Department of Medicine, Carbone Cancer Center, University of Wisconsin-Madison, Madison, Wisconsin, USA
Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, Wisconsin, USA.
J Immunother Cancer. 2022 Mar;10(3). doi: 10.1136/jitc-2021-004198.
We previously reported a trial using a DNA vaccine encoding prostatic acid phosphatase (MVI-816, pTVG-HP), given over 12 weeks concurrently or sequentially with pembrolizumab, in patients with mCRPC. We report the final analysis of this trial following two additional treatment arms in which patients with mCRPC continued concurrent treatment until progression.
Patients with mCRPC were treated with MVI-816 and pembrolizumab every 3 weeks (arm 3, n=20) or MVI-816 every 2 weeks and pembrolizumab every 4 weeks (arm 4, n=20). The primary objectives were safety, 6-month progression-free survival (PFS), median time to radiographic progression, and objective response rates. Secondary objectives included immunological evaluations.
In 25 patients with measurable disease, there were no complete response and one confirmed partial response in a patient who subsequently found to have an MSI tumor. 4/40 patients (10%) had a prostate-specific antigen decline >50%. The estimated overall radiographic PFS rate at 6 months was 47.2% (44.4% arm 3, 61.5% arm 4). Accounting for all off-study events, overall median time on treatment was 5.6 months (95% CI: 5.4 to 10.8 months), 5.6 months for arm 3 and 8.1 months for arm 4 (p=0.64). Thirty-two per cent of patients remained on trial beyond 6 months without progression. Median overall survival was 22.9 (95% CI: 16.2 to 25.6) months. One grade 4 event (hyperglycemia) was observed. Immune-related adverse events (irAEs) >grade 1 were observed in 42% of patients overall. Interferon-γ and/or granzyme B immune response to prostatic acid phosphatase was detected in 2/20 patients in arm 3 and 6/20 patients in arm 4. Plasma cytokines associated with immune activation and CD8+ T-cell recruitment were augmented at weeks 6 and 12. The development of irAE was significantly associated with a prolonged time on treatment (HR=0.42, p=0.003). Baseline DNA homologous recombination repair mutations were not associated with longer time to progression.
Findings here demonstrate that combining programmed cell death 1 blockade with MVI-816 is safe, can augment tumor-specific T cells, and can result in a favorable 6-month disease control rate. Correlative studies suggest T-cell activation by vaccination is critical to the mechanism of action of this combination. Future randomized clinical trials are needed to validate these findings.
NCT02499835.
我们之前报告了一项试验，该试验使用编码前列腺酸性磷酸酶的 DNA 疫苗（MVI-816，pTVG-HP），在 mCRPC 患者中，12 周内同时或序贯使用派姆单抗进行治疗。我们报告了在另外两个治疗臂中继续进行同时治疗直至疾病进展的情况下，该试验的最终分析。
mCRPC 患者每 3 周接受 MVI-816 和派姆单抗治疗（臂 3，n=20）或每 2 周接受 MVI-816 和每 4 周接受派姆单抗治疗（臂 4，n=20）。主要目标是安全性、6 个月无进展生存期（PFS）、中位影像学进展时间和客观缓解率。次要目标包括免疫评估。
在 25 名可测量疾病患者中，无完全缓解，1 名患者确认部分缓解，随后发现该患者存在 MSI 肿瘤。40 名患者中有 4 名（10%）前列腺特异性抗原下降>50%。6 个月时总影像学 PFS 率估计为 47.2%（臂 3 为 44.4%，臂 4 为 61.5%）。考虑所有停药事件，总体中位治疗时间为 5.6 个月（95%CI：5.4 至 10.8 个月），臂 3 为 5.6 个月，臂 4 为 8.1 个月（p=0.64）。32%的患者在没有进展的情况下继续治疗超过 6 个月。总生存期中位数为 22.9 个月（95%CI：16.2 至 25.6）。观察到 1 例 4 级事件（高血糖症）。总体上有 42%的患者发生>1 级的免疫相关不良事件（irAE）。在臂 3 的 20 名患者中有 2 名和臂 4 的 20 名患者中有 6 名检测到针对前列腺酸性磷酸酶的干扰素-γ和/或颗粒酶 B 免疫反应。与免疫激活和 CD8+T 细胞募集相关的血浆细胞因子在第 6 周和第 12 周增加。irAE 的发生与治疗时间延长显著相关（HR=0.42，p=0.003）。基线 DNA 同源重组修复突变与进展时间延长无关。
这些发现表明，将程序性细胞死亡 1 阻断与 MVI-816 联合使用是安全的，可以增强肿瘤特异性 T 细胞，并可获得有利的 6 个月疾病控制率。相关研究表明，疫苗接种引起的 T 细胞激活是该联合作用机制的关键。需要进行未来的随机临床试验来验证这些发现。
NCT02499835。
