Controlling Release Kinetics of an Adjuvant from a Depot Improves the Efficacy of Local Immunotherapy in Metastatic Cancer

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Abstract

Biomaterials can improve cancer immunotherapies by controlling their release and thereby optimizing their time-dependent engagement of the immune system. In this study, an approach is described to control the release of a potent immunostimulant-CpG oligodeoxynucleotide-from a genetically-encoded elastin-like polypeptide (ELP) depot. A CpG-binding ELP containing an oligolysine domain (ELP-Lys₁₂) is synthesized that electrostatically complexes CpG and formulate it with an excipient ELP. The ELP-CpG complex retains the thermally responsive phase behavior of the parent ELP, transitioning into a viscous depot at body temperature. Stepwise addition of excipient ELP predictably changes ELP-CpG transition temperature, depot dissolution kinetics, and retention of CpG within the depot. Mixtures of ELP-Lys₁₂, excipient ELP, and CpG undergo microphase separation, forming a porous, sponge-like depot that contains tunable amounts of soluble CpG in the pores. In vivo, the modified formulations exhibit varying degrees of CpG retention over multiple weeks following a single intratumoral injection. Finally, by modifying the release kinetics of CpG, optimized ELP-CpG achieves greater reduction of metastatic disease in a murine metastatic breast cancer model than soluble CpG. These results demonstrate that ELPs can be used to precisely tune the release kinetics of immunotherapies for better outcomes in the treatment of metastatic cancer.

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