Intratumoral Injection of Clostridium novyi -NT Spores in Patients with Treatment-refractory Advanced Solid Tumors.

Purpose: Intratumorally injected Clostridium novyi -NT (nontoxic; lacking the alpha toxin), an attenuated strain of C. novyi , replicates within hypoxic tumor regions resulting in tumor-confined cell lysis and inflammatory response in animals, which warrants clinical investigation.
Patients and Methods: This first-in-human study (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection of C. novyi -NT across 6 dose cohorts (1 × 10 ⁴ to 3 × 10 ⁶ spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLT), and the maximum tolerated dose.
Results: Among 24 patients, a single intratumoral injection of C. novyi -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 ⁶ spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis ( n = 2) and grade 4 gas gangrene ( n = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture ( n = 1), limb abscess ( n = 1), soft-tissue infection ( n = 1), respiratory insufficiency ( n = 1), and rash ( n = 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. C. novyi -NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses.
Conclusions: Single intratumoral injection of C. novyi- NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of C. novyi- NT in humans.
(©2020 American Association for Cancer Research.)