000005714 001__ 5714 000005714 005__ 20240523045646.0 000005714 0247_ $$2doi$$a10.6082/uchicago.5714 000005714 041__ $$aen 000005714 245__ $$aEngineering Tumor Binding Polymeric Glyco-Adjuvants for Cancer Immunotherapy 000005714 260__ $$bThe University of Chicago 000005714 269__ $$a2023-03 000005714 300__ $$a95 000005714 336__ $$aDissertation 000005714 502__ $$bPh.D. 000005714 520__ $$aCancer immunotherapy utilizing immune checkpoint inhibitors has been heralded as one of the most important scientific and medical breakthroughs in the early 21st century. It has revolutionized the standard of care in many challenging cancer types including colon cancer, melanoma, and Hodgkin lymphoma, leading to unprecedented clinical responses in these challenging tumors. Despite this, most patients fail to adequately respond to these treatments due to the lack of appropriate T cells within the tumor microenvironment. Further strategies are needed to enhance the T cell infiltrate and boost endogenous antitumor immunity. Many promising strategies have been developed; however, they are often associated with immune-related adverse events and require expensive patient-specific formulations. In this work, we aim to develop an in-situ cancer vaccine that relies on endogenous patient-specific tumor neoantigens. The benefit of this approach is that it can be tumor agnostic and is readily available without additional formulation. To achieve this, we engineered CpG-p(PDS-Man), a potent adjuvant-polymer conjugate able to bind unpaired cysteines on the tumor cell surface and on extracellular tumor debris in the tumor microenvironment. CpG is a potent adjuvant in clinical development and conjugating it to our cysteine binding polymer allows for sustained delivery in the tumor microenvironment, eliciting a strong antitumor immune response against endogenous tumor antigens. In this work, we found that our CpG-p(PDS-Man) conjugate could be readily constructed and purified. Upon intratumoral injection, CpG-p(PDS-Man) prolonged survival in multiple murine tumor models, including in tumors resistant to checkpoint inhibitors, such as the B16F10 melanoma. Furthermore, we found decreased systemic toxicity of our construct compared to free adjuvant. Our developed platform demonstrates a flexible, ready-to-use adjuvant-based immunotherapy that can trigger a widespread anti-tumor immune response with the appropriate vigor for successful treatment. Our research illustrates the potential of using CpG-p(PDS-Man) as a treatment platform for various types of cancer. 000005714 542__ $$fCC BY-NC-ND 000005714 650__ $$aBiomedical engineering 000005714 650__ $$aPolymer chemistry 000005714 650__ $$aImmunology 000005714 653__ $$aCancer Immunotherapy 000005714 653__ $$aCancer Vaccine 000005714 653__ $$aCpG 000005714 653__ $$aPolymer-Drug Conjugate 000005714 653__ $$aTLR9 000005714 690__ $$aPritzker School of Molecular Engineering 000005714 7001_ $$aBennish, Levi Y.$$uUniversity of Chicago 000005714 72012 $$aJeffrey Hubbell 000005714 72014 $$aAaron Esser-Kahn 000005714 72014 $$aMelody Swartz 000005714 8564_ $$9bfac08d7-58cd-4907-a128-f97013c57dfe$$s2178257$$uhttps://knowledge.uchicago.edu/record/5714/files/Bennish_uchicago_0330D_16755.pdf$$eEmbargo (2025-03-22) 000005714 909CO $$ooai:uchicago.tind.io:5714$$pDissertations$$pGLOBAL_SET 000005714 983__ $$aDissertation