Building upon our expertise in the biology of T cell homeostasis, we seek to develop therapies that will enhance antitumor immunity during the phase of lymphopenia, which occurs in nearly all patients who 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 remission in patients with pediatric cancer. Research subjects include mice, used to model the changes in immune physiology which occur during lymphopenia, and children, young adults and adults with lymphopenia as a result of cancer chemotherapy or HIV infection, treated on IRB approved clinical trials in the NIH Clinical Center. Recent major accomplishments of this project prior to 2006 can be summarized by two reports: #1) In Melchionda et al, J Clin Invest 2005, we demonstrated for the first time that IL7 therapy can potently augment responses to immunization, thus providing solid evidence that IL7 should be considered as agent for clinical use in the context of tumor vaccines. #2) In Zhang et al, Nature Medicine, 2005, we demonstrated that a specific suppressive subset of T cells (so-called CD4+CD25+ Tregs) increase in response to lymphopenia and administration of IL2 in this setting further expanded the suppressive subset of T cells. This observation was paradigm changing since it demonstrated that IL2, an agent previously assumed to be immune activating, had potent immunosuppressive effects. As a result of this work, we have focused our efforts of specifically manipulating Treg populations in lymphopenic hosts as a way of augmenting the effectiveness of immunotherapy in this setting. During the past year, two major accomplishments were the completion of the first two clinical trials of rhIL7. Results from the first completed trial were published as part of a collaborative study with the NCI Surgery Branch (Rosenberg et al., J of Immunoth, 2006). It provided proof-of-principle that IL-7 dramatically modulates T cell homeostasis in humans and demonstrated that, unlike IL2, which augments suppressive T cells, IL7 increases CD4+ T cell numbers without preferentially expanding the suppressive subset. However, because this study did not provide significant insight into the mechanisms by IL-7 exerts its effects, we also undertook a second Phase I trial in patients with refractory cancer. This study incorporated extensive biologic studies that provided remarkable insight into the basis for the dramatic changes in T cell homeostasis induced by IL-7. Most notably, we observed that IL-7 causes a broad repertoire of T cells to undergo cell cycling and to resist programmed cell death, resulting in rapid, significant expansion of both blood and tissue T cells. The expansion is tightly regulated by dynamic regulation of the IL7 receptor, thus preventing dangerous increases in lymphocyte with IL7 therapy. Because IL7 selectively expands the youngest or most nave T cell populations, T cells in IL7 treated patients resembled T cells normally present at young ages. Thus, IL7 has an anti-aging effect on the immune system. This capacity to expand a broad pool of nave cells is predicted to be very important for immune competence, especially in the context of T cell depletion. Most importantly, we saw little to no evidence of toxicity with IL-7, providing a solid basis for Phase II trials of this agent in combination with directed immunotherapy. This work has been submitted for publication. A third major accomplishment was completion of a series of studies demonstrating the successes and limitation of immune reconstitution in children in a variety of clinical settings by conducting detailed immunologic evaluation of varied clinical populations, and therefore represented collaborative projects. They build on previous work by our group published in the 1990s demonstrating profound lymphopenia in children and young adults treated with chemotherapy for cancer and a recent collaborative study (Hakim, J Clin Invest 2005) demonstrating that adult women treated for breast cancer with autologous stem cell transplantation show prolonged incomplete recovery of CD4+ T cell populations. In the first study, we studied adolescents and young adults 4-30 years after completion of dose intensive therapy for pediatric sarcomas. Remarkably, all successfully restored lymphocyte homeostasis (Br J Haematol. 2006 Oct;135(2):270-1). This is in direct contrast to studies in older adults, where prolonged follow-up did not show evidence of full immune reconstitution in substantial percentages of patients over age 40 at the time of lymphocyte depletion. Together, this work provides further evidence that age is the central factor determining the extent of immune reconstitution that occurs in human beings, even with prolonged follow-up. We also published a collaborative study in children undergoing HAART for HIV infection, which also demonstrated remarkably good capacity to restore immune responses: (Viral Immunol. 2007 Spring;20(1):131-41). Finally, we studied immune reconstitution in children and young adults treated with a non-myeloablative bone marrow transplantation and observed remarkably early thymic-dependent immune reconstitution, which was more rapid and complete that observed following myeloablative transplants and following adult patients treated on a similar study. This study, which has been presented at the American Society of Hematology meeting in December 2006, is currently being prepared for publication. In studies aimed at applying the principles gleaned regarding immune reconstitution to antitumor imunotherapy, we published the first evidence that immune reconstitution can prevent metastatic recurrence of osteosarcoma. This was performed using a mouse model wherine differential effects of the immune system on bulky primary tumors could be distinguished from effects on microscopic disease. Remarkably, while a fully recovered immune system did not impact growth of primary tumors, rapid immune reconstitution dramatically reduced the development of metastatic osteosarcoma (Merchant, 2006, Cancer Immunol Immunoth). This observation serves as the basis for ongoing development of multiple new tumor models in our laboratory which more accurately reflect the process of spontaneous metastases and will allow us to evaluate and optimize immunotherapies based upon their effects on metastatic disease, which is most highly relevant to the clinical setting. Finally, during the past year we completed the arduous process of developing a new clinical trial of immunotherapy for pediatric sarcomas. This required extensive reviews multiple committees at the NCI as well as the approval of an Institutional New Drug Application at the FDA. This protocol has already enrolled its first patient and will directly apply the principles gleaned from our animal studies to determine whether combining immune reconstitution, depletion of suppressor T cells and the administration of dendritic cell vaccines will improve outcomes for patients with metastatic and recurrent Ewings sarcoma family of tumors, rhabdomyosarcoma and neuroblastoma
| 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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