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| Item Type: | Article |
|---|---|
| Title: | Eradication of large solid tumors by gene therapy with a T cell receptor targeting a single cancer-specific point mutation |
| Creators Name: | Leisegang, M., Engels, B., Schreiber, K., Yew, P.Y., Kiyotani, K., Idel, C., Arina, A., Duraiswamy, J., Weichselbaum, R.R., Uckert, W., Nakamura, Y. and Schreiber, H. |
| Abstract: | PURPOSE: Cancers usually contain multiple unique tumor-specific antigens produced by single amino acid substitutions (AAS) and encoded by somatic non-synonymous single nucleotide substitutions. We determined whether adoptively transferred T cells can reject large, well-established solid tumors when engineered to express a single type of T cell receptor (TCR) that is specific for a single AAS. EXPERIMENTAL DESIGN: By exome and RNA sequencing of an UV-induced tumor, we identified an AAS in p68 (mp68), a co-activator of p53. This AAS seemed to be an ideal tumor-specific neoepitope because it is encoded by a trunk mutation in the primary autochthonous cancer and binds with highest affinity to the MHC. A high-avidity mp68-specific TCR was used to genetically engineer T cells as well as to generate TCR-transgenic mice for adoptive therapy. RESULTS: When the neoepitope was expressed at high levels and by all cancer cells, their direct recognition sufficed to destroy intra-tumor vessels and eradicate large, long-established solid tumors. When the neoepitope was targeted as autochthonous antigen, T cells caused cancer regression followed by escape of antigen-negative variants. Escape could be thwarted by expressing the antigen at increased levels in all cancer cells or by combining T cell therapy with local irradiation. Therapeutic efficacies of TCR-transduced and TCR-transgenic T cells were similar. CONCLUSIONS: Gene therapy with a single TCR targeting a single AAS can eradicate large established cancer but a uniform expression and/or sufficient levels of the targeted neoepitope or additional therapy are required to overcome tumor escape. |
| Keywords: | T Cell Receptor (TCR), Tumor-Specific Single Amino Acid Substitution (AAS), Adoptive T Cell Therapy (ATT), Tumor Heterogeneity, Tumor Escape, Animals, Mice |
| Source: | Clinical Cancer Research |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Volume: | 22 |
| Number: | 11 |
| Page Range: | 2734-2743 |
| Date: | 1 June 2016 |
| Official Publication: | https://doi.org/10.1158/1078-0432.CCR-15-2361 |
| PubMed: | View item in PubMed |
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