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BackgroundEGFR, KRAS and TP53 have frequent somatic hotspot mutations giving rise to biologically relevant amino acid substitutions in EGFR, KRAS and p53 proteins, respectively, that can be processed and presented on the cell surface by human leukocyte antigen (HLA) molecules as neoantigens to T cells through their T-cell receptor (TCR). These mutations are critical for the cancer cell and are absent in normal tissue; thus, these shared neoantigens are attractive and likely safe targets. Given the complexity of different neoantigen/HLA combinations needed to effectively target a large patient population, a TCR library approach is warranted and can be used ”off-the-shelf” for any patient with matching somatic hotspot mutation and HLA restriction. Sleeping Beauty transposition is the most advanced non-viral gene transfer technology for TCR-T cells and is appealing for TCR libraries given its low cost, speed, and flexibility.MethodsIn this study, Sleeping Beauty transposons were constructed with TCRs targeting EGFR, KRAS and p53 neoantigens restricted by either or both HLA Class-I and HLA Class-II molecules. Donor T cells from peripheral blood were co-electroporated with TCR transposon and Sleeping Beauty transposase and grown in vitro to clinical scale quantities (>109 TCR-T cells) with high expression (>60%) of the introduced neoantigen-specific TCRs.ResultsThe specificity of TCRs to neoantigens was confirmed in TCR-T cell co-cultures with antigen-presenting cells pulsed with peptides, which demonstrated interferon-γ secretion and/or up-regulation of 41BB on the TCR-T cell surface in response to the neoantigen with high avidity (Sleeping Beauty transposition, and TCR-T cells will be adoptively transferred for the treatment of bile duct, colon, lung, pancreas and gynecological cancers.ConclusionsZiopharm’s library TCR-T cell program has the potential to result in safe, durable, objective clinical regressions of cancer at a commercial scale.

Meeting abstracts Adoptive cell therapy with T cells bearing mutation specific T cell receptors (TCR) can be an effective method for treating metastatic cancers. The objective of this study was to identify mutation reactive T cells in the circulation of patients with different types of metastatic

Meeting abstracts Novel interventions are needed for the treatment of women with metastatic ovarian cancer that causes 14,000 deaths each year in the USA. Retrospective analysis of tumor infiltrating lymphocytes (TIL) infused into patients who achieved complete, durable regressions of metastatic