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Published on: September 10, 2017
Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus
Stefan Barisic1, Elizabeth M Brahmbhatt2, Elena Cherkasova1
1Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
Background:
We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells).
Methods:
We isolated a CD8+ T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells.
Results:
The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8+ T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11+ ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC.
Conclusions:
This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).
Insights
Researchers engineered T cells to target a novel human endogenous retrovirus (CT-RCC HERV-E) found in clear cell renal cell carcinoma (ccRCC). These HERV-E T cells demonstrated potent antitumor activity against ccRCC in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Retrovirus Research
Background:
- A novel human endogenous retrovirus, CT-RCC HERV-E, is selectively expressed in clear cell renal cell carcinoma (ccRCC).
- This retrovirus serves as a source of antigens for T cell-mediated killing of ccRCC cells.
Purpose of the Study:
- To describe the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC.
- To characterize the antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells).
Main Methods:
- Isolated a CD8+ T cell clone recognizing a CT-RCC HERV-E-derived peptide in an HLA-A11-restricted manner.
- Cloned the HERV-E TCR using 5'Rapid Amplification of cDNA Ends (RACE) and generated retrovirus for T cell transduction.
- Characterized HERV-E T cells in vitro and in a murine xenograft model, implementing good manufacturing practice (GMP) for scalable production.
Main Results:
- HERV-E TCR-engineered CD8+ T cells specifically recognized the CT-RCC-1 peptide and exhibited potent antitumor activity against HLA-A11+ ccRCC cells.
- HERV-E T cells induced regression of established ccRCC tumors in mice and improved survival.
- GMP-compliant production of HERV-E T cells from healthy donors retained specific antigen recognition and cytotoxicity.
Conclusions:
- This study is the first to demonstrate selective recognition and killing of human ccRCC cells by TCR-engineered T cells targeting a HERV-derived antigen.
- Preclinical findings support the evaluation of HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC, as initiated in clinical trial NCT03354390.
