:42 (4_suppl): 435-435
标识
DOI:10.1200/jco.2024.42.4_suppl.435
摘要

435 Background: Human endogenous retrovirus type E (HERV-E) is specifically expressed in ccRCC providing a safe target for T cell-based therapies. We investigated T cells transduced with a TCR targeting HERV-E (HERV-E T cells) for the treatment of mccRCC. Methods: This first-in-human study assessed the safety & efficacy of escalating doses of HERV-E T cells and manufacturing/clinical endpoints correlative analysis. HLA-A*11+ mccRCC patients (pts) were treated with a conditioning regimen, infusion of HERV-E T cells & IL-2. (NCT03354390). Results: Nineteen of185 pts tested were found to express HLA-A*11. 17 HLA-A*11 + pts enrolled on the study: 3 pts on each DL1-3 & 6 pts on DL4. 2 pts did not receive HERV-E T cells given disease progression during manufacturing period. Median age was 57 years. 86% received ≥ 3 prior systemic treatment (range 1-8). The manufacturing failure rate after first apheresis was 12% (n=2); both met target dose after second apheresis and repeat in vitro expansion. All HERV-E T cell products met release criteria for infusion including INF-γ production in response to HERV-E/HLA-A11-expressing tumor cells. Median HERV-E vector copy number (VCN) was 1.9. No dose-limiting toxicities (DLT), off-target toxicities or treatment-related deaths occurred. Pt#17 is on DLT monitoring period. 7 pts completed the planned 14 doses of IL-2 and all received at least 8 doses. Reasons for IL-2 discontinuation: hemodynamic (57%), cardiovascular (28%), pulmonary (28%), renal (14%) criteria & pts decision (14%). The best response was partial response in 7% & stable disease at least 8 weeks in 29% pts. HERV-E mRNA expression was detected in 5 primary & 9 metastatic specimens. HERV-E T cells were measurable in circulation post-dosing, with peak concentrations in the peripheral blood mononuclear compartment on day(D)+7. [DL1: 0.3 %, DL2: 1.2%, DL3: 0.5%, DL4: 12.3%]. Median HERV-E T cell VCN showed no correlation with HERV-E T cells peak concentration on D+4 & D+7. Conclusions: Proof of concept that HERV-T cells can induce tumor regression without evidence of causing off-target toxicities has been established by this trial. Infused HERV-E T cells were detectable transiently in vivo and induce effector cytokine production. Our initial results support the further development of HERV-E-directed therapies that focus on methods to improve in vivo persistence of TCR engineered T-cells and to target HERV-E antigens expressed on more commonly expressed HLA alleles.[Table: see text]
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