Targeting tumor vasculature with TNF leads effector T cells to the tumor and enhances therapeutic efficacy of immune checkpoint blockers in combination with ACT

Purpose: Irregular blood flow and endothelial cell anergy, which characterize many solid tumors, hinder tumor infiltration by cytotoxic T lymphocytes (CTLs). This confers resistance to cancer immunotherapy with monoclonal antibodies directed against regulatory pathways in T lymphocytes (i.e., immune checkpoint blockade, ICB). We investigated whether NGR-TNF, a TNF derivative capable of targeting the tumor vasculature, and improving intra-tumor infiltration by activated CTLs, could sensitize tumors to ICB with antibodies specific for the PD-1 and CTLA-4 receptors. Experimental Design: Transgenic adenocarcinoma of the mouse prostate (TRAMP) mice with autochthonous prostate cancer, and C57BL/6 mice with orthotopic B16 melanoma were treated with NGR-TNF, adoptive T cell therapy (ACT), and ICB, and monitored for immune surveillance and disease progression. Results: The combination of ACT, NGR-TNF and ICB was the most effective in delaying disease progression, and in improving overall survival of mice bearing ICB-resistant prostate cancer or melanoma. Mechanistically, the therapeutic effects associated with potent tumor infiltration especially by endogenous but also by adoptively transferred PD-1+, granzyme B+, and interferon-+ CTLs. The therapeutic effects also associated with favorable T-effector/Treg ratios. Conclusions:Targeting the tumor vasculature with low-dose TNF in association with ACT may represent a novel strategy for enhancing T-cell infiltration in tumors and overcoming resistance to immune checkpoint blockers.

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