帕博利珠单抗联合瘤内注射新诺维梭菌-NT治疗晚期实体瘤的Ib期研究。

Phase Ib Study of Pembrolizumab in Combination with Intratumoral Injection of Clostridium novyi-NT in Patients with Advanced Solid Tumors.

作者信息

Nelson Blessie Elizabeth, Janku Filip, Fu Siqing, Dumbrava Ecaterina E, Hong David S, Karp Daniel D, Naing Aung, Rodon Jordi, Tsimberidou Apostolia M, Murthy Ravi, Sheth Rahul A, Amaria Rodabe N, Conley Anthony P, Damodaran Senthil, Raghav Kanwal P S, Carapanceanu Nicoleta, Singh Mahendra Pal, Carapanceanu Valentin, Pezeshki Abdulmohammad, Leontovich Alexey A, Kreider Brent L, Tung David, Varterasian Mary, Khazaie Khashayarsha, Piha-Paul Sarina A

机构信息

The University of Texas MD Anderson Cancer Center, Houston, Texas, United States.

The University of Texas MD Anderson Cancer Center, Houston, TX, United States.

出版信息

Clin Cancer Res. 2025 Jul 11. doi: 10.1158/1078-0432.CCR-24-3952.

DOI:10.1158/1078-0432.CCR-24-3952

PMID:40643985

Abstract

PURPOSE

Intratumoral injection of Clostridium novyi-NT, lacking alpha toxin, germinates and subsequently replicates in the tumor hypoxic regions, causing cell lysis and inflammation. This phase 1b study investigated the safety and synergistic effects of pembrolizumab and C. novyi-NT in advanced solid tumors.

EXPERIMENTAL DESIGN

Patients with injectable solid tumors received one intratumoral (IT) C. novyi-NT injection (Day 8) across four dose cohorts (3x104 to 100x104 spores) with pembrolizumab (200mg intravenous (IV) every 3 weeks, Day 0 to 24 months). Sixteen patients were enrolled with a median age of 62.5 years and the most common tumor types being breast cancer and melanoma.

RESULTS

The combination therapy demonstrated a manageable safety profile, with one grade 3 dose-limiting toxicity (DLT) of abscess formation and the remainder of treatment-related adverse events (TRAEs) in ≥ 10% of patients being grade 1 or 2 injection site reaction (25%), pyrexia (19%), pruritus (13%), leukopenia (13%) and anemia (13%). The maximum tolerated dose (MTD) was determined as pembrolizumab IV 200mg every 3 weeks and a single dose of 100x104 C.novyi-NT spores IT on Day8. The confirmed overall objective response rate of 25%(n=4) was observed among patients with undifferentiated nasopharyngeal squamous carcinoma, squamous cell carcinoma of the base of the tongue, vulvar melanoma, and chordoma. Among these patients we obtained 3 partial responses and one complete response. Median duration of response was 10.93 months, and stable disease was observed in 69% patients.

CONCLUSION

This study highlights the potential of the C. novyi-NT and pembrolizumab combination as a promising therapeutic strategy for treatment-refractory solid tumors.

摘要

目的

瘤内注射缺乏α毒素的诺维氏梭菌NT（Clostridium novyi-NT），其在肿瘤缺氧区域发芽并随后复制，导致细胞裂解和炎症。这项1b期研究调查了帕博利珠单抗和诺维氏梭菌NT在晚期实体瘤中的安全性和协同作用。

实验设计

可注射实体瘤患者在四个剂量组（3×10⁴至100×10⁴个孢子）中接受一次瘤内（IT）诺维氏梭菌NT注射（第8天），同时接受帕博利珠单抗治疗（每3周静脉注射（IV）200mg，第0天至24个月）。共入组16例患者，中位年龄62.5岁，最常见的肿瘤类型为乳腺癌和黑色素瘤。

结果

联合治疗显示出可控的安全性，有1例3级剂量限制性毒性（DLT）为脓肿形成，其余≥10%患者的治疗相关不良事件（TRAEs）为1级或2级注射部位反应（25%）、发热（19%）、瘙痒（13%）、白细胞减少（13%）和贫血（13%）。最大耐受剂量（MTD）确定为每3周静脉注射200mg帕博利珠单抗，第8天单次瘤内注射100×10⁴个诺维氏梭菌NT孢子。在未分化鼻咽鳞状细胞癌、舌根鳞状细胞癌、外阴黑色素瘤和脊索瘤患者中观察到确认的总体客观缓解率为25%（n = 4）。在这些患者中，我们获得了3例部分缓解和1例完全缓解。中位缓解持续时间为10.93个月，69%的患者病情稳定。