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

Autor:	Manzo T; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele, Milan, Italy., Sturmheit T; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele, Milan, Italy., Basso V; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy., Petrozziello E; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.; Università Vita-Salute San Raffaele, Milan, Italy., Hess Michelini R; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy., Riba M; Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy., Freschi M; Department of Pathology, San Raffaele Scientific Institute, Milan, Italy., Elia AR; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy., Grioni M; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy., Curnis F; Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy., Protti MP; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy., Schumacher TN; Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands., Debets R; Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands., Swartz MA; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.; Institute for Molecular Engineering, University of Chicago, Chicago, Illinois., Corti A; Università Vita-Salute San Raffaele, Milan, Italy.; Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy., Bellone M; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy., Mondino A; Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy. anna.mondino@hsr.it.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Feb 01; Vol. 77 (3), pp. 658-671. Date of Electronic Publication: 2016 Nov 21.
DOI:	10.1158/0008-5472.CAN-16-0725
Abstrakt:	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. Cancer Res; 77(3); 658-71. ©2016 AACR. (©2016 American Association for Cancer Research.)
Databáze:	MEDLINE
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