Single-Cell Multi-Omics Integration to Exploit Autoimmunity Induced by Checkpoint Immunotherapy in Malignant Pleural Mesothelioma
Abstract
The proposed work is motivated by the Fiscal Year 2021 (FY21) Peer Reviewed Cancer Research Program (PRCRP) Overarching Challenge Improve immunotherapy and eliminate the risks of therapy-associated toxicity in malignant pleural mesothelioma (MPM). MPM is a rare and highly aggressive malignancy characterized by unique morphology, which is a lining around the lungs that is usually acquired by inhaling asbestos fibers. Military personnel and Veterans are at higher risk for MPM from asbestos exposures. Treatment for mesothelioma has included surgery, chemotherapy, and radiation, but these measures are not very effective. Despite significant efforts to develop novel therapeutics, a 5-year overall survival rate of patients with MPM still remains less than 5%, regardless of stage. A new hopeful treatment strategy against this cancer targets a cell structure called immune checkpoints. Cancer cells use these immune checkpoints to hide from the body’s own immune system. Immune checkpoint inhibitors (ICIs) block the immune regulatory checkpoint receptors that can boost up our own immune system. As the recent clinical trial showed that checkpoint immunotherapy in MPM significantly prolong the survival over traditional chemotherapy, ICIs has been now a standard of care of MPM. However, immunotherapy causes side effects called immune-related adverse events (irAEs), some of which severely affect vital organs such as the heart, lungs, pancreas, skin, and guts. Given the increasing use of ICIs in MPM, the incidence of irAEs is expected to rise, especially since irAEs may occur in up to 90% of cases affecting any organ system. Approximately 30% of ICI-treated MPM patients develop serious adverse events, requiring discontinuation of immunotherapy. However, there are no biomarkers to predict or clinical tools to detect early signs of potentially serious irAEs. Furthermore, there are no strategies to prevent vital organs from causing side effects, without deterioration of tumor-killing immune response. Therefore, understanding who develops these toxicities, why many patients develop them, and what impact they have on response to therapy is an essential part of optimizing the use of ICIs and an important public health question of high clinical significance. The goal of this research is to identify new biomarkers in the blood to predict who can benefit from immune checkpoint therapy, who is likely to survive long-term, and to determine how the cancer of each individual patient will react to immunotherapy. That way, patients may avoid unnecessary toxicity associated from the wrong treatment and ultimately live longer with better quality of life. Our studies are greatly facilitated by a multidisciplinary team of investigators with expertise in autoimmune diseases, bioinformatics, and onco-immunology from the Mesothelioma Treatment Cancer, which was founded by a legendary MPM surgeon, Dr. David J. Sugarbaker, and the Immunotoxicity Working Group at Baylor College of Medicine. By bringing together a team of multidisciplinary researchers and health care providers whose expertise spans basic, translational research, as well as cutting-edge immunology, this study is ideally poised to make substantial inroads for precision immunotherapy in patients with MPM, including military Service Members, Veterans, and their families in a way that is consistent with the PRCRP’s goals.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210657
Entities
People
- Hyun-sung Lee
Organizations
- Baylor College of Medicine
- United States Army