Our Science – Mackall Website

Crystal L. Mackall, M.D.

Pediatric Oncology Branch Head, Immunology Section Branch Chief National Cancer Institute Building 10-CRC, Room 1W-3750 10 Center Drive, MSC 1104 Bethesda, MD 20892 Phone:   301-402-5940 Fax:   301-451-7010 E-Mail:   cm35c@nih.gov

Biography

Crystal L. Mackall is Chief of the Pediatric Oncology Branch of the National Cancer Institute. She completed an accelerated 6-year B.S./M.D. program at the Northeastern Ohio Universities College of Medicine in 1984 followed by a combined Internal Medicine/Pediatrics Residency in 1988. She came to the NCI in 1989 as a Clinical Associate in the Pediatric Oncology Branch where she completed her clinical subspecialty training in 1992. She is Board Certified in Internal Medicine, Pediatrics and Pediatric Hematology/Oncology. Dr. Mackall undertook postdoctoral scientific training in the Experimental Immunology Branch from 1990-1996. Since that time she has directed an independent research effort in the Pediatric Oncology Branch. Dr. Mackall has received international recognition for her work on T cell homeostasis and tumor immunology and she leads an active translational research program which incorporates basic studies of immunology with clinical trials of immunotherapy for pediatric cancer. 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 the NCI Director's Award in 2003. She has authored over 100 scientific publications and is a member of the American Society of Clinical Investigation. She was appointed Acting Chief of the Pediatric Oncology Branch in 2005 and was formally named Chief of the POB in 2008.

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 to enhance immune responses to tumor associated antigens following T cell depleting chemotherapy and to 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 oncogenesis, but for patients with clinically apparent cancer there is a quantitative disconnect between the size of the tumor burden present and the potency of the existent immune response. One way to enhance the effectiveness of existent or naturally induced antitumor immunity, it to amplify it immediately following cytotoxic therapy, overall effectiveness should improve, since tumor burdens are low at that point. Further, since the natural response to T cell depletion is the amplification of weak immune responses in order to reestablish immunocompetence, the study of the immunobiology of lymphopenia and the factors which regulate T cell homeostasis is predicted to lead to discoveries of new therapeutic approaches which mimic the natural mechanisms for amplifying immunity in the setting of T cell depletion. Such new approaches could potentially amplify immune responses to tumor associated antigens even in T cell replete hosts.

Studies in the Mackall laboratory focus on two primary projects: 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 immunobiology of T cell depletion using basic studies in murine systems 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. We have shown that IL7 therapy can potently modulate immune reconstitution by increasing the number of progeny derived from each of these pathways. Based upon this, we are currently engaged in the first clinical trial of rhIL-7 to assess the capacity for this agent to modulate T cell homeostasis in humans. We have 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. We have also recently completed work demonstrating that IL2, long believed to be a potent immune stimulant, is actually also a potent inducer of regulatory T cells in humans. Thus, our future goals are to contribute to the development of IL7 as an 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.

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 any 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 host: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. Ongoing work is underway to study provide the preclinical basis for 4-1BB based expansion of cytolytic T cells for use in adoptive immunotherapy. We have also recently completed studies of TRAIL mediated programmed cell death in pediatric sarcomas. These studies demonstrated that Ewing sarcoma is highly susceptible to TRAIL mediated cell death in vitro and that TRAIL agonists have activity in vivo against Ewing sarcoma, but this is diminished compared to that observed in vitro. Further work demonstrated that in vivo acquired TRAIL resistance appears to occur even in animal which are not treated with TRAIL receptor agonists, it is associated with loss of TR2 cell surface expression and it can be reversed using inteferon gamma. We are currently planning a Phase I clinical trial of anti-TRAIL receptor 2 moAb therapy in pediatric sarcomas and hope to also study the ability to combine this therapy with interferon gamma in a clinical trial.

In summary, we believe that a critical hurdle for further progress of immunotherapy for cancer is the identification of approaches which can increase the magnitude of the immune response generated toward tumor associated antigens. 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. Finally, the development of approaches which can more optimally direct immune responses toward specific antigens in T cell depleted hosts may also have important applications in other clinical settings such as following bone marrow transplantation and HIV infection.

This page was last updated on 9/11/2008.