T-cell receptor gene-modified T cells with shared renal cell carcinoma specificity for adoptive T-cell therapy.
OBJECTIVE
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.


METHODS
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.
Leisegang
Matthias
M
Max-Delbrück-Center for Molecular Medicine, Berlin, Germany.
Turqueti-Neves
Adriana
A
Engels
Boris
B
Blankenstein
Thomas
T
Schendel
Dolores J
DJ
Uckert
Wolfgang
W
Noessner
Elfriede
E
D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D015789:HLA-A2 Antigen / Q000235:genetics / Q000276:immunology; D006801:Humans; D016219:Immunotherapy, Adoptive; D007668:Kidney / Q000166:cytology / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics*; D037182:T-Cell Antigen Receptor Specificity; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*
D015789:HLA-A2 Antigen; D016693:Receptors, Antigen, T-Cell, alpha-beta