The primary goal of the Mackall laboratory is to develop effective immune based therapies for pediatric cancer. The approach builds upon our expertise in the biology of T cell homeostasis to develop therapies that will enhance antitumor immunity during the phase of lymphopenia which occurs in nearly all patients which receive chemotherapy for childhood cancer. By exploiting the combination of low tumor burdens and the heightened capacity to induce responses to tumor antigens as a result of the changes in T cell homeostasis induced by lymphopenia, we seek to use tumor directed immunotherapies to consolidate remissions in patients with pediatric cancer. Research subjects include both mice which are used to model the changes in immune physiology which occur during lymphopenia and blood samples from children and young adults treated for aggressive tumors on IRB approved clinical trials in the Pediatric Oncology Branch. The primary accomplishments of this work can be summarized by three published reports. #1) (Melchionda et al, J Clin Invest 2005) We demonstrated for the first time that IL7 therapy can potently augment responses to immunization both in the short term and the long term, such that the improved immune responses that occur when immunization is undertaken at the same time as IL7 therapy lasts long after the cytokine is discontinued. These studies were performed in mice and also demonstrated that a tumor vaccine administered with IL7 was better able to protect against subsequent tumor challenge than a vaccine administered without IL7. We also saw similar increases in vaccine responses with concomitant IL15 therapy but not with IL2 therapy. These results provide firm evidence that IL7 should be considered as agent for clinical use in the context of tumor vaccines. #2) (Zhang et al, Nature Medicine, 2005) By careful study of immune reconstitution in children and young adults treated with infusions of autologous T cells and tumor vaccines, with or without IL2 following chemotherapy, we discovered that a specific suppressive subset of T cells (so-called CD4+CD25+ Tregs) are substantially increased in response to lymphopenia. Furthermore, where IL2 therapy was considered to be an agent which could improve immune function during lymphopenia, we showed that administration of IL2 in this setting potently expanded the suppressive subset of T cells. This observation is paradigm changing in that it demonstrates that IL2, an agent which was previously assumed to be immune activating, also have potent immunosuppressive effects via the specific CD4+CD25+ subset regulation. #3) (Rosenberg et al., J of Immunoth, 2006) In a collaborative study with the NCI Surgery Branch, the first clinical trial of rhIL7 in humans was completed and provided proof of principle that this agent dramatically modulates T cell homeostasis in humans. Furthermore, the study demonstrated that unlike IL2 which augments suppressive T cells, IL7 increases CD4+ T cell numbers without preferentially expanding the suppressive subset. This early phase trial provides the first evidence the IL7 may be an effective and safe agent in humans to modulate T cell homeostasis.
| Capitini, Christian M; Cooper, Laurence J N; Egeler, R Maarten et al. (2009) Highlights of the First International ""Immunotherapy in Pediatric Oncology: Progress and Challenges"" Meeting. J Pediatr Hematol Oncol 31:227-44 |
| Guimond, Martin; Veenstra, Rachelle G; Grindler, David J et al. (2009) Interleukin 7 signaling in dendritic cells regulates the homeostatic proliferation and niche size of CD4+ T cells. Nat Immunol 10:149-57 |
| Fluur, Caroline; De Milito, Angelo; Fry, Terry J et al. (2007) Potential role for IL-7 in Fas-mediated T cell apoptosis during HIV infection. J Immunol 178:5340-50 |
| Hazra, Rohan; Jankelevich, Shirley; Mackall, Crystal L et al. (2007) Immunologic, virologic, and neuropsychologic responses in human immunodeficiency virus-infected children receiving their first highly active antiretroviral therapy regimen. Viral Immunol 20:131-41 |
| Merchant, Melinda S; Melchionda, Fraia; Sinha, Manoj et al. (2007) Immune reconstitution prevents metastatic recurrence of murine osteosarcoma. Cancer Immunol Immunother 56:1037-46 |
| Crooks, Gay M; Weinberg, Kenneth; Mackall, Crystal (2006) Immune reconstitution: from stem cells to lymphocytes. Biol Blood Marrow Transplant 12:42-6 |
| Lucas, Philip J; Kim, Seong-Jin; Mackall, Crystal L et al. (2006) Dysregulation of IL-15-mediated T-cell homeostasis in TGF-beta dominant-negative receptor transgenic mice. Blood 108:2789-95 |
| Krupica Jr, Tom; Fry, Terry J; Mackall, Crystal L (2006) Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 120:121-8 |
| Snyder, Kristen M; Mackall, Crystal L; Fry, Terry J (2006) IL-7 in allogeneic transplant: clinical promise and potential pitfalls. Leuk Lymphoma 47:1222-8 |
| Guimond, Martin; Fry, Terry J; Mackall, Crystal L (2005) Cytokine signals in T-cell homeostasis. J Immunother (1997) 28:289-94 |
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