Harnessing the Power of Onco-Immunotherapy with Checkpoint Inhibitors

Abstract

Oncolytic viruses represent a diverse class of replication competent viruses that curtail tumor growth. These viruses, through their natural ability or through genetic modifications, can selectively replicate within tumor cells and induce cell death while leaving normal cells intact. Apart from the direct oncolytic activity, these viruses mediate tumor cell death via the induction of innate and adaptive immune responses. The field of oncolytic viruses has seen substantial advancement with the progression of numerous oncolytic viruses in various phases of clinical trials. Tumors employ a plethora of mechanisms to establish growth and subsequently metastasize. These include evasion of immune surveillance by inducing up-regulation of checkpoint proteins which function to abrogate T cell effector functions. Currently, antibodies blocking checkpoint proteins such as anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) and anti-programmed cell death-1 (PD-1) have been approved to treat cancer and shown to impart durable clinical responses. These antibodies typically need pre-existing active immune tumor microenvironment to establish durable clinical outcomes and not every patient responds to these therapies. This review provides an overview of published pre-clinical studies demonstrating superior therapeutic efficacy of combining oncolytic viruses with checkpoint blockade compared to monotherapies. These studies provide compelling evidence that oncolytic therapy can be potentiated by coupling it with checkpoint therapies.

Tumor-Localized Secretion of Soluble PD1 Enhances Oncolytic Virotherapy

“…Due to the known propensity for OV to induce initially robust anti-tumor immune responses, and the ability of PD1-blockade to maintain these responses, the combination of OV and checkpoint blockade is viewed as therapeutically attractive (24, 25). Unfortunately, preliminary data from clinical trials combining IMLYGIC® with PD1-blockade suggests that this combination likely results in the same increases in autoimmune-like toxicity seen with other combination therapies (26).…”

TGF-β Inhibition Improves Oncolytic Herpes Viroimmunotherapy in Murine Models of Rhabdomyosarcoma

“…Modulating the tumor microenvironment to better support virus-induced antitumor immunity thus marks a logical next step toward further improving oncolytic virotherapy. Several preclinical and clinical studies combining oncolytic virotherapy with immune checkpoint inhibitors have since been initiated with this goal in mind 11, 12, 13, 14…”

Oncolytic activity of the rhabdovirus VSV‐GP against prostate cancer

“…3 Oncolytic viruses (OVs), which selectively infect and kill tumor cells, have shown promising results in preclinical models and clinical trials in a wide range of tumor types both as monotherapies and in combination with other compounds. [4][5][6] Moreover, the OV Talimogene Laherparepvec (Imlygic V R , T-VEC) has recently been licensed in the United States and Europe for the treatment of melanoma. 7,8 In the few earlyphase clinical trials that have included PCa patients, safety and efficacy data were also encouraging.…”