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| Item Type: | Article |
|---|---|
| Title: | T-cell receptor gene-modified T cells with shared renal cell carcinoma specificity for adoptive T-cell therapy |
| Creators Name: | Leisegang, M. and Turqueti-Neves, A. and Engels, B. and Blankenstein, T. and Schendel, D.J. and Uckert, W. and Noessner, E. |
| Abstract: | PURPOSE: Adoptive therapy with genetically engineered T cells carrying redirected antigen specificity is a new option for the treatment of cancer. This approach is not yet available for metastatic renal cell carcinoma (RCC), due to the scarcity of therapeutically useful reagents. We analyzed tumor-infiltrating lymphocytes (TIL) from RCC to identify T-cell specificities with shared tumor-specific recognition to develop T-cell receptor (TCR)-engineered T lymphocytes for adoptive therapy of RCC. EXPERIMENTAL DESIGN: We established a T-cell clone from TIL that recognized a human leukocyte antigen (HLA)-A2-restricted tumor antigen. The TCR alpha- and beta-chain genes were isolated, modified by codon optimization and murinization, and retrovirally transduced into peripheral blood lymphocytes (PBL). A TCR-expressing indicator line (B3Z-TCR53) was established to screen for antigen prevalence in RCC, other malignancies, and normal cell counterparts. RESULTS: TCR53-engineered PBL recapitulated the specificity of the TIL and showed tumor-specific HLA-A2-restricted effector activities (IFN-gamma, tumor necrosis factor-alpha, interleukin-2, macrophage inflammatory protein-1beta, cytotoxicity). PBL-TCR53 of healthy donors and RCC patients exhibited similar transduction efficiency, expansion, and polyfunctional profile. Using B3Z-TCR53 cells, 130 tumor and normal cells were screened and shared TCR53 peptide: MHC expression was found in >60% of RCC and 25% of tumor lines of other histology, whereas normal tissue cells were not recognized. CONCLUSIONS: To date, TCR53 is the only TCR with shared HLA-A2-restricted recognition of RCC. It fulfills the criteria for utilization in TCR gene therapy and advances T cell-based immunotherapy to patients with RCC and other malignancies expressing the TCR ligand. |
| Keywords: | Adoptive Immunotherapy, alpha-beta T-Cell Antigen Receptors, Carcinoma, Renal Cell, Cultured Cells, Flow Cytometry, HLA-A2 Antigen, Immunologic Cytotoxicity, Kidney, Kidney Neoplasms, T-Cell Antigen Receptor Specificity, T-Lymphocytes, Tumor-Infiltrating Lymphocytes |
| Source: | Clinical Cancer Research |
| ISSN: | 1078-0432 |
| Publisher: | American Association for Cancer Research |
| Volume: | 16 |
| Number: | 8 |
| Page Range: | 2333-2343 |
| Date: | 15 April 2010 |
| Official Publication: | https://doi.org/10.1158/1078-0432.CCR-09-2897 |
| PubMed: | View item in PubMed |
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