title: T Cells Redirected to a Minor Histocompatibility Antigen Instruct Intratumoral TNFα Expression and Empower Adoptive Cell Therapy for Solid Tumors.
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. Cancer Res; 77(3); 658-71. ©2016 AACR.
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.|Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Teresa
authors.initials: T
authors.lastname: Manzo
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.|Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Tabea
authors.initials: T
authors.lastname: Sturmheit
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Basso
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.|Università Vita-Salute San Raffaele, Milan, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Petrozziello
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hess Michelini
authors.affiliation: Center for Translational Genomics and Bioinformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Riba
authors.affiliation: Department of Pathology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Freschi
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Angela R
authors.initials: AR
authors.lastname: Elia
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Grioni
authors.affiliation: Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Flavio
authors.initials: F
authors.lastname: Curnis
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Maria Pia
authors.initials: MP
authors.lastname: Protti
authors.affiliation: Division of Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
authors.forename: Ton N
authors.initials: TN
authors.lastname: Schumacher
authors.affiliation: Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
authors.forename: Reno
authors.initials: R
authors.lastname: Debets
authors.affiliation: Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.|Institute for Molecular Engineering, University of Chicago, Chicago, Illinois.
authors.forename: Melody A
authors.initials: MA
authors.lastname: Swartz
authors.affiliation: Università Vita-Salute San Raffaele, Milan, Italy.|Division of Experimental Oncology, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Corti
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bellone
authors.affiliation: Division of Immunology, Transplantation and Infectious Disease, San Raffaele Scientific Institute, Milan, Italy. anna.mondino@hsr.it.
authors.forename: Anna
authors.initials: A
authors.lastname: Mondino
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D016219:Immunotherapy, Adoptive / Q000379:methods*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000473:pathology*; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*
chemical_list: D015778:Minor Histocompatibility Antigens; D014409:Tumor Necrosis Factor-alpha