Dendritic cell (DC)-based vaccines have shown some degree of success for the treatment of prostate cancer (PC). However, the highly immunosuppressive tumor microenvironment leads to DC dysfunction, which has limited the effectiveness of these vaccines. We hypothesized that use of a fully serotype 3 oncolytic adenovirus (Ad3-hTERT-CMV-hCD40L; TILT-234) could stimulate DCs in the prostate tumor microenvironment by expressing CD40L. Activated DCs would then activate cytotoxic T cells against the tumor, resulting in therapeutic immune responses. Oncolytic cell killing due to cancer cell-specific virus replication adds to antitumor effects but also enhances the immunological effect by releasing tumor epitopes for sampling by DC, in the presence of danger signals. In this study, we evaluated the companion effect of Ad3-hTERT-CMV-hCD40L and DC-therapy in a humanized mouse model and PC histocultures. Treatment with Ad3-hTERT-CMV-hCD40L and DC resulted in enhanced antitumor responses in vivo. Treatment of established histocultures with Ad3-hTERT-CMV-hCD40L induced DC maturation and notable increase in proinflammatory cytokines. In conclusion, Ad3-hTERT-CMV-hCD40L is able to modulate an immunosuppressive prostate tumor microenvironment and improve the effectiveness of DC vaccination in PC models and patient histocultures, setting the stage for clinical translation.

中文翻译：

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编码 CD40L 的溶瘤腺病毒 3 型促进人源化小鼠和患者样本中前列腺癌的树突状细胞治疗

基于树突细胞 (DC) 的疫苗在治疗前列腺癌 (PC) 方面取得了一定程度的成功。然而，高度免疫抑制的肿瘤微环境导致DC功能障碍，这限制了这些疫苗的有效性。我们假设使用完全血清型 3 溶瘤腺病毒（Ad3-hTERT-CMV-hCD40L；TILT-234）可以通过表达 CD40L 来刺激前列腺肿瘤微环境中的 DC。激活的 DC 然后会激活针对肿瘤的细胞毒性 T 细胞，从而导致治疗性免疫反应。由于癌细胞特异性病毒复制导致的溶瘤细胞杀伤增加了抗肿瘤作用，但也通过在存在危险信号的情况下释放肿瘤表位以供 DC 取样来增强免疫学作用。在这项研究中，我们评估了 Ad3-hTERT-CMV-hCD40L 和 DC 疗法在人源化小鼠模型和 PC 组织培养物中的伴随效应。用 Ad3-hTERT-CMV-hCD40L 和 DC 治疗可增强抗肿瘤反应体内。用 Ad3-hTERT-CMV-hCD40L 处理已建立的组织培养物可诱导 DC 成熟和促炎细胞因子显着增加。总之，Ad3-hTERT-CMV-hCD40L 能够调节免疫抑制性前列腺肿瘤微环境并提高 PC 模型和患者组织培养中 DC 疫苗接种的有效性，为临床转化奠定基础。