In:
Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 16, No. 8 ( 2010-04-15), p. 2333-2343
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 α- and β-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-γ, tumor necrosis factor-α, interleukin-2, macrophage inflammatory protein-1β, 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 & gt;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. Clin Cancer Res; 16(8); 2333–43. ©2010 AACR.
Type of Medium:
Online Resource
ISSN:
1078-0432
,
1557-3265
DOI:
10.1158/1078-0432.CCR-09-2897
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2010
detail.hit.zdb_id:
1225457-5
detail.hit.zdb_id:
2036787-9
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