Development of T cell receptors targeting the common cancer antigen PRAME in pediatric malignancies
Antigen presentation is a universal process in which proteins in a cell are degraded into small fragments (peptides) and displayed on the cell surface for interrogation by the immune system. If a peptide is derived from an abnormal protein (i.e. viral or mutated protein), T cells of the immune system recognize it as foreign and destroy that cell. Since malignant cells also present peptides, T cells recognizing abnormal, cancer-specific peptides can stimulate a potent anti-tumor immune response. This immune response is the basis of modern immunotherapy and can produce complete and durable regression of solid tumors. Pediatric sarcomas are associated with relatively few mutations and no known associations with viral infection. Developmental and reproductive genes which are absent from mature tissue, are occasionally expressed in tumors and can also be targets for immunotherapy. Our group recently performed a widespread search for such genes from nearly 800 pediatric solid tumors. The most frequently overexpressed targetable antigen was PRAME, a gene expressed in embryonic development and adult reproductive organs but absent from normal mature tissue. The unique overexpression of PRAME in pediatric sarcomas makes it an ideal target for T cell immunotherapy. The overall goal of this grant is to develop T cells which can specifically recognize PRAME-derived peptides and generate a potent anti-sarcoma immune response. Each T cell in the body is specific for a single antigen due to the presence of a unique protein complex called the T cell receptor (TCR). It is estimated that each person has >10 million unique TCR clonotypes, each with unique protein specificities. The purpose of our study is to identify TCRs which have specific recognition of peptides derived from PRAME. TCRs can be subsequently cloned, optimized, and transferred to large numbers of T cells, giving the patient’s immune system the new ability to recognize and kill cancer cells expressing PRAME. In Specific Aim 1, we plan to enhance the functionality of a previously identified anti-PRAME TCR. In Specific Aim 2, we will isolate new TCRs which have high functional avidity to PRAME peptides using a pipeline which we have optimized. T cells engineered to target developmental or reproductive genes reactivated in cancer have had success in adult cancers like melanoma, synovial sarcoma, and multiple myeloma. Our long-term goal is to translate this success to pediatric sarcomas which has lagged far behind in target identification and development of successful immune therapies. The studies proposed herein will help develop a targeted immune therapy against one of the most frequently overexpressed sarcoma antigens identified to date and will provide the foundation for launching a Phase 1 Clinical Trial, through the NCI Pediatric Oncology Branch.