Oncolytic Virotherapy: A Contest between Apples and Oranges

Abstract

Viruses can be engineered or adapted for selective propagation in neoplastic tissues and further modified for therapeutic transgene expression to enhance their antitumor potency and druggability. Oncolytic viruses (OVs) can be administered locally or intravenously and spread to a variable degree at sites of tumor growth. OV-infected tumor cells die in situ, releasing viral and tumor antigens that are phagocytosed by macrophages, transported to regional lymph nodes, and presented to antigen-reactive T cells, which proliferate before dispersing to kill uninfected tumor cells at distant sites. Several OVs are showing clinical promise, and one of them, talimogene laherparepvec (T-VEC), was recently granted marketing approval for intratumoral therapy of nonresectable metastatic melanoma. T-VEC also appears to substantially enhance clinical responsiveness to checkpoint inhibitor antibody therapy. Here, we examine the T-VEC paradigm and review some of the approaches currently being pursued to develop the next generation of OVs for both local and systemic administration, as well as for use in combination with other immunomodulatory agents.

Keywords: T-VEC; competitive landscape; oncolytic virotherapy; viro-immuno-oncology.

Figure 1

Oncolytic Virotherapy Is Not Just Immunotherapy The viro-immunotherapy paradigm involves tumor-selective infection and replication of the virus, followed by cell killing, inducing local inflammation and trafficking of immune cells to the infected tumor nodule, priming and amplifying systemic antitumor immunity, resulting in the induction of tumor-antigen-specific T cells that would participate in the elimination of uninfected or distant metastases.

Figure 2

Complete Remission of Disseminated Multiple Myeloma after One Intravenous Dose of Measles Virus MV-NIS (A) CT rendering of plasmacytoma on the forehead of the patient showing the tumor protruding from the forehead and osteolytic lesion in the skull. (B) ¹⁸F-fludeoxyglucose positron emission tomography image of the glucose avid left frontal plasmacytoma in patient before virus treatment and the lower panel showing resolution of the tumor 7 weeks after MV-NIS treatment. (C) High-sensitivity eight-color plasma cell (PC) flow cytometry on bone marrow plasma cells before and after MV-NIS treatment, showing CD38- and CD138-positive, CD19-negative monoclonal plasma cells (λ-restricted) with hyperdiploid DNA content. In the bone marrow samples obtained 6 weeks after therapy (right panels), the abnormal PCs are not present (adapted from Russell et al. Mayo Clinic Proceedings).