肿瘤细胞治疗研究
英文原题：Targeting CD38 and PD-1 with isatuximab plus cemiplimab in patients with advanced solid malignancies: results from a phase I/II open-label, multicenter study.
本研究提示，Isa+Cemi对CD38和PD-1的调节具有可控的安全性特征，可减少TME中的CD38+免疫细胞，并激活外周T细胞；然而，这种CD38抑制与显著的抗肿瘤活性无关。在这些mCRPC或NSCLC患者的小型队列中观察到缺乏疗效。试验注册号：NCT03367819。
临床前数据表明，同时使用抗CD38和抗程序性死亡1（PD-1）/程序性死亡配体1（PD-L1）抗体治疗，通过逆转T细胞耗竭，从而增强抗PD-1/PD-L1的疗效，可显著减少原发性肿瘤生长。
这项I/II期研究纳入了转移性去势抵抗性前列腺癌（mCRPC）或晚期非小细胞肺癌（NSCLC）患者。I期的主要目的是研究isatuximab（抗CD38单克隆抗体）+cemiplimab（抗PD-1单克隆抗体，Isa+Cemi）在mCRPC（未接受过抗PD-1/PD-L1治疗）或NSCLC（含抗PD-1/PD-L1治疗期间进展）患者中的安全性和耐受性。II期采用Simon两阶段设计，以缓解率作为主要终点。计划在II期前24例（mCRPC）和前20例（NSCLC）接受Isa+Cemi治疗的患者入组后进行中期分析。评估安全性、免疫原性、药代动力学、药效动力学和抗肿瘤活性，包括肿瘤微环境（TME）中的CD38、PD-L1和TIL（肿瘤浸润淋巴细胞），以及外周免疫细胞表型分析。
Isa+Cemi 显示出可控的安全性特征，未出现新的安全性信号。所有患者均发生了至少 1 起治疗中出现的不良事件。mCRPC 患者中有 13 例（54.2%）、NSCLC 患者中有 12 例（60.0%）发生了≥3 级事件。根据 PCWG3 标准，Isa+Cemi 在 mCRPC 中的最佳总体缓解评估显示无完全缓解（CR），1 例（4.2%）未经证实的部分缓解（PR），5 例（20.8%）疾病稳定（SD）。根据 RECIST V.1.1，接受 Isa+Cemi 的 NSCLC 患者未达到 CR 或 PR，13 例（65%）达到 SD。在从 mCRPC 或 NSCLC 患者获取的治疗后活检中，Isa+Cemi 治疗使中位 CD38+ 肿瘤浸润免疫细胞从 40% 降至 3%，TME 中肿瘤细胞或 T 调节细胞上的 PD-L1 未见一致调节。该联合方案引发了外周活化 T 细胞和细胞溶解性 T 细胞的显著增加，但有趣的是，NK 细胞减少。
BACKGROUND: Preclinical data suggest that concurrent treatment of anti-CD38 and antiprogrammed death 1 (PD-1)/programmed death ligand 1 (PD-L1) antibodies substantially reduce primary tumor growth by reversing T-cell exhaustion and thus enhancing anti-PD-1/PD-L1 efficacy. METHODS: This phase I/II study enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) or advanced non-small cell lung cancer (NSCLC). The primary objectives of phase I were to investigate the safety and tolerability of isatuximab (anti-CD38 monoclonal antibody)+cemiplimab (anti-PD-1 monoclonal antibody, Isa+Cemi) in patients with mCRPC (naïve to anti-PD-1/PD-L1 therapy) or NSCLC (progressed on anti-PD-1/PD-L1-containing therapy). Phase II used Simon's two-stage design with response rate as the primary endpoint. An interim analysis was planned after the first 24 (mCRPC) and 20 (NSCLC) patients receiving Isa+Cemi were enrolled in phase II. Safety, immunogenicity, pharmacokinetics, pharmacodynamics, and antitumor activity were assessed, including CD38, PD-L1, and tumor-infiltrating lymphocytes in the tumor microenvironment (TME), and peripheral immune cell phenotyping. RESULTS: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. All patients experienced ≥1 treatment-emergent adverse event. Grade≥3 events occurred in 13 (54.2%) patients with mCRPC and 12 (60.0%) patients with NSCLC. Based on PCWG3 criteria, assessment of best overall response with Isa+Cemi in mCRPC revealed no complete responses (CRs), one (4.2%) unconfirmed partial response (PR), and five (20.8%) patients with stable disease (SD). Per RECIST V.1.1, patients with NSCLC receiving Isa+Cemi achieved no CR or PR, and 13 (65%) achieved SD. In post-therapy biopsies obtained from patients with mCRPC or NSCLC, Isa+Cemi treatment resulted in a reduction in median CD38+ tumor-infiltrating immune cells from 40% to 3%, with no consistent modulation of PD-L1 on tumor cells or T regulatory cells in the TME. The combination triggered a significant increase in peripheral activated and cytolytic T cells but, interestingly, decreased natural killer cells. CONCLUSIONS: The present study suggests that CD38 and PD-1 modulation by Isa+Cemi has a manageable safety profile, reduces CD38+ immune cells in the TME, and activates peripheral T cells; however, such CD38 inhibition was not associated with significant antitumor activity. A lack of efficacy was observed in these small cohorts of patients with mCRPC or NSCLC. TRIAL REGISTRATION NUMBERS: NCT03367819.
MEMBER ACCOUNT
登录成功会直接打开下一页。
