Abstract
Purpose Hypoxic environments, as occurs in tumors, are favorable for Clostridium subspecies to germinate. Clostridium novyi-NT (C. novyi-NT) induces a microscopic & tumor-confined lysis after intratumoral (IT) injection in rat orthotopic brain tumor models & spontaneous solid tumors in dogs, with the commonest toxicity being the traditional accompanying symptoms of bacterial infections. A first-in-man phase 1 study selecting therapy-refractory solid tumors palpable or identifiable under imaging guidance and amenable to percutaneous injection of C. novyi-NT spores is being conducted. Tumor environment hypoxia is dynamic, spatially heterogenic, and not evaluable using clinical imaging technology, thereby rendering a priori localization of the optimal IT location for spore inoculation impossible. In order to compensate for this unknown parameter, we employed a staged, multifocal IT delivery process to theoretically increase the likelihood of spore deposition within a milieu conducive for germination. We present our initial experience with C. novyi-NT spore delivery adopting this approach. Material and Methods Advanced solid tumor cancer patients with at least 1 injectable tumor >1 cm are being enrolled in 5 dose-escalating cohorts to receive single 3-cc IT injections of 1E4, 3E4, 1E5, 3E5, or 1E6 C. novyi-NT spores. Results Four patients have been treated (3 in cohort 1, 1 in cohort 2). Median tumor diameter measured at point of guide needle access was 5.4 cm (2.3-8.9 cm). Sites included intermuscular upper extremity and subcutaneous fat abdominal lesion (2 each), which were uneventful; in toto delivery of the agent was accomplished. Two patients demonstrated clinical evidence of germination within 72 hours corroborated by imaging. Pathology confirmed oncolysis. The liquefied components of the tumor were managed with evacuation via percutaneous drainage and pre-specified protocol-mandated multi-antimicrobial therapy. Conclusions Clostridium novyi-NT spores can be delivered using existing imaging technologies and devices producing clinical evidence of germination and confirming the capability of inducing oncolysis in human neoplastic tissues.
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