This program project was initiated in 1973 as a comprehensive effort to study the biology of blood and marrow transplantation (BMT) as treatment for human disease. 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. Several issues, including graft-versus-host disease (GVHD), immunodeficiency, infections, conditioning regimen toxicities, and inability to completely eradicate tumor, have limited the successfulness of BMT. Major advances, particularly in the area of supportive care, have decreased the magnitude of many of these problems, but clinical progress in improving disease control, while at the same time limiting GVHD, has generally lagged behind advances in BMT supportive care. The overall goal of this proposal is to improve on the current state of the art in BMT by the translation of novel biologic approaches from the laboratory to the clinic. Most of the clinical trials arising from the research in this Program Project will involve BMT approaches. However, concepts stemming from ongoing preclinical studies in transplantation biology (immunology and hematopoiesis) funded by this grant since its inception, have led to the development of novel non-transplant treatments as well. Moreover, several of the concepts being studied in this new proposal, such as high-dose cyclophosphamide (CY) as the sole high-dose conditioning agent and as treatment for GVHD, have arisen from studies initiated in the first submission of this grant over 30 years ago. Thus, the grant's title remains biologically and historically appropriate, although its findings will continue to have implications beyond BMT. Specifically, the hypotheses to be tested in this proposal are: 1) targeting cancer stem cells can decrease tumor relapse;2) the combination of cell cycle inhibition and growth factors will induce clinical differentiation of cancer stem cells;3) high-dose CY alone (i.e., without BMT) has similar effectiveness to standard myeloablative conditioning regimens plus autologous BMT in lymphoid malignancies, while reducing toxicity and avoiding reinfusion of cancer cells;4) high-dose CY will diminish both GVHD and graft rejection after allogeneic BMT, without ablating normal hematopoiesis;5) cancer vaccines augment cancer specific immunity in both the autologous and allogeneic settings;6) immunomodulation can activate latent cancer-specific immunity.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA015396-35
Application #
7778277
Study Section
Special Emphasis Panel (ZCA1-RPRB-M (J1))
Program Officer
Merritt, William D
Project Start
1995-12-01
Project End
2012-02-28
Budget Start
2010-04-20
Budget End
2011-02-28
Support Year
35
Fiscal Year
2010
Total Cost
$2,933,594
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Ghosh, Nilanjan; Ye, Xiaobu; Tsai, Hua-Ling et al. (2017) Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Multiple Myeloma. Biol Blood Marrow Transplant 23:1903-1909
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Kanakry, Christopher G; Bolaños-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
Alonso, Salvador; Jones, Richard J; Ghiaur, Gabriel (2017) Retinoic acid, CYP26, and drug resistance in the stem cell niche. Exp Hematol 54:17-25
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Fuchs, Ephraim Joseph (2017) Related haploidentical donors are a better choice than matched unrelated donors: Point. Blood Adv 1:397-400
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
Gladstone, D E; Petri, M; Bolaños-Meade, J et al. (2017) Long-term systemic lupus erythematosus disease control after allogeneic bone marrow transplantation. Lupus 26:773-776
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

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