Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor–Engineered T Cells for Ovarian Cancer

Abstract

<b>Purpose:</b> Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anticancer cytotoxic T cells. Adoptive T-cell therapy with neoantigen-specific T-cell receptor (TCR)-engineered T cells would be an attractive therapeutic option for advanced cancers where the host antitumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor. Our protocol required only 2 weeks from stimulation of T cells with neoantigen-loaded dendritic cells to the identification of neoantigen-specific TCRs. We conducted the pilot study to validate our protocol.<b>Experimental Design:</b> We used tumors from 7 ovarian cancer patients to validate our protocol.<b>Results:</b> We chose 14 candidate neoantigens from 7 ovarian tumors (1-3 candidates for each patient) and then successfully induced three neoantigen-specific T cells from 1 healthy donor and identified their TCR sequences. Moreover, we validated functional activity of the three identified TCRs by generating TCR-engineered T cells that recognized the corresponding neoantigens and showed cytotoxic activity in an antigen dose-dependent manner. However, one case of neoantigen-specific TCR-engineered T cells showed cross-reactivity against the corresponding wild-type peptide.<b>Conclusions:</b> This pilot study demonstrated the feasibility of our efficient process from identification of neoantigen to production of the neoantigen-targeting cytotoxic TCR-engineered T cells for ovarian cancer and revealed the importance of careful validation of neoantigen-specific TCR-engineered T cells to avoid severe immune-related adverse events. <i>Clin Cancer Res; 24(21); 5357-67. ©2018 AACR</i> <i>See related commentary by Anczurowski and Hirano, p. 5195</i>.