Dr. Patricia Ernst and Dr. Terry Fry at the Human Immunology and Immunotherapy Initiative at University of Colorado School of Medicine and Children’s Hospital of Colorado, whose project is entitled “Developing a pediatric B-ALL model to uncover epigenetic mechanisms of relapse from CAR-T cell immunotherapy,” and focuses on developing more effective CAR-T immune therapy treatments to prevent relapse in poor-prognosis leukemia. The improvement in the survival of children diagnosed with leukemia represents one of the most inspiring cancer treatment success stories in the last 50 years. However, certain types of poor-prognosis childhood leukemias do not respond to current therapies. In addition to optimized use of conventional chemotherapy, a promising new strategy utilizing the patient’s own genetically engineered immune cells (termed chimeric antigen receptor or CAR T cell therapy) has remarkably improved prognoses of children with a type of leukemia called “B cell acute lymphocytic leukemia”, or B-ALL. However, the same poor-prognosis B-ALL also has a remarkable propensity to evade chemotherapy or CAR T cell therapy resulting in a high relapse rate. This proposal will focus on how this leukemia evades CAR T cell therapy by developing new model systems in which we can study how this immune evasion occurs. In this proposal, we will establish a childhood B-ALL model system in which we can determine how the leukemia escapes CAR T cell treatment and explore effective combinations of immune therapy and other therapeutic modalities to prevent relapse in young patients that suffer from this poor-prognosis leukemia.

Dr. Tsz-Kwong “Chris” Man at the Cancer Genomics and Genetics Program at Baylor College of Medicine and Texas Children’s Cancer Center whose project is entitled “The Role of CXCL 10-CXCR3 AXIS in Osteosarcoma Metastasis,” and seeks to develop a biomarker-guided treatment approach that will eliminate metastasis in osteosarcoma. Osteosarcoma is the most common malignant bone tumor in adolescents and young adults representing significant costs in terms of the suffering and economic and emotional burdens of these patients and their families. Currently, children with osteosarcoma are treated with a combination of surgery and chemotherapy. Nonetheless, no specific therapies are available for patients with a metastatic disease. For this reason, the survival of osteosarcoma patients has been stagnant over the past three decades, while the outcome of metastatic patients remains dismal with a survival rate less than 20%. To overcome this lack of progress, the field has recently reached a consensus that the development of innovative strategies to target metastatic progression may hold the key for new therapeutics advancements. The long-term goal of our study is to specifically address this critical but unmet need by developing a novel and effective biomarker-guided therapeutic approach that can abolish metastasis in osteosarcoma. Based on our previous study and preliminary data, we propose to examine the role of the chemokine axis CXCL10CXCR3 in osteosarcoma and elucidate its relationship with the tumor suppressor p27 for metastatic promotion. The study is significant because it will eliminate the bottleneck of current chemotherapy-based treatments to increase the survival of metastatic patients. Determining the causative role of CXCL10 in osteosarcoma metastasis will likely advance the clinical management of this deadly childhood cancer.

Dr. Martina Roos, Dr. Vivian Chang and Dr. John Chute at The David Geffen School of Medicine at UCLA, whose project is entitled “Novel Targeted Therapy to Eliminate Leukemic Stem Cells in Pediatric Acute Myeloid Leukemia,” and seeks to develop a pioneering approach to target pediatric leukemic stem cells that could very likely lead to a new class of drugs for precision medicine in pediatric AML therapy. Relapse following initial treatment is the biggest problem in pediatric acute myeloid leukemia (AML), a devastating blood cancer where blood producing stem cells are damaged and become abnormally functioning, chemotherapy-resistant leukemic stem cells. We identified novel compounds that inhibit important growth mechanisms of these leukemic stem cells and show remarkable anti-leukemia activity in animal models of pediatric AML. We believe that our project is a pioneering, innovative approach to target pediatric leukemic stem cells and has high potential to develop a new class of drugs for precision medicine in pediatric AML therapy.