Precision Combinatorial Immunotherapeutic Targeting of Cytokine Receptor Kinase Signaling in CRLF2-Rearranged ALL
Abstract
Fiscal Year 2018 (FY18) Peer Review Cancer Research Program (PRCRP) Topic Area(s): (1) Blood cancers, (2) Immunotherapy, (3) Cancer in children, adolescents, and young adults Scientific Objective and Rationale: While cure of most children with leukemia using modern treatment regimens is one of the major cancer treatment success stories in the last 50 years, outcomes remain poor for most adults with leukemia and for children with certain types of high-risk leukemias when treated with best-available chemotherapy. Recent advances in targeted therapies that attack specific proteins on or within cancer cells have the potential to decrease relapse and increase cure rates for such patients. One type of novel therapy involves drugs targeted at important pathways within the leukemia cells that contribute to their cancerous behavior. Although these targeted inhibitor drugs have shown promise in the laboratory and in patients, leukemia cells often eventually outsmart the drugs and become resistant. A second promising targeted therapy uses genetic engineering of patients own immune cells to see and then powerfully kill leukemia cells (termed chimeric antigen receptor or CAR T cell therapy). CAR T cell therapies have remarkably improved outcomes for some children with a type of leukemia called B cell acute lymphocytic leukemia (B-ALL), although we now know that B-ALL can also learn to evade and become resistant to CAR T cell therapy. This proposal will focus on how to best combine these two new treatments (targeted inhibitor drugs and CAR T cells) against a specific high-risk type of B-ALL that has mutations in a gene called CRLF2. This leukemia type occurs commonly in both children and adults with B-ALL and is poorly responsive to usual chemotherapy treatments, demonstrating a need for novel therapies. In this project, we will also study normal T cell biologic characteristics in typically difficult-to-treat patients such as children with Down syndrome and older adults to develop the best CAR T cell therapy approaches for these medically fragile populations that may help to minimize toxic chemotherapy in the future. Our prior laboratory studies have been swiftly translated into active clinical trials testing new targeted therapies in patients with high-risk leukemias. We anticipate that results from the current studies will similarly engender the next generation of clinical trials of novel immunotherapies in patients with these high-risk types of blood cancers within 2-3 years of study completion. FY18 PRCRP Military Relevance Focus Area(s): B-ALL is the most common childhood cancer and the second most common leukemia of adulthood. The CRLF2-rearranged leukemia subtype occurs in 15%-20% of children and adolescents with high-risk B-ALL, 60% of children with Down syndrome-associated ALL, and 20%-40% of adults with B-ALL. Our studies thus have broad relevance for treatment of patients with leukemia across the age spectrum and, importantly, are directly relevant to the care of active military personal and Veterans who develop leukemias or whose dependent children develop leukemias.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910196
Entities
People
- Terry Fry
Organizations
- United States Army
- University of Colorado Denver