Toward safe, systemic immunotherapies for treatment of metastatic disease: Developing dendritic cell-biased immunomodulators with precise control over magnitude and timing of immune stimulation

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).

Grant Number: 5K00CA264404-05
NIH Institute/Center: NIH
Principal Investigator: Sachin Bhagchandani