The central goals of this proposal are a) to support the acquisition of advanced training in clinical research methodologies, ethical principles and human immunology as it pertains to conducting patient-oriented investigations in allogeneic hematopoietic stem cell transplantation (HCT) and b) to vigorously pursue a deep understanding of biology guided proof-of-concept trials in HCT directed at reducing relapse in Acute Myeloid Leukemia (AML). I will achieve these goals within five years by completing the following career development activities: 1) serving as a mentored principle investigator on a clinical study directly translated from the laboratory 2) acquiring in-depth laboratory training in monitoring human allogeneic HCT immune responses and 3) completing graduate coursework in immunology together with a Master's of Science in Clinical Research Design and Statistical Analysis (CRDSA). Allogeneic HCT represents the lone curative approach for several malignant hematologic diseases including AML. HCT delivers potent immunotherapeutic effects through graft-versus-leukemia (GVL) responses of donor lymphocytes. Despite this great potential, relapse remains the major impediment to improving survival after HCT. Reducing relapse by increasing high dose chemotherapy (conditioning) or administration of donor lymphocytes (DLI) are limited by major toxicity, primarily graft-versus-host disease (GVHD). Shared immunity against normal and malignant host tissues underlies the difficulty in separating GVL from GVHD. To overcome this barrier, donor T cells must be `primed' to more specifically respond to leukemia antigens that are not presented directly but instead presented by the professional antigen presenting cells (APCs), a process known as cross-presentation. Specialized APCs found in mice (CD8?+ DCs) and their counterparts in humans (BDCA3+ DCs), are crucial for initiating leukemia antigen specific T cell responses. In preclinical studies of HCT, we demonstrate enhancing cross-presentation on CD8?+DCs promotes GVL responses without aggravating GVHD. Moreover, type 1 interferon (IFN-?) is capable of enhancing cross- presentation and subsequent GVL in models of HCT.
In Specific Aim 1, these concepts are directly translated to a proof-of-concept phase I/II clinical trial to reduce the recurrence of AML after HCT in patients at high risk for relapse. We will test the hypothesis that treatment with the FDA approved agent pegylated IFN-? will reduce relapse without increasing the frequency or severity of GVHD.
In Specific Aim 2, we determine the impact of pegylated IFN-? on cross-presentation of leukemia antigens on BDCA3+ DCs. We will test the hypothesis that enhancing cross-presentation will result in increases in leukemia antigen specific T cell responses. This proposal reflects a logical extension of my prior research and follows a well laid out plan for career development. It is the first HCT study specifically designed to target antigen cross-presentation as a mechanism for safely increasing GVL responses. If successful, this will provide evidence of direct clinical translation from the bench and provide a new approach for restoring protective immunity following HCT.

Public Health Relevance

Each year more than 20,000 stem cell transplants are performed to treat patients with blood cancers and other life threatening blood disorders using donor cells collected from healthy volunteers. This procedure uses the donor's immune cells to fight cancer, but despite this stem cell transplants are often complicated by relapse and infection. Our project's goal is to safely strengthen the immunity of the donor cells to increase their effectiveness in eliminating cancer.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Mentored Patient-Oriented Research Career Development Award (K23)
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Allergy, Immunology, and Transplantation Research Committee (AITC)
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Gondre-Lewis, Timothy A
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University of Michigan Ann Arbor
Internal Medicine/Medicine
Schools of Medicine
Ann Arbor
United States
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Magenau, John M; Goldstein, Steven C; Peltier, Dan et al. (2018) ?1-Antitrypsin infusion for treatment of steroid-resistant acute graft-versus-host disease. Blood 131:1372-1379