Crystal L. Mackall, M.D.
Crystal L. Mackall, M.D.
Chief
Head, Immunology Section

Crystal Mackall MD is Head of Immunology Section and Chief of the Pediatric Oncology Branch at the National Cancer Institute. She leads a translational research program focused on developing new immune based therapies for childhood cancer. She is an expert in the field of T cell homeostasis and led clinical development of recombinant interleukin-7, conducting first-in-human studies with this agent. She has developed dendritic cell based vaccines for pediatric sarcomas, is leading clinical trials of adoptive T cell and NK cell therapies, and co-Leads the StandUp2Cancer/St.Baldrick’s/NCI Pediatric Dream Team, which focuses on development of immune based therapies for childhood cancer.

Areas of Expertise
1) childhood cancers 2) pediatric oncology 3) immunotherapy 4) T cell homeostasis 5) chimeric antigen receptors 6) interleukin-7

Contact Info

Crystal L. Mackall, M.D.
Center for Cancer Research
National Cancer Institute
Building 10 - Hatfield CRC, Room 1W-3750
Bethesda, MD 20892-1104
301-402-5940
mackallc@mail.nih.gov

Immunology Section

The mission of the Immunology Section is to develop effective immune based therapies for pediatric cancer. Studies in the Section focus on three projects: 1) Biology and Therapy of Lymphopenia, 2) Immunobiology and Immunotherapy of Pediatric Tumors, and 3) Clinical Immunotherapy Program in Childhood Cancer.

Project 1: Biology and Therapy of Lymphopenia.  The specific aims of this project are to improve our understanding of the biology of T cell depletion in humans and to develop new approaches to enhance immune reconstitution or to exploit changes in physiology induced by lymphopenia. We previously elucidated an essential role for thymic pathways of T cell regeneration in the recovery from lymphopenia and described the limitations of this pathway in cancer patients (Mackall CL, et al., N Engl J Med 1995). We also discovered that interleukin-7 (IL-7), a cytokine produced by non-lymphoid stromal cells, augments thymic-independent immune reconstitution (Mackall CL, et al., Blood 2001). We also identified IL-7 as a master regulator of T cell homeostasis in human, demonstrating that lymphopenia results in elevations in this homeostatic cytokine, a finding that is now routinely exploited in the context of immune-based therapies for cancer (Fry TJ, et al., Blood 2001).  We further demonstrated that lymphopenia-induced elevations in IL-7 do not result from increased production, but rather diminished consumption (Guimond M, et al., Nat Immunol 2009).  In order to take these fundamental discoveries to the next level, we have devoted considerable effort to clinical development of recombinant human IL-7 (rhIL-7), as we hypothesized that treatment with this agent would overcome the limitations present in patients with cancer. We undertook the first-in-human trials of this agent (Sportes C, et al., J Exp Med 2008; Sportes C, et al., Clin Can Res 2010), which demonstrated safety and biologic activity, and we are currently conducting a trial of rhIL-7, administered to children and young adults after treatment with dose-intensive chemotherapy for high-risk pediatric solid tumors. Results thus far show the agent to be well tolerated, and potently able to hasten the pace of immune reconstitution following cytotoxic chemotherapy. More recent emerging studies have focused on increasing our understanding of soluble interleukin-7 receptor (IL7R)α, which circulates in humans at high molar excess compared to IL-7, but has not been well studied. We were compelled to study this molecule because of recently published genetic data demonstrating that polymorphisms in IL7R predispose to autoimmunity. Our studies demonstrate that soluble IL7Rα is an important modulator of the bioactivity of IL-7 in vivo, such that increased levels substantially potentiate the activity of IL-7, and therefore predispose to autoimmunity (Lundstrom W, et al., Proc Natl Acad Sci USA 2013). Future studies will seek to determine whether soluble IL7Rα can be used to augment the potency of rhIL-7 therapy.

Project 2:  Immunobiology and Immunotherapy of Pediatric Tumors. Our second project focuses on identifying principles of tumor immunology as they relate to cancers occurring in children and using these insights to develop and optimize new therapeutics to target pediatric tumors. Much energy is currently focused on developing chimeric antigen receptors to target pediatric tumors, given the exciting preliminary data in clinical trials targeting leukemia with chimeric antigen receptors (Lee DW, et al., Lancet 2014). The ability to target cell surface antigens, irrespective of HLA type, makes these novel therapeutics particularly appealing for rare diseases such as pediatric cancers. We currently have active preclinical studies underway using several chimeric antigen receptors, including those targeting CD19, CD22, GD2, ALK, B7-H3, CSPG-4, and O-acetyl-GD2. The CD22-CAR generated in our laboratory showed potent activity against B-cell acute lymphoblastic leukemia (B-ALL) and is poised for clinical development (Haso W, et al., Blood, 2013).  T cells expressing these receptors are generated in the laboratory, then tested in vitro for activity against cell lines and in xenograft models. Those with a high level of potency and a favorable predicted safety profile are prioritized for clinical development.  We have also committed substantial effort to the study of the microenvironment in pediatric solid tumors with an effort toward developing approaches that can modify the immunosuppressive factors within the microenvironment and thus render immune-based therapies more effective.  To this end, we have undertaken extensive characterization of myeloid-derived suppressor cells (MDSCs) present in murine models of rhabdomyosarcoma and in patients with pediatric sarcomas.  This work identified CXCR signaling via CXCL chemokines as a novel axis that was required for trafficking of neutrophilic MDSCs into pediatric solid tumors.  Treatment with CXCR inhibitors enhanced the efficacy of checkpoint blockade in murine rhabdomyosarcoma and levels of CXCL8 (IL-8), which is a ligand for CXCR1/2 had adverse prognostic significance in children and young adults with metastatic solid tumors (Highfill SL, et al., Sci Transl Med 2014).  We also identified a novel subset of MDSCs circulating in patients with solid tumor that bore hallmarks of fibrocytes, cells that are hematopoietically derived but generate fibroblasts in tissues.  Notably, fibrocytes expressed TSLPR (CRLF2), which is a cytokine receptor that could potentially be targeted via CAR therapy (Zhang H, et al., Blood, 2013).

Project 3: Clinical Immunotherapy Program in Childhood Cancer. Our third project is an active clinical trials program of immunotherapies in pediatric cancer.

Vaccines/Cytokines.  We have conducted the first-in-children trial of rhIL-7 administered in the context of dendritic cell-based tumor vaccines. Results showed favorable survival in patients with newly diagnosed metastatic Ewing sarcoma and are being prepared for publication.  We are also studying administration of activated natural killer (NK) cells generated using 4-1BB expressing artificial antigen-presenting cells plus IL-15 for treatment of patients with refractory solid tumors and, in this trial, are conducting first-in-children studies of systemic administration of rhIL-15. This trial is ongoing. 

Antibody Therapy Including Checkpoint Blockade.  We recently published results of the first in children trial of anti-TRAIL receptor 2 therapies in pediatric solid tumors (Merchant MS, et al., J Clin Oncol 2012). Results demonstrate good tolerability, and some evidence for antitumor effects as well as intriguing data suggesting an interaction between irradiation and TRAIL-receptor 2 agonists. We have recently completed the only study of ipilimumab (anti-CTLA4) in children, which demonstrated significant toxicity related to autoimmune adverse events without evidence for objective tumor regressions (manuscript in preparation).  We plan to lead a global Phase I trial of nivolumab (anti-PD1) in children, which will launch in the first quarter of 2015.

Adoptive NK Cell Therapy. We have also initiated a novel trial of activated NK cell therapy administered in patients with very high-risk solid tumors following allogeneic stem cell transplantation which unexpectedly revealed the capacity for such cells to induce or augment acute graft versus host disease (GVHD; Shah N, et al., submitted). This work builds on a previous study conducted by our group (Baird K, et al., Biol Blood Marrow Transplant 2012) wherein a non-myeloablative allogeneic peripheral blood stem cell transplant was administered to patients with ultra high-risk pediatric solid tumors.

T Cell Adoptive Therapy.  We currently have three open trials using chimeric antigen receptor-based therapies.  Using CD19-CAR for relapsed, refractory B-ALL, we reported a 70% complete response rate in the only intent-to-treat study published thus far for this therapy.  We have also developed a novel grading system for cytokine release syndrome, which is the most common and most dangerous side effect associated with these therapies, that incorporates a treatment algorithm aimed at diminishing the risks associated with this therapy.  We are currently enrolling patients with GD2+ solid tumors on a clinical trial of GD2-CAR therapy and this trial is ongoing.  Within the next month, the Branch will launch a clinical trial of CD22-CAR therapy for relapsed/refractory B-ALL under the leadership of Terry Fry, M.D. (Head, Hematologic Malignancies Section).  We are also leading a multicenter trial of adoptive T cell therapy using cells engineered to express a high affinity T cell receptor targeting NY-ESO-1 in synovial sarcoma.  Early results are promising and we anticipate submission of a manuscript reporting these findings in 2015.

In summary, we believe that there are many immunotherapies for childhood cancer that show promise for improving long-term outcomes while avoiding the toxicity associated with traditional cytotoxic approaches (Mackall CL, et al., Nat Rev Clin Oncol 2014). We posit that the recent dramatic progress in the field of immunotherapy for adult tumors can be leveraged to extend these therapies to pediatric cancer. Ultimately, we envision immunotherapy as a modality that can be added to future regimens that will employ less toxic doses of standard cytotoxic therapies to eradicate minimal residual disease and we envision that successful immunotherapy regimens are likely to be multimodal, including combinations of cell-based therapies, monoclonal antibodies (or their derivatives), immunomodulators and/or cytokines.

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology

View Dr. Mackall's PubMed Summary.

Selected Recent Publications
  1. Orentas RJ, Nordlund J, He J, Sindiri S, Mackall C, Fry TJ, Khan J.
    Front Oncol. 4: 134, 2014. [ Journal Article ]
  2. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL.
    Blood. 124: 188-95, 2014. [ Journal Article ]
  3. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, Kaplan RN, Mackall CL.
    Sci Transl Med. 6: 237ra67, 2014. [ Journal Article ]
  4. Prieto DA, Johann DJ, Wei BR, Ye X, Chan KC, Nissley DV, Simpson RM, Citrin DE, Mackall CL, Linehan WM, Blonder J.
    Biomark Med. 8: 269-86, 2014. [ Journal Article ]
  5. Duncan BB, Highfill SL, Qin H, Bouchkouj N, Larabee S, Zhao P, Woznica I, Liu Y, Li Y, Wu W, Lai JH, Jones B, Mackall CL, Bachovchin WW, Fry TJ
    J Immunother. 36: 400-11, 2013. [ Journal Article ]

Crystal L. Mackall is Chief of the Pediatric Oncology Branch of the National Cancer Institute. She completed clinical training in Pediatrics and Internal Medicine, then came to the NCI in 1989 to undertake subspecialty training in Pediatric Hematology/Oncology. In 1990, Dr. Mackall initiated her scientific career under the mentorship of Ron Gress. During her postdoctoral work, 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. Here, she has continued to make important contributions to our understanding of the biology of T cells homeostasis, she has led clinical development of interleukin-7 as a therapeutic immunorestorative and she has conducted translational studies of pediatric tumor immunology. She also leads a cutting edge clinical immunotherapy program that seeks to bring recent progress in tumor immunotherapy to the problem of 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 Directors 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.

Name Position
Donna Bernstein R.N. Senior Nurse Specialist
John Buckley Senior Research Technician (Contr)
Yongzhi (Karen) Cui Ph.D. Research Biologist
Samuel Haile Ph.D. Postdoctoral Fellow (CRTA)
Sabine Heitzeneder Ph.D. Postdoctoral Fellow (Visiting)
Daniel Lee M.D. Assistant Clinical Investigator
Adrienne Long Ph.D. Postdoctoral Fellow (CRTA)
Robbie Majzner M.D. Clinical Fellow
Sebastien Maury M.D. Special Volunteer
Jillian Smith Postbaccalaureate Fellow (CRTA)
Alec Walker B.S. Postbaccalaureate Fellow
Hua Zhang M.D. Research Biologist
Ling Zhang Ph.D. Research Biologist (Contr)

Clinical Trials

Research

Immunology Section

The mission of the Immunology Section is to develop effective immune based therapies for pediatric cancer. Studies in the Section focus on three projects: 1) Biology and Therapy of Lymphopenia, 2) Immunobiology and Immunotherapy of Pediatric Tumors, and 3) Clinical Immunotherapy Program in Childhood Cancer.

Project 1: Biology and Therapy of Lymphopenia.  The specific aims of this project are to improve our understanding of the biology of T cell depletion in humans and to develop new approaches to enhance immune reconstitution or to exploit changes in physiology induced by lymphopenia. We previously elucidated an essential role for thymic pathways of T cell regeneration in the recovery from lymphopenia and described the limitations of this pathway in cancer patients (Mackall CL, et al., N Engl J Med 1995). We also discovered that interleukin-7 (IL-7), a cytokine produced by non-lymphoid stromal cells, augments thymic-independent immune reconstitution (Mackall CL, et al., Blood 2001). We also identified IL-7 as a master regulator of T cell homeostasis in human, demonstrating that lymphopenia results in elevations in this homeostatic cytokine, a finding that is now routinely exploited in the context of immune-based therapies for cancer (Fry TJ, et al., Blood 2001).  We further demonstrated that lymphopenia-induced elevations in IL-7 do not result from increased production, but rather diminished consumption (Guimond M, et al., Nat Immunol 2009).  In order to take these fundamental discoveries to the next level, we have devoted considerable effort to clinical development of recombinant human IL-7 (rhIL-7), as we hypothesized that treatment with this agent would overcome the limitations present in patients with cancer. We undertook the first-in-human trials of this agent (Sportes C, et al., J Exp Med 2008; Sportes C, et al., Clin Can Res 2010), which demonstrated safety and biologic activity, and we are currently conducting a trial of rhIL-7, administered to children and young adults after treatment with dose-intensive chemotherapy for high-risk pediatric solid tumors. Results thus far show the agent to be well tolerated, and potently able to hasten the pace of immune reconstitution following cytotoxic chemotherapy. More recent emerging studies have focused on increasing our understanding of soluble interleukin-7 receptor (IL7R)α, which circulates in humans at high molar excess compared to IL-7, but has not been well studied. We were compelled to study this molecule because of recently published genetic data demonstrating that polymorphisms in IL7R predispose to autoimmunity. Our studies demonstrate that soluble IL7Rα is an important modulator of the bioactivity of IL-7 in vivo, such that increased levels substantially potentiate the activity of IL-7, and therefore predispose to autoimmunity (Lundstrom W, et al., Proc Natl Acad Sci USA 2013). Future studies will seek to determine whether soluble IL7Rα can be used to augment the potency of rhIL-7 therapy.

Project 2:  Immunobiology and Immunotherapy of Pediatric Tumors. Our second project focuses on identifying principles of tumor immunology as they relate to cancers occurring in children and using these insights to develop and optimize new therapeutics to target pediatric tumors. Much energy is currently focused on developing chimeric antigen receptors to target pediatric tumors, given the exciting preliminary data in clinical trials targeting leukemia with chimeric antigen receptors (Lee DW, et al., Lancet 2014). The ability to target cell surface antigens, irrespective of HLA type, makes these novel therapeutics particularly appealing for rare diseases such as pediatric cancers. We currently have active preclinical studies underway using several chimeric antigen receptors, including those targeting CD19, CD22, GD2, ALK, B7-H3, CSPG-4, and O-acetyl-GD2. The CD22-CAR generated in our laboratory showed potent activity against B-cell acute lymphoblastic leukemia (B-ALL) and is poised for clinical development (Haso W, et al., Blood, 2013).  T cells expressing these receptors are generated in the laboratory, then tested in vitro for activity against cell lines and in xenograft models. Those with a high level of potency and a favorable predicted safety profile are prioritized for clinical development.  We have also committed substantial effort to the study of the microenvironment in pediatric solid tumors with an effort toward developing approaches that can modify the immunosuppressive factors within the microenvironment and thus render immune-based therapies more effective.  To this end, we have undertaken extensive characterization of myeloid-derived suppressor cells (MDSCs) present in murine models of rhabdomyosarcoma and in patients with pediatric sarcomas.  This work identified CXCR signaling via CXCL chemokines as a novel axis that was required for trafficking of neutrophilic MDSCs into pediatric solid tumors.  Treatment with CXCR inhibitors enhanced the efficacy of checkpoint blockade in murine rhabdomyosarcoma and levels of CXCL8 (IL-8), which is a ligand for CXCR1/2 had adverse prognostic significance in children and young adults with metastatic solid tumors (Highfill SL, et al., Sci Transl Med 2014).  We also identified a novel subset of MDSCs circulating in patients with solid tumor that bore hallmarks of fibrocytes, cells that are hematopoietically derived but generate fibroblasts in tissues.  Notably, fibrocytes expressed TSLPR (CRLF2), which is a cytokine receptor that could potentially be targeted via CAR therapy (Zhang H, et al., Blood, 2013).

Project 3: Clinical Immunotherapy Program in Childhood Cancer. Our third project is an active clinical trials program of immunotherapies in pediatric cancer.

Vaccines/Cytokines.  We have conducted the first-in-children trial of rhIL-7 administered in the context of dendritic cell-based tumor vaccines. Results showed favorable survival in patients with newly diagnosed metastatic Ewing sarcoma and are being prepared for publication.  We are also studying administration of activated natural killer (NK) cells generated using 4-1BB expressing artificial antigen-presenting cells plus IL-15 for treatment of patients with refractory solid tumors and, in this trial, are conducting first-in-children studies of systemic administration of rhIL-15. This trial is ongoing. 

Antibody Therapy Including Checkpoint Blockade.  We recently published results of the first in children trial of anti-TRAIL receptor 2 therapies in pediatric solid tumors (Merchant MS, et al., J Clin Oncol 2012). Results demonstrate good tolerability, and some evidence for antitumor effects as well as intriguing data suggesting an interaction between irradiation and TRAIL-receptor 2 agonists. We have recently completed the only study of ipilimumab (anti-CTLA4) in children, which demonstrated significant toxicity related to autoimmune adverse events without evidence for objective tumor regressions (manuscript in preparation).  We plan to lead a global Phase I trial of nivolumab (anti-PD1) in children, which will launch in the first quarter of 2015.

Adoptive NK Cell Therapy. We have also initiated a novel trial of activated NK cell therapy administered in patients with very high-risk solid tumors following allogeneic stem cell transplantation which unexpectedly revealed the capacity for such cells to induce or augment acute graft versus host disease (GVHD; Shah N, et al., submitted). This work builds on a previous study conducted by our group (Baird K, et al., Biol Blood Marrow Transplant 2012) wherein a non-myeloablative allogeneic peripheral blood stem cell transplant was administered to patients with ultra high-risk pediatric solid tumors.

T Cell Adoptive Therapy.  We currently have three open trials using chimeric antigen receptor-based therapies.  Using CD19-CAR for relapsed, refractory B-ALL, we reported a 70% complete response rate in the only intent-to-treat study published thus far for this therapy.  We have also developed a novel grading system for cytokine release syndrome, which is the most common and most dangerous side effect associated with these therapies, that incorporates a treatment algorithm aimed at diminishing the risks associated with this therapy.  We are currently enrolling patients with GD2+ solid tumors on a clinical trial of GD2-CAR therapy and this trial is ongoing.  Within the next month, the Branch will launch a clinical trial of CD22-CAR therapy for relapsed/refractory B-ALL under the leadership of Terry Fry, M.D. (Head, Hematologic Malignancies Section).  We are also leading a multicenter trial of adoptive T cell therapy using cells engineered to express a high affinity T cell receptor targeting NY-ESO-1 in synovial sarcoma.  Early results are promising and we anticipate submission of a manuscript reporting these findings in 2015.

In summary, we believe that there are many immunotherapies for childhood cancer that show promise for improving long-term outcomes while avoiding the toxicity associated with traditional cytotoxic approaches (Mackall CL, et al., Nat Rev Clin Oncol 2014). We posit that the recent dramatic progress in the field of immunotherapy for adult tumors can be leveraged to extend these therapies to pediatric cancer. Ultimately, we envision immunotherapy as a modality that can be added to future regimens that will employ less toxic doses of standard cytotoxic therapies to eradicate minimal residual disease and we envision that successful immunotherapy regimens are likely to be multimodal, including combinations of cell-based therapies, monoclonal antibodies (or their derivatives), immunomodulators and/or cytokines.

Scientific Focus Areas:
Cancer Biology, Clinical Research, Immunology

Publications

View Dr. Mackall's PubMed Summary.

Selected Recent Publications
  1. Orentas RJ, Nordlund J, He J, Sindiri S, Mackall C, Fry TJ, Khan J.
    Front Oncol. 4: 134, 2014. [ Journal Article ]
  2. Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, Grupp SA, Mackall CL.
    Blood. 124: 188-95, 2014. [ Journal Article ]
  3. Highfill SL, Cui Y, Giles AJ, Smith JP, Zhang H, Morse E, Kaplan RN, Mackall CL.
    Sci Transl Med. 6: 237ra67, 2014. [ Journal Article ]
  4. Prieto DA, Johann DJ, Wei BR, Ye X, Chan KC, Nissley DV, Simpson RM, Citrin DE, Mackall CL, Linehan WM, Blonder J.
    Biomark Med. 8: 269-86, 2014. [ Journal Article ]
  5. Duncan BB, Highfill SL, Qin H, Bouchkouj N, Larabee S, Zhao P, Woznica I, Liu Y, Li Y, Wu W, Lai JH, Jones B, Mackall CL, Bachovchin WW, Fry TJ
    J Immunother. 36: 400-11, 2013. [ Journal Article ]

Biography

Crystal L. Mackall is Chief of the Pediatric Oncology Branch of the National Cancer Institute. She completed clinical training in Pediatrics and Internal Medicine, then came to the NCI in 1989 to undertake subspecialty training in Pediatric Hematology/Oncology. In 1990, Dr. Mackall initiated her scientific career under the mentorship of Ron Gress. During her postdoctoral work, 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. Here, she has continued to make important contributions to our understanding of the biology of T cells homeostasis, she has led clinical development of interleukin-7 as a therapeutic immunorestorative and she has conducted translational studies of pediatric tumor immunology. She also leads a cutting edge clinical immunotherapy program that seeks to bring recent progress in tumor immunotherapy to the problem of 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 Directors 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.

Team

Name Position
Donna Bernstein R.N. Senior Nurse Specialist
John Buckley Senior Research Technician (Contr)
Yongzhi (Karen) Cui Ph.D. Research Biologist
Samuel Haile Ph.D. Postdoctoral Fellow (CRTA)
Sabine Heitzeneder Ph.D. Postdoctoral Fellow (Visiting)
Daniel Lee M.D. Assistant Clinical Investigator
Adrienne Long Ph.D. Postdoctoral Fellow (CRTA)
Robbie Majzner M.D. Clinical Fellow
Sebastien Maury M.D. Special Volunteer
Jillian Smith Postbaccalaureate Fellow (CRTA)
Alec Walker B.S. Postbaccalaureate Fellow
Hua Zhang M.D. Research Biologist
Ling Zhang Ph.D. Research Biologist (Contr)