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Xbiome
Title:XA-511: A Live Biotherapeutic Product That Enhances The Efficacies Of ICI Therapies Through Reprogramming Of The Tumor Microenvironment
The XA-511 lines of wt and genetically modified bacteria are the first therapies aimed at selectively modifying the tumor microenvironment (TME) for improving the efficacies of ICI treatments. XA-511 wt were found to be specifically associated within the tumors of long-term survivors of pancreatic cancers (Frontiers in Immunology, 2022, 785422).
The TME represents a significant barrier to the efficacies of ICIs as its mostly immunosuppressive components limit T-cell activation and induces T-cell dysfunction. XA-511 have shown high capacity to reprogram important aspects of the immunosuppressive TME by consuming lactate, normalizing pH, locally releasing high concentrations of relevant SCFAs, and metabolizing adenosine to inosine. Following iv administration, XA-511 colonize and expand within the hypoxic tumor niches, from where they generate massive T-cells infiltration, reduce tumor masses and prevent metastatic events. Concomitantly, these strict anaerobes are unable to survive in healthy, normoxic organs; they also produce under-acylated LPS variants which act as antagonists of the TLR4s. Altogether, these properties allow for maximal intra-tumor efficacy, while avoiding the generation of a “cytokine storm” or scepsis. XA-511 administration thus appears to be presenting a very favorable safety and tolerability profile.
As a re-programmer of the TME, the XA-511 bacteria should be considered in combination treatment together with CPI and other immune-based therapeutical modalities including CAR-T and vaccines.