This P01 was initiated in 1973 as a comprehensive effort to study the biology of blood and marrow transplantation (BMT). Since then, BMT has proven to be effective therapy, and even the treatment of choice, for a variety of malignant and nonmalignant diseases that affect the lymphohematopoietic system. A number of issues, including conditioning regimen toxicities, infections, graft-versus-host disease (GVHD), immunodeficiency, and inability to completely eradicate tumor, have limited the success of BMT over the years. Major advances, particularly in the area of supportive care, have gradually decreased the magnitude of many of these problems. However, two inter-related issues, GVHD and tumor recurrence, remain as major obstacles to successful allogeneic (allo) BMT. Translational studies funded by this P01 over the past decade have found that high-dose cyclophosphamide (Cy) early after BMT effectively generates bi-directional tolerance, even in partially HLA mismatched donor-recipient pairs in animals studies and clinically. Importantly, our clinical data demonstrating that haploidentical related donor BMT is safe and effective, producing results similar to that seen with HLA-matched alloBMT, was confirmed by a recent BMT CTN clinical trial. Additionally, although the importance of the cancer stem cell (CSC) concept has been a matter of debate because of limited data demonstrating clinical relevance, work over this P01's last funding period suggest that CSCs in a variety of hematologic malignancies are in fact the cells responsible for relapse. Accordingly, the new proposal will build on continuing work from the past funding period primarily in the areas of modulating GVHD with high-dose post-BMT Cy and targeting CSCs. Because of the effects of GVHD on relapse, the studies into modulating GVHD and targeting CSCs are highly interdependent with most Projects studying both areas. There are 5 interactive Projects and 3 Cores. The specific hypotheses to be tested in this proposal are: 1) high-dose post-transplant Cy's ability to modulate GVHD allows safe and effective mismatched BMT, making AlloBMT a feasible alternative for severe non-malignant hematologic diseases and allowing donor selection based on genetic factors other than HLA, 2)improved immunologic recovery after high-dose post-transplant Cy allows early and effective utilization of immunologic antitumor approaches, and 3) targeting CSC can decrease relapse after BMT.

Public Health Relevance

Two interrelated issues, GVHD and tumor recurrence, remain as major obstacles to successful allogeneic BMT. The renewal builds on, and expands, this P01's ongoing work in two major themes from the current funding period: 1) high-dose post-transplant Cy to modulate GVHD and 2) targeting CSC in an attempt to reduce relapse. Preliminary data suggest that advances in these two areas should improve the outcome of BMT patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA015396-39
Application #
8727261
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (J1))
Program Officer
Merritt, William D
Project Start
1995-12-01
Project End
2017-08-31
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
39
Fiscal Year
2014
Total Cost
$1,797,810
Indirect Cost
$688,051
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Schoch, Laura K; Cooke, Kenneth R; Wagner-Johnston, Nina D et al. (2018) Immune checkpoint inhibitors as a bridge to allogeneic transplantation with posttransplant cyclophosphamide. Blood Adv 2:2226-2229
Kasamon, Yvette L; Fuchs, Ephraim J; Zahurak, Marianna et al. (2018) Shortened-Duration Tacrolimus after Nonmyeloablative, HLA-Haploidentical Bone Marrow Transplantation. Biol Blood Marrow Transplant 24:1022-1028
Robinson, Tara M; Prince, Gabrielle T; Thoburn, Chris et al. (2018) Pilot trial of K562/GM-CSF whole-cell vaccination in MDS patients. Leuk Lymphoma 59:2801-2811
Grant, Melanie L; Bollard, Catherine M (2018) Cell therapies for hematological malignancies: don't forget non-gene-modified t cells! Blood Rev 32:203-224
Fuchs, Ephraim Joseph (2017) Related haploidentical donors are a better choice than matched unrelated donors: Point. Blood Adv 1:397-400
Kanakry, Christopher G; BolaƱos-Meade, Javier; Kasamon, Yvette L et al. (2017) Low immunosuppressive burden after HLA-matched related or unrelated BMT using posttransplantation cyclophosphamide. Blood 129:1389-1393
Kasamon, Yvette L; Ambinder, Richard F; Fuchs, Ephraim J et al. (2017) Prospective study of nonmyeloablative, HLA-mismatched unrelated BMT with high-dose posttransplantation cyclophosphamide. Blood Adv 1:288-292
Llosa, Nicolas J; Cooke, Kenneth R; Chen, Allen R et al. (2017) Reduced-Intensity Haploidentical Bone Marrow Transplantation with Post-Transplant Cyclophosphamide for Solid Tumors in Pediatric and Young Adult Patients. Biol Blood Marrow Transplant 23:2127-2136
Klein, Orly R; Buddenbaum, Jessica; Tucker, Noah et al. (2017) Nonmyeloablative Haploidentical Bone Marrow Transplantation with Post-Transplantation Cyclophosphamide for Pediatric and Young Adult Patients with High-Risk Hematologic Malignancies. Biol Blood Marrow Transplant 23:325-332
McCurdy, Shannon R; Kasamon, Yvette L; Kanakry, Christopher G et al. (2017) Comparable composite endpoints after HLA-matched and HLA-haploidentical transplantation with post-transplantation cyclophosphamide. Haematologica 102:391-400

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