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

Abstract

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 × 104 to 3 × 106 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 × 106 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.

The Evolution and Future of Targeted Cancer Therapy: From Nanoparticles, Oncolytic Viruses, and Oncolytic Bacteria to the Treatment of Solid Tumors

“…At the forefront of S. typhimurium research is the strain called Saltikva, which in addition to the knockout of virulence factors, has been engineered to induce IL-2 gene expression in the TME [258]. Pairing of these oncolytic bacteria with an immunostimulatory cytokine is a consistent trend in the field [386], as already demonstrated with aforementioned Imlygic and Reolysin. A phase II clinical trial for patients with metastatic pancreatic cancer is currently in progress [387].…”

Efficient Secretion of Murine IL-2 From an Attenuated Strain of Clostridium sporogenes, a Novel Delivery Vehicle for Cancer Immunotherapy

“…The ability of Clostridium species, including wild type C. sporogenes NCIMB 10696, to colonise hypoxic/necrotic tumours is well documented ( Zhou et al, 2018 ). The most advanced example of this is a recently reported first-in-human (FIH) study using C. novyi -NT for treatment of treatment-refractory solid tumours ( Janku et al, 2020 ). C. novyi -NT differs from its wild-type parental strain due to the absence of the alpha toxin.…”

Bacterial-Based Methods for Cancer Treatment: What We Know and Where We Are

“…Moreover, certain bacteria such as Clostridium spp. and Bifidobacterium longum strains-which can endure and progress in hypoxic conditionscan proliferate and surround the tumor, causing tumor destruction [7,10].…”