Terry J. Fry, M.D.
Pediatric Oncology Branch
Building 10 - Hatfield CRC, Room 2-3942
Bethesda, MD 20892-1104
Hematologic Malignancies Section
Despite substantial improvements in outcome over the past 3 decades, leukemia remains the leading cause of cancer-related mortality in children. Furthermore, even in patients cured by modern risk-adapted therapy, there are substantial long-term sequelae. Thus, newer treatments are needed, particularly those not based on standard cytotoxic agents. The Hematologic Malignancies Section (HMS) conducts lab-based translational research focused on immunotherapeutic approaches for leukemia. Clinical efforts in the treatment of leukemia occur within the Pediatric Oncology Branch (POB) clinical program where early phase clinical trials are conducted. Studies in immunotherapy for leukemia in the HMS were initially grounded in the optimization of the graft versus leukemia effect that contributes to the curative potential of hematopoietic stem cell transplantation (HSCT) for hematologic malignancies. Much of the work currently taking place in the HMS and in the POB clinical program is now focused on the use of cell-based immunotherapy for pediatric leukemia outside of the HSCT setting as well as more basic studies in leukemia biology related to the bone marrow microenvironment and immune escape. In a particular, the HMS is now heavily focused on the use of genetically modified T cells expressing chimeric antigen receptors (CAR) for the treatment of pediatric acute lymphoblastic leukemia. Initial early phase clinical studies using a CD19-targeted CAR in patients with pre-B cell acute lymphoblastic leukemia (ALL), including a trial conducted in the Branch, have demonstrated a 70-80% complete remission rate. However, not all patients respond and approximately 10% of patients will relapse with leukemia that loses the CD19 epitope targeted by the CAR.
Aim 1: Translational development of chimeric antigen receptors for the treatment of pediatric leukemia. Using in vitro studies and xenograft models of pediatric ALL in immune-deficient mice, the HMS has performed much of the preclinical optimization of a novel CD22-targeted CAR. Dr. Fry will be leading the first-in-human clinical trial using this CAR in children and young adults with relapsed and refractory pre-B cell ALL. The HMS has also developed 2 other CAR constructs that target antigens expressed on pre-B cell ALL that will likely enter clinical trials in the near future. Finally, the HMS is extending CAR therapy to other forms of pediatric leukemia including acute myelogenous leukemia and T cell ALL.
Aim 2: Elucidation of the biologic principles involved in the immunotherapeutic targeting of pediatric leukemia. The HMS utilizes a novel syngeneic murine model of CAR therapy for pre-B cell ALL that is being used to study in vivo biology of CAR therapy in an immunologically intact system. Collectively, these studies have provided an opportunity to study immunotherapeutic resistance of ALL to CAR T cells. Finally, using these syngeneic murine ALL models, the HMS is conducting studies on the role the bone marrow microenvironment plays in immunotherapeutic resistance.
Capitini CM, Nasholm NM, Chien CD, Larabee SM, Qin H, Song YK, Klover PJ, Hennighausen L, Khan J, Fry TJ. Absence of STAT1 in donor-derived plasmacytoid dendritic cells results in increased STAT3 and attenuates murine GVHD. Blood. 2014;124(12):1976-86.
Shand JC, Qin H, Nasholm N, Capitini CM, Fry TJ. Minor antigen distribution predicts site-specific graft-versus-tumor activity of adoptively transferred, minor antigen-specific CD8 T Cells. Biol Blood Marrow Transplant. 2014;20(1):26-36.
Capitini CM, Nasholm NM, Duncan BB, Guimond M, Fry TJ. Graft-versus-host disease impairs vaccine responses through decreased CD4+ and CD8+ T cell proliferation and increased perforin-mediated CD8+ T cell apoptosis. J Immunol. 2013;190(3):1351-9.
Fry TJ, Mackall CL. T-cell adoptive immunotherapy for acute lymphoblastic leukemia. Hematology Am Soc Hematol Educ Program. 2013;2013:348-53.
Mackall CL, Merchant MS, Fry TJ. Immune-based therapies for childhood cancer. Nat Rev Clin Oncol. 2014;11(12):693-703.