CRYOVATE：肺癌冷冻激活与免疫疗法相结合治疗晚期 NSCLC 的试点研究

IF 3 Q2 ONCOLOGY

JTO Clinical and Research Reports Pub Date : 2024-10-15 DOI:10.1016/j.jtocrr.2024.100737

Antoine Desilets MD, MSc , Gabryella Pinheiro PhD , Wiam Belkaid PhD , Olivier Salko MD , Julie Malo , Eleyine Zarour MD , Adeline Jouquan MSc , Anne-Julie Thibaudeau MSc , Marc-Antoine Nolin MSc , John Stagg PhD , Marie Florescu MD , Mustapha Tehfe MD , Normand Blais MD, MSc , Samer Tabchi MD , Jean Chalaoui MD , Philippe Stephenson MD , Arielle Elkrief MD , Vincent Quoc-Huy Trinh MD, MSc , Bertrand Routy MD, PhD , Moishe Liberman MD, PhD

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引用次数: 0

摘要

导言：NSCLC 是癌症相关死亡的主要原因。尽管免疫检查点抑制剂（ICIs）提高了晚期NSCLC患者的生存率，但耐药性仍然是一个挑战。冷冻激活是一种通过冷冻和解冻循环诱导细胞死亡的技术，与 ICIs 联用时有可能增强肿瘤反应。患者接受低温激活，5天后开始接受ICI单药治疗。主要终点是客观反应率。次要终点包括手术的安全性和可行性以及总生存率。免疫组化法对治疗前后的配对样本进行免疫细胞浸润检测，并根据临床获益率（CB）（CB 与无 CB [NCB]）对患者进行二分法。两名患者获得了部分应答，客观应答率为25%。无进展生存期和总生存期的中位数分别为 3.8 个月和 13.0 个月。冷冻激活过程耐受性良好，未出现 3 至 4 级不良反应。事后分析显示，CB率为50%。免疫组化分析表明，在治疗前和治疗后的活组织切片中，CB 与 NCB 的分化簇 8 阳性 (CD8+) T 细胞浸润在数量上存在差异（p = 0.09），而在治疗后的活组织切片中，CB 与 NCB 的 CD8+ T 细胞有所增加（p = 0.03）。结论虽然低温激活联合 pembrolizumab 对 NSCLC 患者安全且耐受性良好，但与 ICI 单药治疗的历史队列相比，治疗效果并不明显。相关分析验证了 CB 患者的 CD8+ T 细胞招募。

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CRYOVATE: A Pilot Study of Lung Cancer Cryoactivation in Combination With Immunotherapy in Advanced NSCLC

Introduction

NSCLC is the leading cause of cancer-related mortality. Although immune-checkpoint inhibitors (ICIs) have improved survival in patients with advanced NSCLC, treatment resistance remains a challenge. Cryoactivation, a technique inducing cell death by cycles of freezing and thawing, has the potential to augment tumor responses when combined with ICIs.

Methods

This single-arm phase 1 clinical trial enrolled patients with previously untreated advanced NSCLC and 50% or higher programmed cell death ligand-1 (PD-L1). Patients underwent cryoactivation followed by ICI monotherapy initiated 5 days later. The primary end point was the objective response rate. Co-secondary end points included the safety and feasibility of the procedure and overall survival. Immune cell infiltration by immunohistochemistry was performed on paired pre- and post-treatment samples, with patients dichotomized according to clinical benefit (CB) rate (CB versus no CB [NCB]).

Results

Eight patients were enrolled. Two patients achieved a partial response, yielding an objective response rate of 25%. Median progression-free survival and overall survival were 3.8 and 13.0 months, respectively. The cryoactivation procedure was well tolerated, without grade 3 to 4 adverse events. Post-hoc analysis reported a CB rate of 50%. Immunohistochemistry analysis reported a numerical difference in the cluster of differentiation 8–positive (CD8⁺) T cell infiltration in CB versus NCB in the pre- and post-treatment biopsies (p = 0.09) and an increase in CD8⁺ T cells in the post-treatment biopsies of CB versus NCB (p = 0.03).

Conclusions

Although cryoactivation combined with pembrolizumab was safe and well tolerated in patients with NSCLC, therapeutic benefits were not evident compared with historical cohorts of ICI monotherapy. Correlative analyses validated CD8⁺ T cell recruitment in patients deriving CB.

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