Augmenting tumor antigen re-presentation to improve immunity to cancer

Immuno-oncology (IO) has revolutionized the treatment of cancer by harnessing and boosting the inherent ability of the immune system to recognize and eliminate tumors. However, only a small portion of patients treated with any single cancer immunotherapy demonstrate a response. Importantly, those patients who do respond, do not typically experience durable long-term benefit. Therefore, it is vital for us to determine how immunotherapy can overcome the barriers to potent anti-tumor immune responses in a greater proportion of patients. An initial requirement for the long-term (i.e., memory) and widespread (i.e., systemic) immune responses is recognition of the tumor by the immune system. This basic function of immunity is thwarted by properties and capabilities of the cancer that allow it to develop and persist. Fundamental among these is reduction and suppression of innate tumor antigen presentation which prohibits memory and systemic adaptive immune responses. Although precision medicine increasingly is allowing us to determine mutations shared across patients with similar tumor types, our current knowledge of which resulting mutation-induced tumor antigens should be targeted for optimal anti-tumor immune responses is lacking. Further, the cost and time necessary to develop these personalized therapies is prohibitive and related clinical trials, thus far, have not demonstrated improved cancer outcomes. Importantly, we know that the immune system is capable of effective responses even in the context of extreme danger. When antigens associated with danger are visible to a stimulated immune system, such as in the context of pathogens, potent actions are taken by immune populations. The hazardous cause is removed, and specific long-term and systemic immunity is created To recreate such outcomes in the context of cancer, in this dissertation work I have sought to develop an efficient, cost-effective, rapidly constructed platform to create augmented anti-tumor immune responses within the tumor microenvironment. Specifically, I have targeted improving tumor antigen presentation by re-presenting the whole spectrum of tumor antigens to the immune system via the utilization of nanoparticle biotechnology. I have termed this platform, the Antigen Maximizing Presentation System [AMPS]. The strength of the approach is that it does not require a priori knowledge of the antigens (including sequence or number) that need to be targeted for an optimal immune response. It is not limited to any specific type of tumor, and it utilizes inherent potent immune responses to deliver improved anti-tumor immunity. Our findings in the context of a mouse melanoma (B16-F10) model suggest that antigen presentation is improved by this platform and results in reduced tumor growth.Ph.D.Includes bibliographical reference