Low doses of a fusion protein comprised of LIGHT (a TNF-related cytokine) and a vascular targeting peptide (VTP) reversed tumor vessel abnormalities in mice with pancreatic tumors and enabled T cell infiltration into the tumor via LIGHT-VTP-stimulated macrophages. Combination of LIGHT-VTP with a vaccine and dual checkpoint blockade (anti-PD-1 and anti-CTLA-4) significantly reduced tumor growth, induced immune memory response, and increased survival.
The tumor microenvironment confers profound resistance to anti-cancer immunotherapy. By targeting LIGHT, a member of the TNF superfamily of cytokines, to tumor vessels via a vascular targeting peptide (VTP), we developed a reagent with the dual ability to modulate the angiogenic vasculature and to induce tertiary lymphoid structures (TLSs). LIGHT-VTP triggered the influx of endogenous T cells into autochthonous or syngeneic tumors, which are resistant to immunotherapy. LIGHT-VTP in combination with checkpoint inhibition generated a large number of intratumoral effector and memory T cells with ensuing survival benefits, while the addition of anti-tumor vaccination achieved maximal therapeutic efficacy. Thus, the combination treatments stimulated the trafficking of pre-existing endogenous effector T cells as well as their intratumoral activation and were more successful than current immunotherapies, which fail due to tumor-intrinsic resistance mechanisms.