Dillard et al. reported on the isolation and preclinical efficacy of novel hTERT-specific CD4+ T cell-derived TCR (Radium-4) from a clinically responding pancreatic cancer patient vaccinated with a long hTERT peptide. Radium-4 TCR-expressing CD4+ and CD8+ T cells recognized hTERT in the context of HLA-DP04 and HLA-DP03, produced inflammatory cytokines and demonstrated cytotoxicity against melanoma cell lines engineered to present TERT peptides grown in 2D and 3D cultures. Radium-4 TCR-transduced T cells reduced tumor growth and prolonged survival in melanoma xenograft models and lacked cytotoxicity against hematopoietic stem cells.
Contributed by Shishir Pant
ABSTRACT: T cell receptor (TCR)-engineered T cell therapy is a promising cancer treatment approach. Human telomerase reverse transcriptase (hTERT) is overexpressed in the majority of tumors and a potential target for adoptive cell therapy. We isolated a novel hTERT-specific TCR sequence, named Radium-4, from a clinically responding pancreatic cancer patient vaccinated with a long hTERT peptide. Radium-4 TCR-redirected primary CD4+ and CD8+ T cells demonstrated in vitro efficacy, producing inflammatory cytokines and killing hTERT+ melanoma cells in both 2D and 3D settings, as well as malignant, patient-derived ascites cells. Importantly, T cells expressing Radium-4 TCR displayed no toxicity against bone marrow stem cells or mature hematopoietic cells. Notably, Radium-4 TCR+ T cells also significantly reduced tumor growth and improved survival in a xenograft mouse model. Since hTERT is a universal cancer antigen, and the very frequently expressed HLA class II molecules presenting the hTERT peptide to this TCR provide a very high (>75%) population coverage, this TCR represents an attractive candidate for immunotherapy of solid tumors.
Author Info: (1) Department of Cellular Therapy, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. (2) Department of Radiation Biology, Institute for Cancer Research, O
Author Info: (1) Department of Cellular Therapy, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. (2) Department of Radiation Biology, Institute for Cancer Research, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. (3) Department of Tumor Biology, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. (4) Department of Pathology, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. (5) Department of Cancer Immunology, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. (6) Department of Cellular Therapy, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. Electronic address: sebastw@rr-research.no. (7) Department of Cellular Therapy, Oslo University Hospital-The Norwegian Radium Hospital, 0379 Oslo, Norway. Electronic address: elsin@rr-research.no.
