Data from T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors

• DOI: 10.1158/0008-5472.c.6509532.v1
• Publication Date: 2023-03-31T02:35:58Z
• Authors: Teresa Manzo; Tabea Sturmheit; Veronica Basso; Elisabetta Petroz...; Rodrigo Hess Mich...; Michela Riba; Massimo Freschi; Angela R. Elia; Matteo Grioni; Flavio Curnis; Maria Pia Protti; Ton N. Schumacher; Reno Debets; Melody A. Swartz; Angelo Corti; Matteo Bellone; Anna Mondino

<div>Abstract<p>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. <i>Cancer Res; 77(3); 658–71. ©2016 AACR</i>.</p></div>