A New Era in Systemic Therapy for Hepatocellular Carcinoma: Atezolizumab plus Bevacizumab Combination Therapy

Scientific Rationale for Combination Immunotherapy with PD-1/PD-L1 Antibody plus Anti-VEGF/Molecular Targeted Agent High levels of vascular endothelial growth factor (VEGF) released from hypoxic tumor cells and the vascular endothelium induce angiogenesis, thereby contributing to proliferation, invasion, and metastasis of cancer cells. [...]despite their presence, neoantigens are not presented on DCs, and the proliferation and activation of CD8-positive cells are impaired. The cancer-immunity cycle is a sequence of antitumor immune responses initiated upon presentation by DCs of neoantigen peptides released by necrotic cancer cells, and comprises seven steps: (1) release of cancer cell antigens, (2) cancer antigen presentation by DCs, (3) priming and activation of T-cells, (4) trafficking of T-cells to tumors, (5) infiltration of T-cells into tumors, (6) recognition of cancer cells by T-cells, and (7) killing of cancer cells (Fig. 3). Based on this theoretical background, anti-VEGF therapies such as anti-VEGF antibodies and multikinase inhibitors that possess VEGF receptor inhibitory activity will (1) enhance the antigen presentation ability of DCs, (2) promote T-cell activation in the priming phase, (3) normalize tumor vasculature and thereby improve trafficking and infiltration of T-cells from the lymph nodes to the tumor, (4) convert an immunosuppressive tumor microenvironment into an immune-permissive one by downregulating Tregs, TAMs, and MDSCs (described earlier), thereby negatively regulating humoral factors such as TGF-β and IL-10 [1-17] (Fig. 5), and, at this point, (5) facilitate the effect of anti-PD-1/PD-L1 therapy to enhance antitumor activity (Fig. 6).