A Novel Bacterially-derived Product to Enhance Immunity and Response to Immune Checkpoint Therapy

Abstract Aumenta is developing a product derived from two commensal bacterial species for use as an innovative immunologic therapy. The product is designed to augment multiple arms of the immune system, offering a safe, novel and innovative therapy for unmet needs in treating infectious disease (e.g. fungal infections) and enhancing the bodyandapos;s response to immuno-oncology therapies (e.g. immune checkpoint therapies for melanoma, colorectal cancer). More than 100 years ago, Coleyandapos;s toxin, a mix of heat-killed Streptococcus pyogenes and Serratia marcescens, was used to stimulate the immune system and frequently resulted in tumor regression, though it carried a risk of sepsis. Evidence from preclinical models, human patient correlative studies, and early fecal microbiota transplant (FMT) clinical trials suggests that utilizing gut microbiota is a viable strategy to enhance the host’s immune response. Immune system stimulation has the potential to improve the efficacy of immune checkpoint therapy (ICT) in cancer patients. Similar to cancers, multiple pathogens take advantage of immune checkpoints to evade immune control, including malaria, HIV and hepatitis B. The use of ICT is also of special interest in treating fungal infections, such as mucormycosis, aspergillosis, and candidiasis in immunocompromised patients. However, the current paradigm of microbiome therapeutics—namely oral probiotics or FMT—is fraught with challenges, including safety, ability to sustain gut colonization, ethical concerns about introducing live organisms into patients, and potential FDA regulatory hurdles. To overcome these challenges, Aumenta’s product is derived from lysates of two commensal gut bacteria associated with a positive response to ICT in adult melanoma patients: the Gram-negative Bacteroides thetaiotaomicron (Bt) and Gram-positive Faecalibacterium prausnitzii (Fp). Through this Bt/Fp microbial lysate (BFML), we aim to augment multiple arms of the immune system via specific bacterial pathogen-associated molecular patterns (PAMPs) that modulate the immune response and that prime CD4 and CD8 T cell responses. In the proposed work, we plan to 1) Determine the maximum tolerated dose in healthy mice and the dose response of BFML in mice with melanoma and colorectal cancer receiving ICT, 2) Demonstrate translatability to humans in relevant in vitro and in vivo models, and 3) Determine the biodistribution of BFML using a click chemistry/fluorescent labeling method, which will provide valuable information on safety and the mechanism of action. Successful completion of these aims will allow Aumenta to seamlessly transition into a Phase II award, initiate IND-enabling studies, and begin planning our manufacturing, regulatory, and clinical trial strategies. Immune-enhancing microbial therapies like BFML have the potential to extend the efficacy of immunotherapy to greater numbers of cancer patients and to open new avenues for treating challenging infections.Narrative Aumenta is developing a novel product derived from two commensal bacterial species, with the goal of stimulating the immune system to enhance the efficacy of immune checkpoint inhibition in cancer patients, and to treat difficult infections. Current microbiome therapeutics, namely probiotics and fecal microbiota transplant, face challenges with safety, ability to sustain gut colonization, and potential FDA regulatory hurdles. Aumentaandapos;s product has the potential to overcome these issues through the use of commensal bacterial lysates, and may make immunotherapy more broadly effective and create new therapeutic options for treating challenging fungal infections.