Crystal Mackall, MD, Section Head
Crystal L. Mackall is Chief of the Pediatric Oncology Branch of the National Cancer Institute. She completed clinical training in Pediatrics and Internal Medicine in 1989, then came to the NCI to undertake training in Pediatric Hematology/Oncology. In 1990, Dr. Mackall initiated her scientific career as a postdoctoral fellow under the mentorship of Ron Gress, where she made pioneering discoveries regarding thymic function in humans and elucidated fundamental principles of T cell homeostasis. In 1998, she initiated an independent research program in the Immunology Section of the Pediatric Oncology Branch. Her group has made important contributions to our understanding of the biology of T cells homeostasis, and has led clinical development of interleukin-7 as a therapeutic immunorestorative. She also leads a vibrant translational program focused on developing new immunotherapies for childhood cancer which includes clinical trials of tumor vaccines, immunomodulators, cytokines and adoptive cell therapy for childhood cancer. Dr. Mackall has received international recognition for her work on T cell homeostasis and tumor immunology. She is the recipient of numerous awards including the NIH Distinguished Clinical Teacher Award in 2000, an NCI Mentor of Merit Award in 2003, and several NCI Director’s awards. She has authored over 130 scientific publications, is a member of the American Society of Clinical Investigation, and serves in numerous editorial and advisory positions. She is Board Certified in Internal Medicine, Pediatrics and Pediatric Hematology/Oncology.Research
The goal of the Immunology Section of the Pediatric Oncology Branch is to develop effective immune based therapies for pediatric cancer. Guided by a bench-to-bedside-to-bench approach to research, we build upon expertise in the biology of T cell homeostasis to develop new therapies that enhance immune responses to tumor associated antigens following T cell depleting chemotherapy and can amplify antitumor immune responses in hosts without T cell depletion. It is now clear that many tumor associated antigens exist and that weak antitumor immune responses are often generated during the earliest phases of tumor growth, but tumors in patients who present with cancer have evaded these host responses. One way to enhance the effectiveness of existent or naturally induced antitumor immunity, it to amplify it immediately following cytotoxic therapy when tumor burdens are lowest and the tumor microenvironment is disrupted. Because the natural response to T cell depletion is amplification of weak immune responses as part of the attempt to reestablish immunocompetence, we believe that the study of the physiology of lymphopenia and identification of factors regulating T cell homeostasis will help to develop more potent immunotherapies for cancer.
Studies in the Mackall laboratory focus on two primary arenas: I. The biology and therapy of T cell depletion II. Immunobiology and immunotherapy of pediatric tumors. Specific aims of Project I are to improve the understanding of the physiology of T cell depletion using basic studies in mouse models and clinical trials of immune reconstitution in children and young adults treated with cytotoxic chemotherapy. Work thus far has demonstrated that thymic-dependent and thymic-independent pathways of T cell regeneration work together to restore host immune competence following T cell depletion. IL-7, a cytokine produced by non-lymphoid stromal cells, plays a crucial role in this process by allowing thymopoiesis to proceed and by inducing peripheral T cells to undergo homeostatic peripheral expansion which essentially comprises an exaggerated proliferative response to both strong cognate antigens and weak self antigens. Treatment with IL7 can potently modulate immune reconstitution by increasing the number of progeny derived from each of these pathways and we undertook the first clinical trial of rhIL-7 which demonstrated that this agent can potently and safely modulate T cell homeostasis in humans. We also discovered that IL7 is also a potent vaccine adjuvant since short course therapy with IL7 around the time of a dendritic cell vaccination in mice led to substantial short term and long term improvements in vaccine responses. Moreover, although IL2 was long believed to be a potent immune stimulant, our work demonstrated that IL2's effects on immune reconstitution occur primarily by expansion of regulatory or suppressive T cells. Thus, our studies demonstrate that IL7 is a promising immune stimulant which we believe may be more effective that IL2 and which may find a role in the immunotherapy of cancer both in lymphopenic and T cell replete hosts. More recently, we have also uncovered a previously unknown axis whereby IL7 plays a central role in regulating or prevented unwanted CD4+ T cell proliferation. Here, IL7 signaling on Class II+ dendritic cells prevents unrestrained CD4 proliferation during lymphopenia, thus identifying a novel role for IL7 in self tolerance.
Because clinical translation of our work on immune reconstitution and immunotherapy is focuses on pediatric sarcomas, Project II comprises projects specifically aimed at understanding the immunobiology of these tumors. Specific aims of Project II are to identify and characterize endogenous immune responses that exist in patients with pediatric sarcomas, to identify and characterize the programmed cell death pathways (e.g. Fas based, TRAIL based) which exist in pediatric sarcomas and to investigate the biology of the immune:tumor interface in pediatric sarcomas. These studies have identified that patients with Ewing's sarcoma have sizable numbers of circulating T cells which display potent cytolytic activity toward autologous tumor targets. The cytolytic cells lack the CD28 costimulatory molecule and express 4-1BB, a costimulatory molecule which is important for survival and expansion of these populations in vivo. Further, we have demonstrated that pediatric sarcomas themselves express 4-1BB ligand which provides costimulation for tumor reactive T cells. Using artificial antigen presenting cells engineered to express 4-1BB, we demonstrate efficient expansion of both cytolytic T cells and activated NK cells that show potent antitumor activity against childhood tumors. On this basis, we are planning studies of adoptive immunotherapy using 4-1BB based expansion of CD8+ T cells and NK cells. In addition, we are conducting a Phase I clinical trial of anti-TRAIL receptor 2 moAb therapy in pediatric sarcomas +/- interferon gamma as an agent which can augment the antitumor effects of this agent.
In summary, we believe that immunotherapy for childhood cancer is a promising area that could improve long term outcomes while avoiding the toxicity associated with traditional cytotoxic approaches. Most importantly, we believe that consolidative immunotherapy could be integrated into existing regimens to improve outcomes using current therapies. The setting of T cell depletion is a particularly ripe one for study in this context, as T cell depleting chemotherapy not only diminishes tumor burden but can also enhance the magnitude of immune responses generated following immune based therapies. Identifying the means by which alterations in T cell homeostasis enhances immunity to weak antigens and exploiting them in the context of tumor directed immunotherapy is predicted to enhance the potency of antitumor immune responses.