Engineering the gut microbiome and immune system to improve cancer immunotherapy

Introduction:: Despite the recent advances in cancer immunotherapy, only a small subset of patients responds to immunotherapies. Thus, new approaches are needed to improve immunotherapies with minimal immune-related adverse events. The gut microbiome has recently emerged as the next frontier in drug development; however, it remains unclear how to effectively alter gut microbiota for treating various diseases, including cancer.

Materials and Methods:: Here, we present two complementary biomaterial-based strategies for improving the safety and efficacy of immune checkpoint blockers. In the first project, we are working to achieve in situ modulation of the gut microbiome to improve the safety and efficacy of cancer immunotherapy. We are developing new dietary fiber-based biomaterials that can restore the dysregulated gut microbiome for augmenting local and systemic immune responses.
In our second research thrust, we are developing a new nanoparticle platform for the systemic delivery of STING (stimulator of IFN genes) agonists. While local STING activation can convert cold tumor into hot tumor, it has been challenging to develop STING agonists that can treat disseminated cancer due to their toxicity.

Results, Conclusions, and Discussions:: Here, we will present our data showing that oral administration of inulin-gel in tumor-bearing mice in combination with anti-PD-1 immune checkpoint blockade led to robust anti-tumor efficacy while mitigating immune-related adverse events.
Moreover, the addition of manganese to STING agonists results in robust synergy. Lipid-based nanoparticles containing manganese and STING agonists allows for systemic cancer immunotherapy with potent efficacy, favorable pharmaceutical properties, and acceptable safety profiles in various murine and rabbit tumor models.
Our biomaterial-based strategies may offer powerful and convenient approaches to regulate the immune system as potential therapies for cancer and other diseases.

Acknowledgements (Optional): : This work was supported in part by NIH R01DE030691, R01DE031951, R01DK125087, R01NS122536, R01CA271799).