Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody

Abstract

The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as ATP and HMGB1 from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

Recombinant oncolytic adenovirus expressing a soluble PVR elicits long-term antitumor immune surveillance

“…These results are consistent with the studies by Kanaya et al. 12 and Zhang et al. 14 However, in the present study, the massive infiltration of lymphocytes did not induce a significant antitumor immune response, and the survival of mice was not prolonged, which suggested that there are potential factors that suppress antitumor immunity and hinder the antitumor effect of the oncolytic virus Ad5con; there may also be insufficient activation of immune costimulatory signals, which may disable infiltrating lymphocytes, including T cells.…”

“…The oncolytic adenovirus H101 with E1B-55kDa deleted was approved for the treatment of head and neck squamous cell carcinoma in 2005. 5 There are currently multiple oncolytic adenoviruses being studied in clinical 6 , 7 , 8 , 9 , 10 and preclinical research, 11 , 12 , 13 , 14 and these oncolytic adenoviruses have shown some application prospects and have characteristics of oncolytic adenovirus-mediated immunotherapy. First, an oncolytic adenovirus can cause immunogenic cell death (ICD) of tumor cells, leading to the release of damage-associated molecular patterns (DAMPs) and the activation of innate immunity.…”

Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer

“…Recently, we have reported that telomerase-specific oncolytic Ad virus such as OBP-301 could induce immunogenic cell death (ICD), which leads to the induction of systemic anti-tumor immune response via the activation of dendritic cells and the facilitation of cytotoxic T lymphocyte recruitment. 48 Therefore, i.p. administration of oncolytic Ad virus treatment might be a promising candidate for combination therapy with immune checkpoint inhibitors (ICIs) in the future.…”

Immunogenic Cell Death-Based Cancer Vaccines

“…Even intratumoral injections of OVs have been proved to activate antitumor immunity not only inside tumors and on adjacent TME, but also on distant untreated focuses (62). Previous studies have revealed that oncolytic viruses such as Coxsackievirus B3, Adenovirus, Measles virus, Semliki Forest virus, Newcastle disease virus, influenza A virus elicit ICDs (33,34,(45)(46)(47)50) and improve immune responses of ICBs (48,49). The additional release of pathogen-associated molecular patterns (PAMPs) derived from oncolytic viruses further increases immuneactivation (63).…”