Abstract 2956
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: 924TiP
| HERV-E TCR T cells (n = 3 donors) | Method | |
|---|---|---|
| Cell number after ex vivo expansion (range) | 7.55 x 108 (1.34 x 108- 6.34 x 109) | Cellometer- based |
| CD34+, % (range) | 96.4 (96.1-96.8) | Flow |
| CT-RCC-1 tetramer+, % (range) | 93.2 (91.3-94.5) | Flow |
| Tumor Specific lysis, % (SD) | 46 ± 8.5 | LDH assay |
| IFN-y secretion, pg/ml (range) | 1635 (1555-1750) | ELISA |
Clinical trial identification
NCT03354390.
Legal entity responsible for the study
National Heart, Lung, and Blood Institute.
Funding
National Institutes of Health.
Editorial Acknowledgement
Disclosure
All authors have declared no conflicts of interest.
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