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

Intratumoral Injection of Clostridium novyi-NT Spores in Patients with Treatment-Refractory Advanced Solid Tumors:

Purpose: Intratumorally injected Clostridium novyi-NT (non-toxic; lackingthe 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. Experimental design: This first-in-humanstudy (NCT01924689) enrolled patients with injectable, treatment-refractory solid tumors to receive a single intratumoral injection ofC. novyi-NTacross 6 dose cohorts (1x10⁴to 3x10⁶spores, 3+3 dose-escalation design) to determine dose-limiting toxicities (DLTs), and the maximum tolerated dose (MTD). 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 (1x10⁶spores) was defined as the MTD; DLTs were grade 4 sepsis (n=2) and grade 4 gas gangrene (n=1), all occurring in 3 patients with injected tumors >8 cm. Other treatment-related grade ≥3 toxicities included pathological fracture (n=1), limb abscess (n=1), soft tissue infection (n=1), respiratory insufficiency (n=1), and rash (n=1), which occurred across 4 patients. Of 22 evaluable patients, 9 (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 anti-tumor activity and the host immune response support additional studies of C. novyi-NT in humans.