Children's Hospital of Pittsburgh Archives - Page 2 of 4

2019

Scholar Grant

Craig Byersdorfer

Pittsburgh, PA

Title: Minimizing Cell Therapy-associated Cytokine Release Syndrome

Executive Summary:
Leukemia remains one of the most common pediatric cancers and high-risk leukemias remain difficult to treat. Using chimeric antigen receptors (CAR) to reprogram T cells to recognize cancer antigens can achieve cure rates >60% in these challenging clinical scenarios, but CAR T cell administration is beset by life-threatening complications including cytokine release syndrome (CRS). CRS, in turn, is driven by massive production of pro-inflammatory cytokines including interleukin-6 (IL-6). Our lab has preliminary data demonstrating that T cells lacking the metabolic energy sensor AMP-activated protein kinase (AMPK) lack both a sensitivity to IL-6 and exhibit a decreased ability to make IL-6 following stimulation. From these data, we hypothesize that targeting AMPK in human CAR T cells will reduce CRS toxicity, through an impaired propagation of early IL-6 signals, but will still allow for maintenance of robust anti-leukemia responses. We will test these hypotheses in two Specific Aims:
Aim 1: Inhibition of AMPK in human CAR T cells
Aim 2: Reduction of CRS using AMPK-deficient cells

From these Specific Aims, we predict the following outcomes:
– Generation of human CAR T cells with impaired AMPK signaling
– Confirmation of AMPK’s role in controlling IL-6 sensitivity in human T cells
– Determination of AMPK’s necessity during CAR T cell-driven anti-leukemia responses
– Elucidating the importance of T cell-related IL-6 signaling in the propagation of CRS
– Development of novel approaches to mitigate CRS in the clinic and hospital

Goals of the project
– Make cancer-fighting immune cells less inflammatory by removing a key metabolic enzyme
– Test our modified immune cells to ensure they continue to fight leukemia while still reducing potential toxicities

Ultimately, the benefit to pediatric cancer we seek is an improved treatment of children with high-risk leukemia. Genetically modified immune cells have enormous therapeutic potential to treat and even cure high-risk relapsed or refractory leukemia. However, administration of genetically engineered cells has serious side effects and can result in life-threatening complications. Finding novel ways to lessen the toxicity of immune-based therapies, without compromising their efficacy, is the next step forward in improving the care of children with high-risk disease and will make the application of a revolutionary treatment more tolerable. In addition, the increased knowledge gained from these studies regarding in vivo T cell biology and important immune cell interactions, is likely to have a profound impact on our development of the next generation of novel, immune-based therapies for the treatment of high-risk and difficult-to-treat cancers.