Project Summary On October 1st, 2015, the FDA granted accelerated approval for the combination of anti-CTLA-4 and anti-PD-1 monoclonal antibodies showing 1-year survival of 94% and 2-year survival of 88% in patients with metastatic melanoma. These treatments, collectively referred to as immune checkpoint blockade therapies (ICBs), comprise a successful class of systemic immunotherapies. Nevertheless, a major subset of patients still do not respond in the long-term to current ICBs and this failure is likely due to the inability of ICBs to generate potent cytotoxic T lymphocyte (CTL) responses against cancer antigens as well as the tolerizing effects of so-called “cold” tumors. Thus, in order to turn non-responsive cold tumors into treatable “hot” tumors, there are countless preclinical investigations exploring other immune pathways that can be pharmacologically modulated as combination immunotherapy strategies. This has resulted in more than 1800 ongoing clinical trials in the US alone looking to combine ICBs with synthetic immunomodulators (IMs) in order to improve long-term survival in cancer patients. A major unmet need with these IMs is the ability to administer multiple therapeutic doses systemically in a safe manner to effectively treat the disease in a metastatic setting. Drug delivery systems and rational dosing schedules have the potential to reduce the toxicity of such compounds that activate the immune system, and they could enable treatment of tumors that do not respond to ICBs via kinetically controlled, targeted and precisely timed delivery of immunomodulating drugs. In the F99-phase of the proposed research, Sachin Bhagchandani will leverage the control of bottlebrush polymers (BBPs) to improve cancer immunotherapy through increasing the therapeutic index of IMs by enabling precise control over the release of these compounds and targeting them to the necessary immune cell subsets in the tumor microenvironment. In the K00-phase of the proposed research, Sachin will focus on understanding immune tolerance post initial dosing of IMs in order to design appropriate dosing schemes to circumvent tolerance since these immunotherapy treatments will require repeat dosing in order to drive an antitumor immune response. The preliminary data generated with BBPs provides a strong basis to systemically deliver these IMs by tuning drug-linker chemistry and aspect ratio (F99 phase) and defining tolerance mechanisms and dosing schedules to obtain parameters that are effective in genetically engineered mouse models which are currently refractive to ICBs (K00 phase).