Periodic Reporting for period 1 - LiveBioThx (Live biotherapeutics to potentiate cancer immunotherapy)
Reporting period: 2023-03-01 to 2024-08-31
Immunotherapy, including immune checkpoint inhibitors (ICIs), has revolutionized the treatment of multiple cancers. Anti-tumor responses are often durable but overall only a subset of patients receiving ICIs has exhibited sustained tumor shrinkage, whereas a substantial fraction receiving these therapies develops immune-related adverse events. The absence of dramatic responses is attributed to several factors, including abnormalities in the tumor microenvironment (TME). Specifically, many tumors such as subsets of colorectal, breast and pancreatic cancer, become stiff as they grow. Tumor stiffening causes compression of intratumor blood vessels, impairing blood flow/perfusion and oxygen supply. Hypoperfusion reduces ICIs delivery to the tumor and hypoxia induces immunosuppression, compromising immunotherapy. To restore these abnormalities, a novel therapeutic strategy to normalize tumor stiffness prior to ICIs has been tested in preclinical studies and in the clinic. This strategy repurposes clinically approved drugs to target the factors contributing to tumor stiffening, leading to a new class of therapeutics, known as mechanotherapeutics. However, drug-repurposing poses certain limitations as adding a new drug to the treatment regimen of patients with cancer is not feasible in many cases. As an alternative to these approaches, we propose here to test the ability of engineered live biotherapeutics in the form of programmable bacteria that offer unique advantages for delivering enzymes to normalize the TME. Even a small fraction of bacterial dose reaching the tumor is sufficient to colonize it and allow therapeutic concentrations of tumor-remodeling enzymes to be maintained for a long period of time. We propose to evaluate the ability of a novel live biotherapeutic product to improve perfusion and potentiate ICIs in preclinical tumor models of colorectal and breast tumors. This bacterial product has great potential for commercialization, and a plan is proposed.
We developed a live biotherapeutic product in the form of programmable bacteria that offers advantages for delivering enzymes to remodel the tumor extracellular matrix (ECM). Using engineered Escherichia coli to express hyaluronidase under a hypoxia-inducible promoter, the bacteria target hyaluronan within the tumor microenvironment. Our study demonstrated that hyaluronan degradation reduces tumor stiffness and restores vascular functionality in murine models of breast and colorectal cancer. This potentiates immune checkpoint inhibition by facilitating immune cell infiltration and immunostimulation. Additionally, our findings suggest that the potency of antitumor responses depends on baseline stiffness levels and ECM composition, highlighting the potential of programmable bacteria to improve immunotherapy outcomes in drug resistant, solid tumors.
A research article with title:
Programmable bacteria act as live biotherapeutics to remodel tumor stoma and potentiate immunotherapy (https://doi.org/10.21203/rs.3.rs-5070038/v1(opens in new window))
This work was performed in collaboration with Neobe Therapeutics (London UK) that produced the bacteria product.
A research article with title:
Programmable bacteria act as live biotherapeutics to remodel tumor stoma and potentiate immunotherapy (https://doi.org/10.21203/rs.3.rs-5070038/v1(opens in new window))
This work was performed in collaboration with Neobe Therapeutics (London UK) that produced the bacteria product.
The vast majority of currently under-development solutions for remodeling the stroma of solid tumors focuses on targeting cancer-associated fibroblasts (CAFs) which are the main contributors to ECM production. However, this strategy poses several challenges due to the high heterogeneity of CAF population within the TME and across different types of solid tumors. Moreover, the degradation of ECM components often extends beyond the tumor itself, affecting healthy tissues that share these components due to the lack of specificity. To address these limitations, in this project, we exploited genetically engineered bacteria as carriers for delivering therapeutic payloads. Using synthetic biology, we developed three live biotherapeutic products, comprising the bacterial chassis E. Coli K12 MG1655 engineered to produce hyaluronidase under the influence of a tumor-inducible promoter, enabling tumor-specific expression and secretion directly into the extracellular space. Through immunotherapy combination studies, we demonstrated that the administration of the programmable bacteria prior to immune checkpoint inhibition treatment potentiates the antitumor responses of immunotherapy, resulting in the regression of metastatic breast tumors, whereas immunotherapy alone proved completely ineffective. This project underscores the novelty and importance of genetically engineered probiotics as a promising therapeutic strategy for enhancing the efficacy of cancer treatment, with significant implications for future clinical applications.
Key needs to ensure further uptake and success include:
1) Optimization of the bacteria product
2) Additional preclinical studies, incorporating more tumor types and novel immunotherapies (e.g. mRNA vaccines and anti-body drug conjugates)
3) regulatory approval
4) Patent filing with the additional preclinical data
5) clinical studies.
Key needs to ensure further uptake and success include:
1) Optimization of the bacteria product
2) Additional preclinical studies, incorporating more tumor types and novel immunotherapies (e.g. mRNA vaccines and anti-body drug conjugates)
3) regulatory approval
4) Patent filing with the additional preclinical data
5) clinical studies.