This program project was initiated 26 years ago as a comprehensive effort to study the biology of bone marrow transplantation (BMT) as treatment for human disease. Over that period of time, BMT has proven to be effective therapy, and even the treatment of choice, for a variety of malignant diseases. However, BMT has failed to reach its full therapeutic potential for a number of reasons, including graft-versus-host disease (GVHD), immunodeficiency, infections, preparative regimen toxicities, and inability to completely eradicate tumor. Major advances, particularly in the area of supportive care, have decreased the magnitude of all these problems. Clinical progress in preventing tumor recurrence has generally lagged behind the advances in BMT supportive care. Tumor recurrence remains the major cause for failure of autologous BMT, accounting for nearly 90% of the failures, and is also the major cause of failure of allogeneic BMT for many malignancies. Modifications of intensive cytotoxic intensive regimens have not made a major impact on the outcome of BMT. Cytotoxic conditioning regimens for BMT are at or near non-hematologic dose-limiting toxicity; this hinders a further increase in the intensity of, or the addition of new cytotoxic agents to, these conditioning regimens. Further, the tumor remaining after the high-dose BMT preparative regimen represents a drug-resistant population of cells. Other approaches for improving the antitumor activity of BMT are therefore needed. The overall goal of this proposal is to study such approaches, primarily biologic in nature, in the laboratory and to translate promising strategies into the clinic. These approaches include: 1) Growth factor-mediated terminal differentiation of myeloid malignancies; 2) methods to augment cyclosporine (CsA)-induced """"""""autologous GVHD""""""""; 3) the immunologic graft-versus-tumor effect associated with allogeneic BMT; 4) specific and non-specific adoptive immunotherapy; and 5) tumor vaccines, specifically in the setting of autologous BMT.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA015396-31
Application #
6862759
Study Section
Subcommittee G - Education (NCI)
Program Officer
Merritt, William D
Project Start
1976-09-30
Project End
2007-02-28
Budget Start
2005-05-16
Budget End
2007-02-28
Support Year
31
Fiscal Year
2005
Total Cost
$2,770,981
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
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
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
Majzner, Robbie G; Mogri, Huzefa; Varadhan, Ravi et al. (2017) Post-Transplantation Cyclophosphamide after Bone Marrow Transplantation Is Not Associated with an Increased Risk of Donor-Derived Malignancy. Biol Blood Marrow Transplant 23:612-617
Alonso, Salvador; Jones, Richard J; Ghiaur, Gabriel (2017) Retinoic acid, CYP26, and drug resistance in the stem cell niche. Exp Hematol 54:17-25
Cruz, Conrad R Y; Bollard, Catherine M (2017) Adoptive Immunotherapy For Leukemia With Ex vivo Expanded T Cells. Curr Drug Targets 18:271-280
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

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