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

Abstract

Intratumorally injected <i>Clostridium novyi</i>-NT (nontoxic; lacking the alpha toxin), an attenuated strain of <i>C. novyi</i>, 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 <i>C. novyi</i>-NT across 6 dose cohorts (1 × 10⁴ to 3 × 10⁶ 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 <i>C. novyi</i>-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 × 10⁶ spores) was defined as the maximum tolerated dose; DLTs were grade 4 sepsis (<i>n</i> = 2) and grade 4 gas gangrene (<i>n</i> = 1), all occurring in three patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathologic fracture (<i>n</i> = 1), limb abscess (<i>n</i> = 1), soft-tissue infection (<i>n</i> = 1), respiratory insufficiency (<i>n</i> = 1), and rash (<i>n</i> = 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. <i>C. novyi</i>-NT injection elicited a transient systemic cytokine response and enhanced systemic tumor-specific T-cell responses. Single intratumoral injection of <i>C. novyi-</i>NT is feasible. Toxicities can be significant but manageable. Signals of antitumor activity and the host immune response support additional studies of <i>C. novyi-</i>NT in humans.