Cancers of the lympho-hematopoietic system are a major cause of morbidity and mortality, with an increasing incidence of myelodysplastic syndrome and non-Hodgkins Lymphoma as the population ages and greater numbers survive prior cancers. Allogeneic hematopoietic stem cell transplant (HSCT) is curative in a proportion of patients who otherwise fail conventional chemotherapy or are known to be high risk of failure. However, this potentially life-saving procedure is restricted in its availability and is itself associated with the high risks of morbidity and mortality, primarily from immunological complications, including graft-versus-host disease (GVHD), and slow immune reconstitution. For those that survive the immediate risks of transplant therapy, relapse is still an obstacle. Toward our goal of facilitating lympho-hematopoietic recovery after umbilical cord blood (UCBT), in Project 1, we propose to 1) determine the impact of large doses of UCB CD34+ cells on the pace of immune reconstitution, 2) optimize dosing T regulatory cells for prevention of acute GVHD, and 3) optimize ex vivo expansion of thymic progenitors for accelerating immune recovery. Toward our goal of engineering a safer and more effective adoptive T cell therapy for leukemia relapse prevention and treatment, in Project 2, we propose to 1) demonstrate that drug regulated anti-hCD19SFv chimeric antigen receptor (CAR) expressing T cells can eradicate malignant CD19+ B cells, determine whether CAR persistence is dependent upon tumor- or host- derived B cell antigenic signals, and demonstrate that infusion of drug antagonists can rapidly halt CAR signaling by precluding dimerization, 2) demonstrate that human T stem-memory (Tsm) cells can be reprogrammed and genetically modified to express CARs providing self-renewable CAR-Tsm cells for adoptive tumor immunotherapy with enhanced survival, and 4) identify and validate essential regulators of the Tsm state to further optimize Tsm-based CAR therapy. And, toward our goal of engineering a safe and more effective adoptive NK cell therapy for relapse treatment, in Project 3 we propose to 1) determine the mechanism underlying the differentiation of adaptive NK cells which have potent and long-lived anti-leukemia activity, and induce their expansion in a phase I trial to eliminate leukemic blasts in patients with relapsed leukemia, and 2) optimize NK activation and tumor-targeting using bispecific killer engager (BiKE) antibodies with a subsequent 'first-in-human' clinical trial in patients with relapsed CD33+ malignancy after UCBT. Each of these strategies is highly innovative with substantial promise individually and in combination for overcoming the most important barriers - immunoincompetence and relapse - previously limiting survival as well as continuing our long-held interest in realizing the full potential of UCB in transplant medicine.

Public Health Relevance

Cancers of the lympho-hematopoietic system are a major cause of morbidity and mortality, with an increasing incidence of myelodysplastic syndrome and non-Hodgkins Lymphoma as the population ages and greater numbers survive prior cancers. Allogeneic hematopoietic stem cell transplant (HSCT) can be curative but delayed lympho-hematopoietic recovery and immune reconstitution and disease relapse remain major causes of treatment failure. The overarching aim of the Program Project Grant is to prevent these major obstacles by using cellular engineering to exploit the power of various cell populations within the hematopoietic compartment. As a result of recent discoveries by our group and others, we now have the tools that will transform the practice of transplant medicine, enhance the chance of cure and improve health quality of life.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA065493-25
Application #
9769631
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Song, Min-Kyung H
Project Start
1997-09-15
Project End
2020-08-31
Budget Start
2019-09-01
Budget End
2020-08-31
Support Year
25
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Pediatrics
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
Owen, David L; Mahmud, Shawn A; Vang, Kieng B et al. (2018) Identification of Cellular Sources of IL-2 Needed for Regulatory T Cell Development and Homeostasis. J Immunol 200:3926-3933
Osborn, Mark J; Lees, Christopher J; McElroy, Amber N et al. (2018) CRISPR/Cas9-Based Cellular Engineering for Targeted Gene Overexpression. Int J Mol Sci 19:
Oh, Felix; Todhunter, Deborah; Taras, Elizabeth et al. (2018) Targeting EGFR and uPAR on human rhabdomyosarcoma, osteosarcoma, and ovarian adenocarcinoma with a bispecific ligand-directed toxin. Clin Pharmacol 10:113-121
Rashidi, Armin; Ebadi, Maryam; Said, Bassil et al. (2018) Absence of early HHV-6 reactivation after cord blood allograft predicts powerful graft-versus-tumor effect. Am J Hematol :
Bejanyan, Nelli; Brunstein, Claudio G; Cao, Qing et al. (2018) Delayed immune reconstitution after allogeneic transplantation increases the risks of mortality and chronic GVHD. Blood Adv 2:909-922
Bachanova, Veronika; Sarhan, Dhifaf; DeFor, Todd E et al. (2018) Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells. Cancer Immunol Immunother 67:483-494
Xing, Yan; Smith, Michelle J; Goetz, Christine A et al. (2018) Thymic Epithelial Cell Support of Thymopoiesis Does Not Require Klotho. J Immunol 201:3320-3328
Prestipino, Alessandro; Emhardt, Alica J; Aumann, Konrad et al. (2018) Oncogenic JAK2V617F causes PD-L1 expression, mediating immune escape in myeloproliferative neoplasms. Sci Transl Med 10:
de Witte, Moniek A; Sarhan, Dhifaf; Davis, Zachary et al. (2018) Early Reconstitution of NK and ?? T Cells and Its Implication for the Design of Post-Transplant Immunotherapy. Biol Blood Marrow Transplant 24:1152-1162
Zeiser, Robert; Blazar, Bruce R (2018) Acute Graft-versus-Host Disease. N Engl J Med 378:586

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