Background Combination immunotherapy has the potential to achieve additive or synergistic effects. Combined local injections of dsRNA analogues (mimicking viral RNA) and repeated vaccinations with tumor-lysate loaded dendritic cells shows efficacy against colon cancer mouse models. In the context of immunotherapy, radiotherapy can exert beneficial abscopal effects. Patients and methods In this two-cohort pilot phase I study, 15 advanced cancer patients received two 4-week cycles of four intradermal daily doses of monocyte-derived dendritic cells preloaded with autologous tumor lysate and matured for 24 h with poly-ICLC (Hiltonol), TNF-α and IFN-α. On days +8 and +10 of each cycle, patients received intratumoral image-guided 0.25 mg injections of the dsRNA-analogue Hiltonol. Cyclophosphamide 600 mg/m2 was administered 1 week before. Six patients received stereotactic ablative radiotherapy (SABR) on selected tumor lesions, including those injected with Hiltonol. Expression of 25 immune-relevant genes was sequentially monitored by RT-PCR on circulating peripheral blood mononuclear cell (PBMCs) and serum concentrations of a cytokine panel were sequentially determined before and during treatment. Pre- and post-treatment PBMC from patients achieving durable stable disease (SD) were studied by IFNγ ELISPOT-assays responding to tumor-lysate loaded DC and by TCRβ sequencing. Results Combined treatment was, safe and well tolerated. One heavily pretreated castration-resistant prostate cancer patient experienced a remarkable mixed abscopal response to SABR+ immunotherapy. No objective responses were observed, while nine patients presented SD (five of them in the six-patient radiotherapy cohort). Intratumoral Hiltonol increased IFN-β and IFN-α mRNA in circulating PBMC. DC vaccination increased serum IL-12 and IL-1β concentrations, especially in patients presenting SD. IFNγ-ELISPOT reactivity to tumor lysates was observed in two patients experiencing durable SD. Conclusions This radio-immunotherapy combination strategy, aimed at resembling viral infection in tumor tissue in combination with a dendritic-cell vaccine and SABR, is safe and shows immune-associated activity and signs of preliminary clinical efficacy.

中文翻译：

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在晚期癌症患者中，结合免疫疗法包括瘤内聚-ICLC，树突状细胞疫苗接种和放射疗法。

背景技术联合免疫疗法具有实现累加或协同作用的潜力。dsRNA类似物（模拟病毒RNA）的局部注射与用肿瘤裂解物负载的树突状细胞重复接种的组合显示出对结肠癌小鼠模型的功效。在免疫疗法的背景下，放射疗法可以发挥有益的辅助作用。患者和方法在这两项研究的第一阶段研究中，有15位晚期癌症患者接受了两个4周周期的治疗，每天皮内注射四个剂量的单核细胞来源的树突状细胞，并预先装载了自体肿瘤裂解物，并使用聚-ICLC进行了24 h的成熟（Hiltonol ），TNF-α和IFN-α。在每个周期的第+8和+10天，患者接受肿瘤内图像引导的0.25 mg dsRNA-类似物Hiltonol注射。1周前给予600 mg / m2的环磷酰胺。六名患者在选定的肿瘤病变上接受了立体定向消融放疗（SABR），包括注射了Hiltonol的那些。在循环外周血单个核细胞（PBMC）上通过RT-PCR顺序监测25个免疫相关基因的表达，并在治疗前和治疗过程中顺序确定细胞因子组的血清浓度。通过对肿瘤裂解物负载的DC作出反应的IFNγELISPOT分析和TCRβ测序研究了实现持久稳定疾病（SD）的患者的治疗前和治疗后PBMC。结果联合治疗安全，耐受性好。一名经过高度预处理的去势抵抗性前列腺癌患者对SABR +免疫疗法表现出明显的混合抽象反应。没有观察到客观反应，9例患者出现了SD（6例放射治疗队列中的5例）。肿瘤内Hiltonol增加循环PBMC中的IFN-β和IFN-αmRNA。DC疫苗接种会增加血清IL-12和IL-1β的浓度，特别是在出现SD的患者中。在两名患有持久性SD的患者中观察到IFNγ-ELISPOT对肿瘤裂解物的反应性。结论这种放射免疫疗法联合策略旨在与树突状细胞疫苗和SABR相结合，类似于肿瘤组织中的病毒感染，它是安全的，并且具有免疫相关活性，并具有初步临床疗效的迹象。在两名患有持久性SD的患者中观察到IFNγ-ELISPOT对肿瘤裂解物的反应性。结论这种放射免疫疗法联合策略旨在与树突状细胞疫苗和SABR相结合，类似于肿瘤组织中的病毒感染，它是安全的，并且具有免疫相关活性，并具有初步临床疗效的迹象。在两名患有持久性SD的患者中观察到IFNγ-ELISPOT对肿瘤裂解物的反应性。结论这种放射免疫疗法联合策略旨在与树突状细胞疫苗和SABR相结合，类似于肿瘤组织中的病毒感染，它是安全的，并且具有免疫相关活性，并具有初步临床疗效的迹象。