1. Fuerst, Mark L.

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NEW YORK-A novel bacterial therapy shows early promise in patients with advanced solid tumors. A phase I clinical trial investigating the use of bacterial Clostridium novyi-NT (C. novyi-NT) spores as an injectable monotherapy had manageable toxicities and showed early clinical efficacy in patients with treatment-refractory solid tumor malignancies.

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"Even after a single injection of this bacterial therapy, we see biological and, in some patients, clinically meaningful activity. This strategy is feasible, has manageable adverse effects, and could be clinically meaningful in patients with few therapeutic options," said Filip Janku, MD, PhD, Associate Professor at the Department of Investigational Cancer Therapeutics (Phase I Clinical Trial Program) at The University of Texas MD Anderson Cancer Center, Houston. He presented the data at the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science Into Survival.


Prior anticancer therapies have utilized bacteria, but these treatments can cause infection and severe side effects, noted Janku. C. novyi-NT is an attenuated bacterium that requires a hypoxic environment, a feature of cancerous lesions, to survive and proliferate and therefore does not affect healthy cells. "By exploiting the inherent differences between healthy and cancerous tissue, C. novyi-NT represents a very precise anticancer therapeutic that can specifically attack a patient's cancer," he said.


Bacteriolytic strategies offer unique advantages to combat a broad range of cancers often refractory to conventional chemotherapies and/or radiotherapies. C. novyi-NT is an attenuated strain of Clostridium novyi, a spore-forming, gram-positive anaerobe that lacks a lethal alpha-toxin, expressed by the parental strain. When administered intravenously or intratumorally with percutaneous injection, C. novyi-NT colonizes and replicates within the hypoxic region of the tumors, eliciting robust, tumor-confined cell lysis.


Study Details

Janku and colleagues conducted an open-label, first-in-human study of the intratumoral injection of C. novyi-NT spores. Patients with injectable treatment-refractory solid tumors received a single intratumoral injection of C. novyi-NT spores across six dose cohorts using a 3+3 trial design. The primary endpoints were to assess the safety profile, the dose-limiting toxicity, and the maximum tolerated dose of C. novyi-NT. Key secondary endpoints included assessments of the preliminary antitumor activity of the injected tumor, overall response evaluated by RECIST criteria, and the host immune and inflammatory response to C. novyi-NT.


Between November 2013 and April 2017, the researchers enrolled 24 patients with treatment-refractory solid tumors, including 15 patients with sarcoma, seven patients with diverse carcinoma, and two patients with melanoma. A single intratumoral injection of C. novyi-NT ranging from 10,000 to 3 million spores led to germination and resultant tumor lysis of injected tumor masses in 46 percent of patients across all dosing cohorts.


Two patients treated with 3 million spores displayed dose-limiting toxicities of grade 4 sepsis and/or grade 4 gas gangrene. The maximum tolerated dose was therefore determined to be 1 million spores.


Of the 22 evaluable patients, 21 patients had stable disease as measured by RECIST for the injected lesion, with tumor shrinkage of greater than 10 percent observed in 23 percent of patients. When both injected and uninjected lesions were included, the stable disease rate was 86 percent.


Janku noted that RECIST criteria may not accurately capture the results of this trial. "When we inject the tumor, the cells within it die and become necrotic while the remaining tissue becomes inflamed, making the lesion larger in size than the original tumor. Because of this, evaluation via RECIST does not accurately reflect the reduction in tumor burden in these patients."


C. novyi-NT injection resulted in transient serum cytokine responses consistent with inflammasome activity, activation of innate immunity, tissue remodeling, and angiogenesis.


Janku and colleagues also evaluated the germination of the bacterial spores through clinical and radiological methods.


Of the 24 patients enrolled in the trial, tumors from 46 percent displayed spore germination and resultant tumor cell lysis. Tumor antigen-specific ELISPOT assays pre-and post-treatment documented enhanced secretion of interferon gamma and tumor necrosis factor alfa by circulating T cells, indicating improved systemic tumor specific T-cell responses.


Promising Results

"Despite the absence of clinical signs of germination in some patients, we saw improved tumor-specific immune responses through the increased secretion of T-cell cytokines and increased presence of tumor infiltrating lymphocytes in injected tumors. From these preliminary results, it appears that C. novyi-NT is able to activate the immune response besides causing tumor destruction," Janku noted.


Because C. novyi-NT elicits an innate immune response, the researchers believe this therapy will be synergistic with immunotherapy with checkpoint inhibitors. The study's results have led to the initiation of a phase I clinical trial investigating the combination of C. novyi-NT with the anti-PD-1 drug pembrolizumab.


"We were extremely encouraged by the results of this trial, especially in patients with advanced sarcomas, where immunotherapy hasn't proven very efficacious. This bacteriolytic strategy has the potential to be clinically meaningful, especially in combination with checkpoint inhibitors, for patients with advanced solid tumors," Janku concluded.


Mark L. Fuerst is a contributing writer.