Splicing Up PD-L1 for Immunotherapy Enhancement in Pediatric Neuronal Tumors
Abstract
One of the most aggressive non-rhabdomyosarcoma soft tissue sarcomas plaguing our pediatric population is malignant peripheral nerve sheath tumors (MPNST). This type of sarcoma has a bleak prognosis due to high relapse rates and metastasis. Though immunotherapy is a possible treatment, pediatric oncologists face common roadblocks, such as adverse side effects and this tumor s acquired resistance to treatment. Thus, there is an urgent need for alternative therapeutic approaches. Malignant peripheral nerve sheath tumors are deceitfully innovative, utilizing the body s immune system to increase the tumor s resistance to an adverse immune response. These tumor cells use a process called deregulation, in which the action of the immune system becomes suppressed. In binding a protein that keeps the body s immune responses regulated, known as PD-L1 (programmed cell death ligand-1), to a protein found on T cells called PD-1 (programmed cell death protein 1 receptor), T cells (the immune system regulator of foreign substances) are tricked into NOT destroying PD-LI containing cells, including these tumors. AntiPD-L1 antibodies can alter this downregulation in some cases, but tumors overcome this antibody treatment by secreting an alternative PD-L1 ligand. We are working to understand how to reverse the tumors ability to overcome therapy through the PD-L1/PD-1 pathway. A process by the name of alternative splicing allows tumors to produce the secreted PD-L1 isoform. By abolishing its capacity to create such isoforms, this process may also be a way to reverse the tumor s immunosuppressive ability. Splice-switching-oligonucleotides (SSOs) can interfere with splicing, increasing events such as exon skipping to create isoforms that work in favor of the immune response. Our work will test the hypothesis that SSOs can be used to inhibit the formation of full-length PD-L1 in order to decrease expression of PD-L1 on the tumor cell membranes, preventing the cellular interaction with T cell-associated PD-1 receptors. We are hopeful that this line of research will ultimately lead to improved survival rates for children that are not responsive to current MPNST treatment regimens. If the data from this study is promising, it will prospectively warrant a human clinical trial. A clinical trial will allow us to partner with clinical and translational colleagues in designing a pilot and applying for funding through the National Cancer Institute. We will team up with our industry partner Ionis Pharmaceuticals to design and produce our splice-altering therapy. Because Ionis has successfully shepherded three nucleic acid drugs from development through clinical trials, U.S. Food and Drug Administration approval, and into the clinical marketplace, there is a good chance for a quick transition into clinical practice.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252311073
Entities
People
- Kevin Cassady
Organizations
- United States Army