Potentiation of immune checkpoint blockade cancer immunotherapy with oncolytic virus.
ABSTRACT
Background: Therapeutic efficacy of agents targeting immune checkpoints has been limited to a subset of patients and cancer types. Preexisting lymphocytic infiltration of tumors has emerged as an important biomarker predictive of clinical benefit, suggesting that therapeutic effect could be enhanced through strategies that induce tumor inflammation. Here we explored whether the inflammatory responses generated by oncolytic viruses could be harnessed to improve systemic therapeutic efficacy of agents targeting immunologic checkpoints.
Methods: For our studies we utilized Newcastle Disease Virus (NDV), an avian virus with robust type I IFN-inducing properties. Metastatic disease was modeled by using bilateral flank B16 mouse melanoma model, with NDV administered unilaterally, allowing us to characterize the immune responses in both virus-injected and distant tumors. Therapeutic efficacy and immune responses utilizing intratumoral NDV with systemic immune checkpoint blocking antibodies were further characterized in several mouse models.
Results: Localized intratumoral therapy of B16 melanoma with NDV induced CD4+ and CD8+ lymphocytic infiltrates and anti-tumor effect in distant (non-virally infected) tumors without viral spread to these sites. Combination therapy with localized NDV and systemic immune checkpoint blockade led to distant tumor rejection in both NDV-susceptible and resistant tumor models and protected the animals from tumor re-challenge. This effect was associated with marked tumor infiltration with activated effector, but not regulatory T cells, and was dependent on CD8 and NK cells, and type I and II interferons. To further enhance the T cell effector function in tumors, we genetically-engineered NDVs expressing co-stimulatory ligands and demonstrated further increase in therapeutic efficacy of the combination therapy in several tumor models.
Conclusions: In summary, in mouse tumor models, localized therapy with NDV induces inflammatory infiltrates in distant tumors, making them susceptible to systemic therapy with immunomodulatory antibodies. This provides a strong rationale for investigation of combination therapies utilizing NDV and immune checkpoint blockade in clinic.