A New Phase for Immunotherapy: Rationally Designed, Thermally Responsive Biomaterials to Sustain Radiation and Immunotherapy within Tumors

Abstract

Metastatic cancer, in which solid tumors spontaneously spread to and grow in distant tissues, is a scourge on public health. Despite advances in early detection and treatment of cancers—greatly improving survival for patients whose disease is detected at a local stage—metastatic disease remains extremely deadly for the vast majority of patients. We have developed a novel treatment strategy that sustains high-dose, ablative radiation therapy to destroy a tumor from the inside (sparing healthy surrounding tissue) and release antigens from within the dying tumor cells. We adjuvant this intratumoral radiotherapy with sustained-release formulations of immunostimulatory adjuvants that potentiate pro-inflammatory and adaptive immune responses against otherwise poorly immunogenic tumors. The combination therapy—which we term an “in situ vaccine,” dramatically reduces the proliferation of metastatic cancer and extends survival.Our strategies center around thermally responsive biomaterials—elastin-like polypeptides (ELPs)—to deliver these therapeutic agents to a tumor. Upon injection as a liquid below body temperature, ELP drugs rapidly transition into a viscous gel-like depot at body temperature. We demonstrate new methods of producing and purifying ELP-formulated immunostimulatory adjuvants. We uncover mechanisms by which changes in the macro-scale composition of a biopolymer-bound drug can dramatically change the nano- and micro-scale morphologies and directly influence behavior of the drug when injected in vivo. And finally, we combine intratumoral ELP-bound radiotherapy with immunotherapy adjuvants whose delivery and release we tune with molecular precision by modifying the ELP formulation, demonstrating that an optimized combination of radiotherapy and immunotherapy adjuvants can effectively control, and in some cases cure, metastatic cancer in preclinical studies. Additionally, explore additional strategies for a biomaterial cancer vaccine platform using exogenous antigen—either peptide or nucleic acid—delivery.We expand upon our findings in small animal studies and demonstrate that ELP-bound radiotherapy can be scaled to large animal porcine models adept for clinical translation. We identify several challenges towards scaling ELP radiotherapy for use in large animals and demonstrate strategies to overcome these obstacles, developing a formulation optimized for injection through endoscopic ultrasound (EUS) or interventional radiology techniques. We perform the first-in-pig studies of ELP “liquid brachytherapy” and demonstrate impressive retention and safety of the drug as a depot in the pancreas and liver, setting the stage for future clinical translation of this novel treatment modality.In combination, these studies demonstrate the importance of engineering biomaterials to formulate radiotherapy and immunotherapy agents to optimize their release profile, dose, and mechanism of action. We find that all these factors play key roles in maximizing efficacy in numerous cancer models, setting the stage for a new generation of biologically-inspired materials that comprise effective cancer vaccines.