Combination of IL13Ralpha2 CAR T-Cell Therapy with PD-1 Immune Checkpoint Blockade for Treatment of Glioblastoma
Abstract
Dr. Pituch is planning, by performing top-quality, translational research as an independent investigator, to use cutting-edge approaches to develop novel, anticancer immunotherapies. Receiving the Horizon Award would be an honor and will allow her to train in the field of immunology to bring anticancer therapy using adoptive, engineered T cell therapy one step closer to the clinic. The work she proposes to perform within the next 2 years is critical for the preparation of clinical trials utilizing chimeric antigen receptor (CAR) T cells to treat the virtually impossible to cure, predominant brain cancer, glioblastoma multiforme (GBM). The occurrence of brain malignancies, including GBM, is associated with the radiation, chemical agents, and industrial solvents exposure encountered by Service members, Veterans, and their families. Consequently, this immunotherapy has very broad applicability and potential impact for the cancer treatment of the military, pediatric, and adult civil populations. One of the most promising forms of adoptive immunotherapy against cancers like GBM employs a genetically engineered type of immune cells known as T cells to specifically recognize and kill malignant cells. These T cells attack only GBM because they are modified with CAR, special receptors recognizing only proteins called antigens expressed by cancers. CAR T cells produce substances that kill GBM upon engagement with the antigen expressed on the cancer cell. Our CAR T cells are designed to recognize interleukin 13 receptor alpha 2 (IL13Ra2), a receptor that is only expressed on malignant cells, but not other brain cells. We produce CAR T cells that exclusively recognize cancer cells, which enables us to avoid off-target toxicity and the killing of a healthy tissue, a problem encountered by many existing preclinical and clinical studies utilizing CAR T cell immunotherapy. In one type of preclinical GBM model that uses animals without a fully functioning immune system, the therapy with CAR T cells specifically targeting IL13Ra2 (IL13Ra2-CAR T cells) showed encouraging data. Scientists also observed that these CAR T cells did not persist long in the GBM tumor environment, thus suggesting that the cancer milieu might have a negative influence on the wellbeing of CAR T cells. It is already established in the literature that GBM, like many other tumors, deregulates the patient’s own immune system by modulating the activity of an immune checkpoint molecule named programmed cell death 1 (PD-1) to evade immune system attack. In healthy individuals, one of the ways that negative responses of the immune system against its own healthy cells are prevented is by the induction of irresponsiveness and/or death of overactive T cells by such immune checkpoints. These processes, possibly mediated by the PD-1 activity, might negatively affect CAR T cell population and lower their persistence in GBM. Importantly, modulation of this checkpoint in other malignancies showed impressive clinical results. Recently published literature investigating other CAR T cell immunotherapy and our preliminary data suggest that combining treatments that target PD-1 might help CAR T cells to survive for longer and execute enduring action against GBM. We will explore the prospective of combining IL13Ra2-CAR T cell therapy with a PD-1 checkpoint blockade against GBM in an animal model with a normally functioning immune system to also determine the involvement of the immune system and GBM to CAR’s function. After completing the proposed experiments, we will better understand the effect of a PD-1 blockade on the regulation of IL13Ra2-CAR T cells. In turn, this will help scientists streamline future treatments utilizing IL13Ra2-CAR T cells for GBM and other IL13Ra2-expressing cancers.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710411
Entities
People
- Katarzyna Pituch
Organizations
- Northwestern University
- United States Army