Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of Bergen , Bergen, Norway.
Department of Urology, Haukeland University Hospital , Bergen, Norway.
Cancer Immunol Immunother. 2023 Jul;72(7):2357-2373. doi: 10.1007/s00262-023-03421-7. Epub 2023 Mar 20.
Metastatic castration-resistant prostate cancer (mCRPC) is an immunologically cold disease with dismal outcomes. Cryoablation destroys cancer tissue, releases tumor-associated antigens and creates a pro-inflammatory microenvironment, while dendritic cells (DCs) activate immune responses through processing of antigens. Immunotherapy combinations could enhance the anti-tumor efficacy. This open-label, single-arm, single-center phase I trial determined the safety and tolerability of combining cryoablation and autologous immature DC, without and with checkpoint inhibitors. Immune responses and clinical outcomes were evaluated. Patients with mCRPC, confirmed metastases and intact prostate gland were included. The first participants underwent prostate cryoablation with intratumoral injection of autologous DCs in a 3 + 3 design. In the second part, patients received cryoablation, the highest acceptable DC dose, and checkpoint inhibition with either ipilimumab or pembrolizumab. Sequentially collected information on adverse events, quality of life, blood values and images were analyzed by standard descriptive statistics. Neither dose-limiting toxicities nor adverse events > grade 3 were observed in the 18 participants. Results indicate antitumor activity through altered T cell receptor repertoires, and 33% durable (> 46 weeks) clinical benefit with median 40.7 months overall survival. Post-treatment pain and fatigue were associated with circulating tumor cell (CTC) presence at inclusion, while CTC responses correlated with clinical outcomes. This trial demonstrates that cryoimmunotherapy in mCRPC is safe and well tolerated, also for the highest DC dose (2.0 × 10) combined with checkpoint inhibitors. Further studies focusing on the biologic indications of antitumor activity and immune system activation could be considered through a phase II trial focusing on treatment responses and immunologic biomarkers.
转移性去势抵抗性前列腺癌（mCRPC）是一种免疫冷肿瘤，预后较差。冷冻消融破坏癌组织，释放肿瘤相关抗原并产生促炎微环境，而树突状细胞（DC）通过抗原加工激活免疫反应。免疫疗法联合可能增强抗肿瘤疗效。这项开放标签、单臂、单中心 I 期试验确定了冷冻消融联合自体未成熟 DC 联合或不联合检查点抑制剂的安全性和耐受性。评估了免疫反应和临床结果。纳入 mCRPC、确诊转移和前列腺完整的患者。第一批参与者接受了前列腺冷冻消融术，同时进行了肿瘤内注射自体 DC 的 3+3 设计。在第二部分，患者接受了冷冻消融术、最高可接受的 DC 剂量和检查点抑制治疗，使用伊匹单抗或 pembrolizumab。通过标准描述性统计分析连续收集不良事件、生活质量、血液值和图像信息。在 18 名参与者中未观察到剂量限制毒性或>3 级不良事件。结果表明通过改变 T 细胞受体谱具有抗肿瘤活性，33%的患者具有持久（>46 周）临床获益，总生存期中位数为 40.7 个月。治疗后疼痛和疲劳与纳入时循环肿瘤细胞（CTC）的存在相关，而 CTC 反应与临床结果相关。该试验表明，mCRPC 中的冷冻免疫疗法是安全且耐受良好的，对于联合检查点抑制剂的最高 DC 剂量（2.0×10）也是如此。通过关注治疗反应和免疫生物标志物的 II 期试验，可以考虑进一步研究针对抗肿瘤活性和免疫系统激活的生物学指征。
