Oncolytic virotherapy as promising immunotherapy against cancer: mechanisms of resistance to oncolytic viruses

Oncolytic virotherapy has currently emerged as a powerful therapeutic approach in cancer treatment. Although the history of using viruses goes back to the early 20th century, the approval of talimogene laherparepvec (T-VEC) in 2015 increased interest in oncolytic viruses (OVs). OVs are multifaceted biotherapeutic agents because they replicate in and kill tumor cells and augment immune responses by releasing immunostimulatory molecules from lysed cells. Despite promising results, some limitations hinder the efficacy of oncolytic virotherapy. The delivery challenges and the upregulation of checkpoints following oncolytic virotherapy also mediate resistance to OVs by diminishing immune responses. Furthermore, the localization of receptors of viruses in the tight junctions, interferon responses, and the aberrant expression of genes involved in the cell cycle of the virus, including their infection and replication, reduce the efficacy of OVs. In this review, we present different mechanisms of resistance to OVs and strategies to overcome them.

A phase II study of talimogene laherparepvec for patients with inoperable locoregional recurrence of breast cancer

Talimogene laherparepvec (T-VEC) is an immunotherapy that generates local tumor lysis and systemic antitumor immune response. We studied the efficacy of intratumoral administration of T-VEC as monotherapy for inoperable locoregional recurrence of breast cancer. T-VEC was injected intratumorally at 106 PFU/mL on day 1 (cycle 1), 108 PFU/mL on day 22 (cycle 2), and 108 PFU/mL every 2 weeks thereafter (cycles ≥ 3). Nine patients were enrolled, 6 with only locoregional disease and 3 with both locoregional and distant disease. No patient completed the planned 10 cycles or achieved complete or partial response. The median number of cycles administered was 4 (range, 3–8). Seven patients withdrew prematurely because of uncontrolled disease progression, 1 withdrew after cycle 3 because of fatigue, and 1 withdrew after cycle 4 for reasons unrelated to study treatment. Median progression-free survival and overall survival were 77 days (95% CI, 63–NA) and 361 days (95% CI, 240–NA). Two patients received 8 cycles with clinically stable disease as the best response. The most common grade 2 or higher adverse event was injection site reaction (n = 7, 78%). Future studies could examine whether combining intratumoral T-VEC with concurrent systemic therapy produces better outcomes.

Unraveling the Effects of a Talimogene Laherparepvec (T-VEC)-Induced Tumor Oncolysate on Myeloid Dendritic Cells

T-VEC, a HSV-1 derived oncolytic virus, is approved for the treatment of advanced melanoma. The mechanisms that underly the systemic anti-tumor effect that is seen following intratumoral injection have not yet been studied but are likely to be mediated by myeloid dendritic cells (myDC) that initiate an adaptive immune response. In this study we could demonstrate that T-VEC is non-toxic for human myDC. T-VEC and a T-VEC oncolysate of melanoma cell lines were able to mature human myDC. myDC were able to take up lysed melanoma cells and cross-present melanoma-derived tumor antigens to antigen-specific T cells. Our results support the possible role of myDC as mediators of an adaptive anti-tumor effect and intratumoral co-administration of T-VEC plus autologous myDC could be a complementary treatment option. A clinical trial that investigates this hypothesis is currently ongoing.