Major Activities: This project uses small animal models to undertake targeted questions, as well as studies of healthy human cells and cells acquired from patients who have experienced lymphocyte depletion. This bench-to-bedside-to-bench approach provides insights that increase basic understanding and set the stage for clinical application. Specific Objectives: Specific objectives of this project are to: 1) improve understanding of the biology of T cell depletion and 2) develop new therapies to improve immune reconstitution or that could replicate the beneficial aspects of lymphopenia while avoiding long-term detrimental effects. Significant Results: We have previously demonstrated that age-, disease- and therapy-associated effects on thymic function are the primary factors limiting T cell immune reconstitution in humans following lymphocyte depletion. We also previously demonstrated that thymic-independent pathways of immune restoration can largely restore immune competence and are well poised for manipulation in the context of immunotherapy for cancer. We previously discovered that interleukin-7 is the major driver of the thymic-independent immune reconstitution and have focused efforts on clinical development of recombinant human IL-7. The first major accomplishment of this project during FY15 was completion of a clinical trial wherein rhIL7 was administered to a large cohort of children and young adults with high-risk pediatric sarcomas following front line therapy. This represents the only clinical experience with rhIL7 in children thus far. We demonstrated the agent to be safe and highly effective at increasing the pace and degree of immune reconstitution following intensive chemotherapy for cancer. We also observed significantly improved survival in patients treated on this study compared to that reported previously in a similar population. These results are being prepared for publication. We also conducted state-of-the-art studies using next generation sequencing to enumerate the T cell receptor repertoire of rhIL7 vs non-IL7 treated patients. These studies demonstrate diversification of the repertoire with recombinant human interleukin-7, confirming what was previously postulated using approaches of much lower resolution.
| Lundström, Wangko; Highfill, Steven; Walsh, Scott T R et al. (2013) Soluble IL7R? potentiates IL-7 bioactivity and promotes autoimmunity. Proc Natl Acad Sci U S A 110:E1761-70 |
| van Den Brink, Marcel; Leen, Ann M; Baird, Kristin et al. (2013) Enhancing immune reconstitution: from bench to bedside. Biol Blood Marrow Transplant 19:S79-83 |
| Lundström, Wangko; Fewkes, Natasha M; Mackall, Crystal L (2012) IL-7 in human health and disease. Semin Immunol 24:218-24 |
| Mackall, Crystal L; Fry, Terry J; Gress, Ronald E (2011) Harnessing the biology of IL-7 for therapeutic application. Nat Rev Immunol 11:330-42 |
| Fewkes, Natasha M; Mackall, Crystal L (2010) Novel gamma-chain cytokines as candidate immune modulators in immune therapies for cancer. Cancer J 16:392-8 |
| Fewkes, Natasha M; Krauss, Aviva C; Guimond, Martin et al. (2010) Pharmacologic modulation of niche accessibility via tyrosine kinase inhibition enhances marrow and thymic engraftment after hematopoietic stem cell transplantation. Blood 115:4120-9 |
| Guimond, Martin; Freud, Aharon G; Mao, Hsiaoyin C et al. (2010) In vivo role of Flt3 ligand and dendritic cells in NK cell homeostasis. J Immunol 184:2769-75 |
| Sportès, Claude; Babb, Rebecca R; Krumlauf, Michael C et al. (2010) Phase I study of recombinant human interleukin-7 administration in subjects with refractory malignancy. Clin Cancer Res 16:727-35 |
| Mackall, C; Fry, T; Gress, R et al. (2009) Background to hematopoietic cell transplantation, including post transplant immune recovery. Bone Marrow Transplant 44:457-62 |
| 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 |
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