Description

Targeting TNF-α and IFN-γ to tumor vessels confer efficacy to adoptive cell therapy with T lymphocytes engineered against tumor-associated self-antigens

V. Basso¹, E. Petrozziello^1,2, T. Sturmheit^1,2,§, M. Freschi³, E. Di Simone¹, M. Bellone¹, F. Curnis⁴, A. Corti^4,2, and A. Mondino^1,*

¹Division of Immunology, Transplantation and Infectious Disease; ³Department of Pathology; ⁴Division of Experimental Oncology; San Raffaele Scientific Institute, Milan, Italy

²Università Vita-Salute San Raffaele, Milan, Italy

^§Current address: Fraunhofer EMB, Lübeck, Germany

Adoptive T cell therapy (ACT) has become a promising immunotherapeutic option for cancer patients. Poor tumor infiltration and a highly immunosuppressive microenvironment often hinder efficacy against solid tumors. We recently reported that T cells redirected to a minor histocompatibility antigen, when combined to tumor-specific T cells, instruct intratumoral TNF-α expression, evoke potent tumor infiltration and debulking and prolong survival of mice with autochthonous prostate adenocarcinoma. We also found that a single injection of picogram amounts of NGR-TNF, a tumor vessel-targeted TNF-a derivative, currently in phase III clinical trials, recapitulates these events and enable tumor debulking by high affinity tumor-redirected T cells (Manzo and Sturmheit et al, In press). Here we report this strategy to be poorly efficacious when adopting T cells engineered with a TCR specific for a tumor-associated self-antigen, i.e. the H4 histone. This was best explained by modest IFN-g production by H4-reactive lymphocytes, and the notion that this cytokine is critical for NGR-TNF activity. We thus exploited the IFN-NGR derivative, and found it to support acute complete tumor debulking in mice treated with H4-reactive lymphocytes. Of note, when NGR-TNF and IFNNGR were both used, engraftment and tumor-directed immune responses were best supported. Thus, we conclude that when exploiting poorly reactive T cells redirected to tumor-associated self-antigens, the simultaneous deliveries of TNF-α and IFN-g to the tumor vessels grant therapeutic efficacy to otherwise unsuccessful ACT.