Background The positive clinical effect of T-cell receptor(TCR) gene therapy on tumor regression has previously been demonstrated by NY-ESO-1 TCR-gene therapy. To seriously increase the number of cancer patients that can be treated with TCR-gene therapy we aim to identify a novel set of high-affinity Cancer Testis (CT) specific TCRs targeting different CT-antigens in a variety of prevalent HLA-class I alleles.
Materials and Methods In this study, we selected by bioinformatic tools the most promising CT-genes to target, and from these genes we identified by HLA-peptidomics the naturally processed and presented HLA-class I peptides. With these peptides HLA-tetramers were generated, and by MACS enrichment and single cell sorting CT-specific CD8+ T-cell clones were selected from the allo-HLA repertoire of healthy donors. By performing several different functional assays the high function avidity CT-clones with a safe recognition pattern were selected. To evaluate the potential for clinical application in TCR-gene therapy, TCRs were sequenced, and transferred into peripheral blood derived CD8+ T cells.
Results In total we identified, 7 novel CT-specific TCRs that effectively target MAGE-A1, MAGE-A3, MAGE-A6 and MAGE-A9 expressing tumors cells in the context of HLA-A1, -A2, -A3, -B7, -C7 and -B35.
Conclusions With this set of 7 novel CT-specific TCRs we expand the arsenal of tumor specific TCRs. With this expanding library of TCRs it would be possible to select in future for each cancer patient, based on HLA typing and gene expression, a useful TCR to generate a personalized TCR-gene therapy products. In addition, patients could be treated with multiple TCRs to enhance the efficacy and increase the durability of clinical responses by reducing the likelihood of tumor escape.
Disclosure Information M.A.J. de Rooij: None. D.M. Steen: None. D. Remst: None. A. Wouters: None. M.G.D. Kester: None. R.S. Hagedoorn: None. P.A. van Veelen: None. E.M.E. Verdegaal: None. J.H.F. Falkenburg: None. M.H.M. Heemskerk: None.
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