T-cell receptor gene-modified T cells with shared renal cell carcinoma specificity for adoptive T-cell therapy.
Clin. Cancer Res. 16, 2333-2343 (2010)
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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Typ der Hochschulschrift
Herausgeber
Schlagwörter
Tumor-infiltrating lymphocytes; Antitumor-activity; Cancer regression; Kidney cancer; In-vivo; Antigen; Expression; Immunotherapy; MHC; Transplantation
Keywords plus
Sprache
englisch
Veröffentlichungsjahr
2010
Prepublished im Jahr
HGF-Berichtsjahr
2010
ISSN (print) / ISBN
1078-0432
e-ISSN
1557-3265
ISBN
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Konferenztitel
Konferzenzdatum
Konferenzort
Konferenzband
Quellenangaben
Band: 16,
Heft: 8,
Seiten: 2333-2343
Artikelnummer: ,
Supplement: ,
Reihe
Verlag
American Association for Cancer Research (AACR)
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0000-00-00
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Prüfer
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0000-00-00
Anmeldedatum
0000-00-00
Anmelder/Inhaber
weitere Inhaber
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Priorität
Begutachtungsstatus
Peer reviewed
POF Topic(s)
30504 - Mechanisms of Genetic and Environmental Influences on Health and Disease
Forschungsfeld(er)
Immune Response and Infection
PSP-Element(e)
G-501700-001
G-501790-001
G-501700-005
G-520400-001
G-501700-002
Förderungen
Copyright
Erfassungsdatum
2010-11-30