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 #
5P01CA015396-34
Application #
7616218
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
2009-03-01
Budget End
2010-02-28
Support Year
34
Fiscal Year
2009
Total Cost
$3,012,562
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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