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

 
: Manzo, T.; Sturmheit, T.; Basso, V.; Petrozziello, E.; Michelini, R.H.; Riba, M.; Freschi, M.; Elia, A.R.; Grioni, M.; Curnis, F.; Protti, M.P.; Schumacher, T.N.; Debets, R.; Swartz, M.A.; Corti, A.; Bellone, M.; Mondino, A.

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Cancer research 77 (2017), No.3, pp.658-671
ISSN: 0008-5472
ISSN: 1538-7445
ISSN: 0099-7013
ISSN: 0099-7374
English
Journal Article
Fraunhofer EMB ()

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.

: http://publica.fraunhofer.de/documents/N-503134.html