Anti-PD-1 and anti-PD-L1
immunotherapy has provided a new therapeutic opportunity for treatment of advanced-stage
non-small cell lung cancer (NSCLC). However, overall objective response rates are approximately 15%-25% in all NSCLC patients who receive anti-PD
therapy. Therefore, strategies to overcome primary resistance to anti-PD
immunotherapy are urgently needed. We hypothesized that the barrier to the success of anti-PD
therapy in most NSCLC patients can be overcome by stimulating the lymphocyte infiltration at
cancer sites through locoregional virotherapy. To this end, in this study, we determined combination effects of anti-PD
immunotherapy and oncolytic adenoviral vector-mediated
tumor necrosis factor-α-related apoptosis-inducing
ligand (TRAIL) gene therapy (Ad/E1-TRAIL) or adenoviral-mediated TP53 (Ad/CMV-TP53) gene
therapy in syngeneic mice bearing subcutaneous
tumors derived from M109
lung cancer cells. Both anti-PD-1 and anti-PD-L1
antibodies failed to elicit obvious
therapeutic effects in the M109
tumors. Intratumoral administration of Ad/E1-TRAIL or Ad/CMV-TP53 alone suppressed
tumor growth in animals preexposed to an adenovector and bearing subcutaneous
tumors derived from M109 cells. However, combining either anti-PD-1 or anti-PD-L1 antibody with these two adenoviral vectors elicited the strongest anticancer activity in mice with existing immunity to adenoviral vectors. Dramatically enhanced intratumoral immune response was detected in this group of combination
therapy based on infiltrations of CD4+ and CD8+ lymphocytes and macrophages in
tumors. Our results demonstrate that resistance to anti-PD-1
immunotherapy in syngeneic mouse
lung cancer can be overcome by locoregional virotherapy.