T cells redirected to a minor histocompatibility antigen instruct intratumoral TNFα expression and empower adoptive cell therapy for solid tumors

Teresa Manzo, T Sturmheit, V Basso, E Petrozziello, Rodrigo Hess-Michelini, M Riba, M Freschi, AR Elia, M Grioni, F Curnis, MP Protti, TN Schumacher, R Debets, MA Swartz, A Corti, M Bellone, A Mondino

Research output: Contribution to journalArticlepeer-review

Abstract

Donor-derived allogeneic T cells evoke potent graft versus tumor (GVT) effects likely due to the simultaneous recognition of tumor-specific and host-restricted minor histocompatibility (H) antigens. Here we investigated whether such effects could be reproduced in autologous settings by TCR gene-engineered lymphocytes. We report that T cells redirected either to a broadly expressed Y-encoded minor H antigen or to a tumor-associated antigen, although poorly effective if individually transferred, when simultaneously administered enabled acute autochthonous tumor debulking and resulted in durable clinical remission. Y-redirected T cells proved hyporesponsive in peripheral lymphoid organs, whereas they retained effector function at the tumor site, where in synergy with tumor-redirected lymphocytes, they instructed TNFα expression, endothelial cell activation, and intratumoral T-cell infiltration. While neutralizing TNFα hindered GVT effects by the combined T-cell infusion, a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNFα derivative currently in phase III clinical trials, substituted for Y-redirected cells and enabled tumor debulking by tumor-redirected lymphocytes. Together, our results provide new mechanistic insights into allogeneic GVT, validate the importance of targeting the tumor and its associated stroma, and prove the potency of a novel combined approach suitable for immediate clinical implementation. ©2016 American Association for Cancer Research.
Original languageEnglish
Pages (from-to)658-671
Number of pages14
JournalCancer Research
Volume77
Issue number3
DOIs
Publication statusPublished - 2017

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