Injectable biomaterials for localized modulation of the breast tumor microenvironment

Presenter: 

Nitasha Bennett

Authors: 

Nitasha Bennett, Lauren Milling, Nikki Thai, Archana Boopathy, Darrell Irvine

Author Affiliation: 

Koch Institute for Integrative Cancer Research, Departments of Biological Engineering and Materials Science and Engineering of Massachusetts Institute of Technology (MIT), Ragon Institute of Massachusetts General Hospital, Howard Hughes Medical Institute

Abstract: 

Therapies that reinstate tumor immunosurveillance are gaining traction for cancer treatment. Our laboratory has recently discovered a four-component immunotherapy that eliminates large tumors in multiple mouse models, including a model of Her2/neu positive breast cancer. The therapy, which includes a Her2/neu-targeting antibody and vaccine, recombinant IL-2, and anti-PD-1, induces tumor regression by triggering activation of innate immune cells and tumor killing by T and NK cells. This outcome demonstrates that an endogenous immune response can clear tumors. To extend this mode of therapy to breast tumors that lack predefined antigens, such as triple negative breast cancer (TNBC), our focus is to bypass the need for tumor-specific components by converting the tumor into a source of antigen for in situ immunization. Our strategy to promote immune activation in the tumor is to inject a biomaterial scaffold containing modulators that activate innate cells and inhibit immunosuppressive pathways, particularly those identified for their key role in TNBC. The scaffold is composed of silk fibroin protein, a naturally biodegradable and biocompatible matrix that can stably encapsulate a range of drug modalities. We have shown that simple treatments of the scaffold can tune crystalline properties of the silk matrix, changing the rate of release of loaded drugs. We have exploited this feature to obtain a silk scaffold that allows continuous drug dosing for an extended period. Additionally, we have also shown that the scaffold can be injected directly into solid tumors, allowing drug delivery to the tumor while minimizing systemic toxicity. Due to the flexibility of our fabrication strategy, we are poised to test therapeutic combinations that promote an immune response in the tumor microenvironment. In doing so we can validate and manipulate key pathways that contribute to immunosurveillance in breast tumors.