Chimeric Antigen Receptor Modified Natural Killer Cells for the Treatment of Solid Tumors
openNCI - National Cancer Institute
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.”
Up to $193K
health research