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

PURPOSE

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.

PATIENTS AND METHODS

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.

RESULTS

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.

CONCLUSIONS

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.