Injectable Controlled Delivery Immunotherapies for the Treatment of Melanoma

dc.contributor.authorHwang, Mintai Peter
dc.contributor.chairWang, Yadong
dc.contributor.committeeMemberPutnam, David A.
dc.contributor.committeeMemberSingh, Ankur
dc.description.abstractThe World Health Organization estimates close to 10 million deaths each year due to cancer. In particular, melanoma is a highly aggressive and metastatic skin cancer that has nearly tripled and quadrupled in incidence since 1975 among female and male populations, respectively. The clinical mainstay for the treatment of melanoma continues to include surgical resection. While earlier treatment plans included chemotherapy in conjunction with surgery, sub-par patient responses and the recent advent of checkpoint inhibitors have shifted much of the focus towards a combinatory approach of surgery and immunotherapy. Comprised of immune-activating cytokines such as IL-2 and checkpoint inhibitors such as αPD-1 and αCTLA-4 antibodies, current immunotherapy regimens necessitate a high dose to overcome immunosuppressive tumor mechanisms. However, due to the nature of immunotherapy, in which immune activators are enhanced while inhibitors are suppressed, severe adverse effects are commonly observed. Furthermore, the high cost of immunotherapy results in an unsustainable economic model; the annual use of αPD-1 antibody alone would generate a bill of over $1,000,000 per patient. Taken together, the use of a controlled delivery platform is highly attractive in its capacity to preserve its payload while simultaneously protecting patients against immunotoxicities. This dissertation examines the utility of various controlled delivery platforms for different immunotherapeutic proteins including IL-12 and αPD-1 antibody. The first part examines the feasibility of using a heparin-based complex coacervate platform to deliver IL-12 in the context of a pre-clinical murine melanoma model. Our results are the first to demonstrate the use of complex coacervation to deliver proteins for anti-cancer applications and provide evidence of significantly improved responses compared to equivalent amounts of IL-12 delivered via bolus injections. The second part of the dissertation investigates the development of a novel polycation using glycine betaine as a pendant group. Our results indicate that the resulting polymer is biocompatible with anti-bacterial and anti-angiogenic properties, underscoring its potential use in anti-cancer applications. Finally, the third part of this dissertation combines the heparin-based complex coacervate with a novel shear-thinning hydrogel based on the glycine betaine-functionalized polycation. The composite platform encapsulates both IL-12 and αPD-1 antibody and is applied in a murine melanoma model. Our results highlight the combined effect of an anti-angiogenic hydrogel and the controlled delivery of immunotherapeutic proteins on improved survival and therapeutic indices. Collectively, this dissertation characterizes the development of minimally-invasive injectable immunotherapies in a preclinical melanoma model.
dc.identifier.otherbibid: 11050785
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.subjectCheckpoint Inhibitor
dc.subjectComplex Coacervation
dc.subjectBiomedical engineering
dc.titleInjectable Controlled Delivery Immunotherapies for the Treatment of Melanoma
dc.typedissertation or thesis
dcterms.license Engineering University of Philosophy, Biomedical Engineering


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