Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, NHLBI, NIH, Bethesda, MD
Rosa Nadal , Stefan Barisic , Gina M. Scurti , Elena Cherkasova , Long Chen , Kristen Wood , Steven L. Highfill , Brian Wells , Georg Aue , Reem Shalabi , Thomas E. Hughes , Xin Tian , Yifei Xu , Ashkan A. Malayeri , Mohammadhadi H. Bagheri , Robert N. Reger , Michael I. Nishimura , Richard W. Childs
Background: The CT-RCC HERV-E is expressed in the majority of ccRCC tumors with no expression in normal tissues. T-cells transduced to express a HERV-E TCR are cytotoxic to ccRCC & mediate tumor regression of human ccRCC in a murine model. We developed a method to manufacture HERV-E TCR transduced T-cells (HERV-E TCR) for clinical development. Methods: We conducted a phase I dose-escalation trial (DL1:1x106, DL2:5x106, DL3:1x107& DL4:5x107cells/kg) to evaluate the safety of adoptively infused HERV-E TCR in mccRCC pts. HERV-E TCR contain T-cells engineered to express an HLA-A*11 restricted HERV-E TCR and a truncated CD34 cassette for in vivo monitoring. Eligible HLA-A*11 pts had mccRCC, ECOG 0-1 & prior antiangiogenic & checkpoint inhibitors therapy unless contraindicated/unavailable. Cyclophosphamide & fludarabine were given followed by HERV-E TCR infusion & IL-2 administration. Results: 14 HLA-A*11+ pts (median age 56) were treated including 3 pts in each DLs 1-3 & 5 pts in DL4. 86% had ≥ 3 prior treatment lines (range 1-7): 36% had high-dose IL2, 57% Ipilimumab-Nivolumab & 50% ≥ 3 lines of anti-VEGFR therapy. Bone, liver & brain metastases were present in 71%, 43%, and 14% of pts. All HERV-E TCR products met sterility, purity, and potency criteria for release and infusion (Table). No HERV-E TCR dose-limiting toxicities or treatment-related deaths occurred. Pts received a mean: 12 IL-2 doses (IQR 11-14). 57% pts had G3-4 febrile neutropenia & 7% G3-4 capillary leak syndrome. 1 pt experienced G2 skin rash possibly related to HERV-E TCR. Best response included 7% pts with partial response & 29% with stable disease ≥ 8 weeks. The mPFS: 62 days (IQR 31,90). At DL4, TCR transgene expression was detectable in PBMCs at a mean 6.3% (range (r) 0.02-25), 12.3% (r 0.01-61.2), 3.45% (r 0.00-13.7) & 2.89% (r 0.00-11.5) on days 4, 7, 14, & 21. HERV-E TCR were detected in the malignant pleural effusion of 1 pt. Conclusions: This is the first trial evaluating TCR-engineered T-cells targeting a human endogenous retrovirus in ccRCC. The manufacturing method utilized produced large numbers of highly purified CD8+ HERV-E reactive T-cells that were not associated with any dose limiting toxicities when given at doses up to 5x107 cells/kg. For pts in DL4, HERV-E TCR were observed to proliferate in vivo, traffic to a metastatic site, and induce tumor regression in one mccRCC pts. Clinical trial information: NCT03354390.
DL | Cell Viability (%) | CD34 + T Cells (%) | CD8+ T Cells (%) | CD8+/ CD34+ T cells (%) | Vector Copy # (D10) | INF-g Release Assay |
---|---|---|---|---|---|---|
Release Criteria | > 70% | > 25% | > 80% | > 25% | < 5 copies/cell | 2 x over background |
Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | Median (IQR) | - | |
DL1 | 94.6 (1.6) | 86.7 (7.7) | 99 (2.8) | 84.2 (10.9) | 1.9 (0.6) | + |
DL2 | 90.2 (4.8) | 90.6 (4.5) | 95.4 (6.5) | 87.9 (2.7) | 1.9 (0.5) | + |
DL3 | 88 (4.5) | 93.4 (4.5) | 99 (0.4) | 91.8 (3.7) | 2.3 (0) | + |
DL4 | 95 (1.7) | 90.3 (3.7) | 98.5 (0.3) | 90 (3.8) | 2 (0.4) | + |
All | 94.6 (5.7) | 90.4 (7.2) | 98.6 (1.7) | 89.6 (7.2) | 2 (0.6) | + |
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Abstract Disclosures
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First Author: Rosa Nadal
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