Enhancing the Responsiveness of Gliomas to Immunotherapy by Pharmacological Inhibition of Chek2: Setting the Stage for a Clinical Trial
Abstract
Dr. Dmello is preparing to be an independent investigator by performing top quality, translational research on a clinically relevant problem. Receiving the Horizon Award would be an honor and will allow her to be trained in the field of genomics and immunology, to evaluate the therapeutic potential of the novel therapeutic strategy in preclinical setting. The work she proposes to perform within the next 2 years is critical for the preparation of clinical trials utilizing combination of PD1 blockade and Chek2 inhibitor, to treat one of the most untreatable tumors, glioblastoma (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 combinatorial approach has very broad applicability and potential impact for the cancer treatment of the military, pediatric, and adult civil populations. GBM is the most common and malignant of all primary brain tumors in adults. Unfortunately, in spite of extensive research and the use of multimodal therapeutic strategies, the median overall survival time is 20 months from diagnosis. However, despite the use of a wide variety of immune therapeutic strategies such as vaccines, dendritic cells, adjuvants, adoptive cellular therapies, and immune checkpoint inhibitors, immunotherapy has not shown efficacy in the treatment of gliomas. Hence, we wanted to make the GBMs more immunogenic in order to be responsive to immunotherapy. Cancer-cell-intrinsic genetic traits are known to dictate the immune landscape around it. Among all the genes in the genome, kinases are potentially relevant in modulating the response to immunotherapy in GBM because: (1) Kinase signaling pathways like RTK/Ras/PI3K are found to be altered in 86%-89.6% of GBM cases studied. (2) Tumor intrinsic kinases are known to modulate response to immune cells. (3) Kinases are druggable, and some kinase inhibitors are blood-brain barrier permeable. (4) Cancer development and progression is dependent on its kinase activity. Furthermore, our patient cohort showed enrichment of BRAF/PTPN11 mutations among tumors responsive to anti-PD-1 therapy, which warrants the need to investigate the causal relationship between kinases over-represented in GBM and response to immunotherapy. An in-vivo kinome knockout CRISPR screen was performed to identify kinases that limit the tumor immunogenicity, in turn leading to escape from CD8 T-cell response. Absence of checkpoint kinase 2 (Chek2), which has a central role in DNA damage response (DDR), was found to render the tumor cell vulnerable to CD8 T cell recognition. Therefore, we want to investigate if the combination of Chek2 inhibitor and PD1 blockade would make the GBMs more vulnerable to T-cell mediated immune response. Prexasertib (a Chek1/2 inhibitor), that is in clinical trials for breast, ovarian, and pediatric solid tumors including Central Nervous System Neoplasms will be used to deplete Chek2 in our glioma model. During the 2-year time course of this project we will evaluate the effect of Chek2 depletion on T cell function (effector/memory) both in an in-vitro and an in-vivo setting. We will assess the synergistic effect of combination of Chek2 inhibition and PD1 blockade on the survival of preclinical GBM models and characterize the mutations acquired in Chek2 depleted tumors that render them vulnerable to CD8 T cell recognition. Chek2 inhibition mediated response to immunotherapy as a novel therapeutic strategy for the treatment of GBM will benefit a large number of GBM patients since 97% of the GBMs are refractory to immunotherapy. In addition, our pre-clinical studies of Chek2 inhibition with PD1 blockade immunotherapy will set the foundation for the clinical trials in glioma patients.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010850
Entities
People
- Crismita Dmello
Organizations
- Northwestern University
- United States Army