Memorial Sloan Kettering Cancer Center, New York, New York, USA
University of Washington, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
J Immunother Cancer. 2023 Mar;11(3). doi: 10.1136/jitc-2022-005702.
This phase 1 study evaluated PF-06753512, a vaccine-based immunotherapy regimen (PrCa VBIR), in two clinical states of prostate cancer (PC), metastatic castration-resistant PC (mCRPC) and biochemical recurrence (BCR).
For dose escalation, patients with mCRPC received intramuscular PrCa VBIR (adenovirus vector and plasmid DNA expressing prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostate stem cell antigen (PSCA)) with or without immune checkpoint inhibitors (ICIs, tremelimumab 40 or 80 mg with or without sasanlimab 130 or 300 mg, both subcutaneous). For dose expansion, patients with mCRPC received recommended phase 2 dose (RP2D) of PrCa VBIR plus tremelimumab 80 mg and sasanlimab 300 mg; patients with BCR received PrCa VBIR plus tremelimumab 80 mg (Cohort 1B-BCR) or tremelimumab 80 mg plus sasanlimab 130 mg (Cohort 5B-BCR) without androgen deprivation therapy (ADT). The primary endpoint was safety.
Ninety-one patients were treated in dose escalation (mCRPC=38) and expansion (BCR=35, mCRPC=18). Overall, treatment-related and immune-related adverse events occurred in 64 (70.3%) and 39 (42.9%) patients, with fatigue (40.7%), influenza-like illness (30.8%), diarrhea (23.1%), and immune-related thyroid dysfunction (19.8%) and rash (15.4%), as the most common. In patients with mCRPC, the objective response rate (ORR, 95% CI) was 5.6% (1.2% to 15.4%) and the median radiographic progression-free survival (rPFS) was 5.6 (3.5 to not estimable) months for all; the ORR was 16.7% (3.6% to 41.4%) and 6-month rPFS rate was 45.5% (24.9% to 64.1%) for those who received RP2D with measurable disease (n=18). 7.4% of patients with mCRPC achieved a ≥50% decline in baseline PSA (PSA-50), with a median duration of 4.6 (1.2-45.2) months. In patients with BCR, 9 (25.7%) achieved PSA-50; the median duration of PSA response was 3.9 (1.9-4.2) and 10.1 (6.9-28.8) months for Cohorts 5B-BCR and 1B-BCR. Overall, antigen specific T-cell response was 88.0% to PSMA, 84.0% to PSA, and 80.0% to PSCA.
PrCa VBIR overall demonstrated safety signals similar to other ICI combination trials; significant side effects were seen in some patients with BCR. It stimulated antigen-specific immunity across all cohorts and resulted in modest antitumor activity in patients with BCR without using ADT.
NCT02616185.
这项 1 期研究评估了 PF-06753512，一种基于疫苗的免疫治疗方案（PrCa VBIR），在前列腺癌（PC）的两种临床状态中，转移性去势抵抗性 PC（mCRPC）和生化复发（BCR）。
为了进行剂量递增，mCRPC 患者接受肌肉内 PrCa VBIR（表达前列腺特异性膜抗原（PSMA）、前列腺特异性抗原（PSA）和前列腺干细胞抗原（PSCA）的腺病毒载体和质粒 DNA），同时使用或不使用免疫检查点抑制剂（ICI，替西木单抗 40 或 80mg 联合或不联合 sasanlimab 130 或 300mg，均为皮下注射）。为了进行剂量扩展，mCRPC 患者接受 mCRPC 推荐的 2 期剂量（RP2D）的 PrCa VBIR 加替西木单抗 80mg 和 sasanlimab 300mg；BCR 患者接受 PrCa VBIR 加替西木单抗 80mg（队列 1B-BCR）或替西木单抗 80mg 加 sasanlimab 130mg（队列 5B-BCR），而不使用雄激素剥夺治疗（ADT）。主要终点是安全性。
91 名患者在剂量递增（mCRPC=38）和扩展（BCR=35，mCRPC=18）中接受治疗。总体而言，64 名（70.3%）和 39 名（42.9%）患者出现与治疗相关和免疫相关的不良事件，最常见的是疲劳（40.7%）、流感样疾病（30.8%）、腹泻（23.1%）和免疫相关甲状腺功能障碍（19.8%）以及皮疹（15.4%）。在 mCRPC 患者中，客观缓解率（ORR，95%CI）为 5.6%（1.2%至 15.4%），所有患者的中位影像学无进展生存期（rPFS）为 5.6 个月（3.5 至不可评估）；对于可测量疾病（n=18）接受 RP2D 的患者，ORR 为 16.7%（3.6%至 41.4%），6 个月 rPFS 率为 45.5%（24.9%至 64.1%）。7.4%的 mCRPC 患者实现了基线 PSA 下降≥50%（PSA-50），中位持续时间为 4.6（1.2-45.2）个月。在 BCR 患者中，9 名（25.7%）实现了 PSA-50；PSA 缓解的中位持续时间为 3.9（1.9-4.2）和 10.1（6.9-28.8）个月，分别为队列 5B-BCR 和 1B-BCR。总的来说，针对 PSMA 的抗原特异性 T 细胞反应为 88.0%，针对 PSA 的反应为 84.0%，针对 PSCA 的反应为 80.0%。
PrCa VBIR 总体上表现出与其他 ICI 联合试验相似的安全性信号；在一些 BCR 患者中观察到一些严重的副作用。它在所有队列中都刺激了抗原特异性免疫，并在不使用 ADT 的情况下导致了 BCR 患者的适度抗肿瘤活性。
NCT02616185。
