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 adenosine triphosphate (ATP) and high-mobility group box protein 1 (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.

中文翻译：

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端粒酶特异性溶瘤腺病毒的免疫调节协同增强抗PD1抗体的抗肿瘤功效。

涉及免疫检查点抑制剂（ICI）（例如抗程序死亡1抗体（PD-1 Ab））的单一疗法的临床获益仅限于少数人群。我们之前开发了一种端粒酶特异性溶瘤腺病毒，端粒细胞溶解素（OBP-301），其安全性已在I期临床研究中得到证实。在这里，我们研究了OBP-301（一种OBP-301变体）作为诱导免疫原性细胞死亡（ICD）并协同使用CT26鼠结肠癌和PAN02鼠与PD-1 Ab协同增强OBP-502功效的潜力胰腺癌细胞系。OBP-502诱导CT26和PAN02细胞释放ICD分子，例如三磷酸腺苷（ATP）和高迁移率族框蛋白1（HMGB1），从而导致CD8阳性淋巴细胞募集并抑制Foxp3阳性淋巴细胞浸润肿瘤。包含OBP-502肿瘤内给药和PD-1 Ab全身给药的联合疗法不仅显着抑制了经OBP-502治疗的肿瘤的生长，而且还抑制了未经OBP-502治疗的肿瘤在CT26和PAN02双侧皮下的生长（所谓的绝对作用）肿瘤模型，其中甚至在未用OBP-502治疗的肿瘤中也观察到CD8阳性淋巴细胞的主动募集。这种联合功效类似于在涉及肝脏转移的CT26直肠原位肿瘤模型中观察到的功效。总之，端粒酶特异性溶瘤腺病毒是与ICI联合治疗的有前途的候选药物。