Chimeric Antigen Receptor Modified Natural Killer Cells for the Treatment of Solid Tumors - Project Summary/Abstract The objective of this proposal is to develop a Natural Killer (NK) cell-based immunotherapy for the treatment of pediatric solid tumors. The use of chimeric antigen receptors (CAR) to augment T cell responses towards cancers has been successful and translated to the clinic for CD19+ hematological malignancies. Conversely, the use of CAR T cells for the treatment of solid tumors has been largely unsuccessful; highlighting the need for alternate strategies and methodologies. Unfortunately, CAR T cell therapies are fraught with catastrophic and fatal adverse events. The use of NK cells for CAR-based therapies is still in its infancy compared to T cells; part of this is because they are understudied. NK cells possess a panoply of germline encoded receptors that help dictate how NK cells react to target cells. These receptors allow NK cells to decide which cells to kill or not, with the addition of powerful signaling from CARs NK cells can still decide which cells to target. Furthermore, NK cells from an unrelated donor may impart the most potent anti-tumor activity and selecting the correct pairing will be critical to CAR NK cell clinical success. Thus, my overarching hypothesis is that NK cells will be better suited than T cells to eradicate malignant cells and preserve healthy cells reducing the risk of adverse effects. This hypothesis will be evaluated in two interrelated research aims. Aim 1 explores the novel orientation and organization of monomeric CAR NK cells with synapse augmentation, Aim 2 is focused on defining a donor selection algorithm for CAR NK cell products. I will pivot from the standard dimeric CAR designs that lead to dysregulated signaling and cellular dysfunction to an optimized monomeric design that has a stable off state reducing aberrant signaling. Donor variability is a critical factor when determining optimal cell source for cell therapies and, to date, the clinical selection parameters for NK cells, I believe, hobbles their full potential. I will utilize in silico protein modeling with functional testing to define a new selection method for donor cell sources. The proposal and will be initially performed at St. Jude Children’s Research Hospital, a state-of-the-art NCI- designated comprehensive cancer center. At the conclusion of the K22 award I will have delineated novel modification CAR designs and a universal donor bank selection algorithm for CAR NK cells. This will allow for the progression of CAR NK cell therapies to translate into the clinic and embodies the goal of the NCI “…to advance scientific knowledge and help all people live healthier, longer lives.”
