SUMMARY: Researchers from UCLA’s Department of Neurosurgery and Pharmacology have developed a rapid discovery platform for the identification of tumor-specific T cell receptors to aid in more personalized and potent immunotherapy for glioblastoma. BACKGROUND: Over the past several years, immunotherapy, or therapies that enlist and strengthen the power of a patient’s immune system to attack tumors with specificity, has emerged as a powerful tool in cancer treatment. To a large extent, the specificity and effectiveness of immunotherapy is dependent on the recognition of specific tumor antigens called neoantigens. For solid tumors, which represent approximately 90% of adult human cancers, a promising immunotherapy strategy is to identify tumor-reactive T cell receptors (TCRs) and to then engineer these receptors into cells capable of mediating a response once infused back into the patient (TCR-T). Most solid tumors have limited immunotherapy treatment options in large part because of the lack of known tumor-specific antigens to target cancer cells with, and the unique immunosuppressive environment associated with solid tumors. TCR-T overcomes these challenges by harnessing a bespoke population of polyclonal TCRs that are identified as reactive to a particular solid tumor. T cells that express these TCRs can be enhanced with phenotypes that encourage activity in spite of the immunosuppressive tumor microenvironment. Development of this strategy has great urgency particularly for the treatment of moderately immunogenic, heterogeneous, and aggressive cancer types, such as glioblastoma (GBM), that have a low patient survival rate – 12 to 18 months for GBM, when treated with the current standards of care that include surgery, chemotherapy, and radiotherapy. However, despite the promise of available immunotherapies, most clinical trials for patients diagnosed with GBM have produced disappointing results to date. Therefore, significant innovation is needed to advance TCR-T for glioblastoma and other heterogeneous cancers. INNOVATION: UCLA researchers in the Department of Neurosurgery and Pharmacology have developed a rapid approach to identify tumor-specific T cell receptors (TCRs) for more personalized and powerful immunotherapy against glioblastoma. Their approach was two-phased; first, using a discovery platform they call Isoform peptides from RNA splicing for Immunotherapy target Screening (IRIS), they successfully identified a series of conserved alternative splice neoantigens from bulk RNA sequencing data; demonstrated on more than 40 glioblastoma and brain metastasis patients. They then synthesized 1000s of TCRs based on the IRIS results and isolated a library of neoantigen-reactive TCRs that recognized alternative splicing variations identified in the IRIS pipeline. Together, this novel approach for identifying tumor-specific T cell receptors could progress personalized TCR-T and off-the-shelf TCR-T targeting alternative splicing based neoantigens towards the clinic. POTENTIAL APPLICATIONS: ● Platform for the identification of tumor-specific T cell receptors, allowing for more potent and personalized immunotherapy against glioblastoma and other solid tumor cancer types ADVANTAGES: ● Synthesis of a library of T cell receptors from single cell sequencing data is fast (days) and affordable ● Identified T cell receptors are tumor-specific ● T cell receptors can recognize a variety of tumor antigens across multiple human leukocyte antigen (HLA) types DEVELOPMENT-TO-DATE: Researchers have successfully used the IRIS pipeline and Jurkat reporter cells to identify and confirm neoantigens, and are continuing to collect data on neoantigen-reactive TCRs.