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- W2896874054 abstract "Background: Our team isolated cytotoxic T lymphocyte (CTL) lines from a patient who had sustained mccRCC regression after an allogeneic transplant that showed specific killing of ccRCC. Utilizing these CTL and cDNA expression cloning, we discovered: transcripts encoding antigens targeted by these CTL were derived from a novel human endogenous retrovirus (HERV-E); selective HERV-E expression was present in most ccRCC tumors but not in normal tissues and VHL inactivation lead to transcription of HERV-E in ccRCC. Using HERV-E reactive CTL, we cloned a TCR that recognizes a HERV-E HLA-A11 restricted peptide (CT-RCC-1) into a retroviral vector containing a truncated CD34 cassette for enrichment of transduced cells. Transduced T cells acquired selective killing of HLA-A11+ ccRCC cells. A GMP method to manufacture enriched HERV-E TCR T cells was developed that incorporated cytokine stimulation of PBMCs followed by CD4+ depletion, T cell transduction, CD34 enrichment & ex vivo expansion. A scale up of this manufacturing process in 3 healthy donors showed transduced T cells: > 90% CD34+ and had > 90% CT-RCC-1 tetramer specificity. When co-cultured with HERV-E+ ccRCC cells, T cells secreted high levels of IFN-y and killed ccRCC cells (Table). Trial design: Phase 1 (3 + 3 design) cell dose-escalation study (1 x 106, 5 x 106, 1 x 107 and 5 x 107 cells/kg) to determine the MTD of HERV-E TCR T cells in mccRCC. Pts first receive cyclophosphamide and fludarabine conditioning, followed by single infusion of HERV-E TCR T cells & moderate-dose IL-2. Eligibility criteria: histologically-confirmed ccRCC, progressive disease and 2 prior lines of therapy. Primary endpoint: safety by day 21. Adverse events assessed using CTCAEv5. Biomarker objectives: persistence of HERV-E TCR T cells in blood, T cell lineage/functionality of these cells over time; cytokine profiles & HERV-E expression and presence of HERV-E TCR T cells in tumor tissue.Table: 924TiPHERV-E TCR T cells (n = 3 donors)MethodCell number after ex vivo expansion (range)7.55 x 108 (1.34 x 108- 6.34 x 109)Cellometer- basedCD34+, % (range)96.4 (96.1-96.8)FlowCT-RCC-1 tetramer+, % (range)93.2 (91.3-94.5)FlowTumor Specific lysis, % (SD)46 ± 8.5LDH assayIFN-y secretion, pg/ml (range)1635 (1555-1750)ELISA Open table in a new tab Clinical trial identification: NCT03354390. Legal entity responsible for the study: National Heart, Lung, and Blood Institute. Funding: National Institutes of Health. Disclosure: All authors have declared no conflicts of interest." @default.
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- W2896874054 date "2018-10-01" @default.
- W2896874054 modified "2023-10-14" @default.
- W2896874054 title "A phase I study of HERV-E TCR transduced autologous T Cells (HERV-E TCR T Cells) in patients (pts) with metastatic clear cell renal cell carcinoma (mccRCC)" @default.
- W2896874054 doi "https://doi.org/10.1093/annonc/mdy283.133" @default.
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