Project Summary
Cardiotoxicities associated with small molecule cancer therapeutics are well documented. However,
emerging reports of adverse cardiac reactions due to monoclonal antibody-based immune checkpoint
inhibitors (ICIs) is a growing concern. These ICIs act on programmed cell death protein 1 (PD-1) receptor or
its ligand programmed cell death-ligand 1 (PD-L1) enhancing antitumor response, and these often lead to
such immune-related adverse events (iRAEs). Several studies point toward the homology between tumor
antigens and cardiac proteins as one of the reasons for outcomes such as myocarditis, changes in cardiac
rhythm, and vasculitis.
Due to the rare, early detection iRAEs and scarcity of patient samples. The mechanism of ICI-induced
cardiac disease remains elusive. Hence, utilizing a unique multi-disciplinary approach and expertise in
induced pluripotent stem cell (iPSC) technology, immunology and bioengineering strategies, I hypothesize
that, iPSC-derived 3-D cardiac organoids (COs) with immune cells can be used to model ICI-induced cardiac
injury. Unraveling the disease mechanism of cardiac injury due to ICI treatment using a reductionist approach
may lead to discovery of new targets that can confer cardioprotection for immunotherapies. In order to
accomplish this goal, I have defined three specific aims: (1) I will generate COs through self-assembly of
iPSC-cardiomyocytes, iPSC-endothelial cells and iPSC-cardiac fibroblasts and test two commonly used ICIs
Pembrolizumab (PD-1 inhibitor) and Atezolizumab (PD-L1 inhibitor). I will for assess for changes in CO
function in the presence and absence of peripheral blood mononuclear cells (PBMCs) used for iPSCs
derivation (2) I will conduct in-depth molecular analyses of the COs at a single cell level and identify potential
targets responsible to hyper immune response can cardiac dysfunction (3) Finally, I will use cutting-edge
genome editing techniques to knockdown the gene targets that help rescue the CO function after ICI
treatment. The targets identified in Aim 2 will be validated again in mouse models by injecting ICIs into mice
with diverse immune backgrounds followed by evaluation of heart function and molecular changes within the
tissue.
In this multidisciplinary project, with the support from my esteemed panel of mentors, advisors and
collaborators, I am confident that I will receive par excellence training to accomplish both scientific and career
development goals. Given my scientific track record to date, and complementary training sought through this
K99/R00 award, together will help me develop and lead several research areas building toward a successful
independent career.