Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, Texas.
BioMed Valley Discoveries Inc., Kansas City, Missouri.
Clin Cancer Res. 2021 Jan 1;27(1):96-106. doi: 10.1158/1078-0432.CCR-20-2065. Epub 2020 Oct 12.
Intratumorally injected -NT (nontoxic; lacking the alpha toxin), an attenuated strain of , replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.
This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of -NT across 6 dose cohorts (1 × 10 to 3 × 10 spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.
Among 24 patients, a single intratumoral injection of -NT led to bacterial spores germination and the resultant lysis of injected tumor masses in 10 patients (42%) across all doses. The cohort 5 dose (1 × 10 spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis ( = 2) and grade 4 gas gangrene ( = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture ( = 1), limb abscess ( = 1), soft-tissue infection ( = 1), respiratory insufficiency ( = 1), and rash ( = 1), which occurred across four patients. Of 22 evaluable patients, nine (41%) had a decrease in size of the injected tumor and 19 (86%) had stable disease as the best overall response in injected and noninjected lesions combined. -NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.
Single intratumoral injection of NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of NT in humans.
瘤内注射 -NT（无毒；缺乏α毒素），一种减毒的 ，在缺氧的肿瘤区域内复制，导致肿瘤内细胞溶解和动物的炎症反应，这值得临床研究。
这是一项首次人体研究（NCT01924689），纳入了可注射、治疗耐药的实体瘤患者，接受单次瘤内注射 -NT，共 6 个剂量组（1×10 至 3×10 孢子，3+3 剂量递增设计），以确定剂量限制性毒性（DLT）和最大耐受剂量。
在 24 例患者中，10 例（42%）所有剂量的患者的肿瘤内注射 -NT 导致细菌孢子萌发，并导致注射的肿瘤块溶解。第 5 剂量组（1×10 孢子）被定义为最大耐受剂量；DLT 为 4 级败血症（=2）和 4 级气性坏疽（=1），均发生在 3 例注射肿瘤>8cm 的患者中。其他与治疗相关的≥3 级毒性包括病理性骨折（=1）、肢体脓肿（=1）、软组织感染（=1）、呼吸功能不全（=1）和皮疹（=1），共发生在 4 例患者中。在 22 例可评估患者中，9 例（41%）注射肿瘤的大小减小，19 例（86%）在注射和非注射病变的最佳总体反应中为稳定疾病。NT 注射引起短暂的全身细胞因子反应，并增强全身肿瘤特异性 T 细胞反应。
单次瘤内注射 NT 是可行的。毒性可能很严重，但可管理。抗肿瘤活性和宿主免疫反应的信号支持在人体中进一步研究 NT。
