Project 4 Program Director/Principal Investigator (Last, First, Middle): JoneS, Rlchard J. Allogeneic BMT (alloBMT) is the treatment of choice for eligible patients with hematologic malignancies that are incurable by chemotherapy. Donor T cell mediated graft-versus-tumor effects have the potential to eradicate residual cancer cells that survive pre-transplant cytotoxic therapies. T cell recognition of alloantigens as well as leukemia-associated antigens (LAAs) has been reported to contribute to this effect. Historically, the beneficial impact of allorecognition on relapse-free survival has been largely offset by the toxicities of graft-versus-host-disease (GVHD) and its treatment, and attempts to diminish the latter by donor T cell depletion or recipient immunosuppression have resulted in increased rates of relapse. The studies pioneered in PROJECT 4 have led to the development of high doses of cyclophosphamide.in the early post- BMT period (PT/Cy) as a strategy for generating bi-directional tolerance. As a result, patients treated with PT/Cy have achieved stable hematopoietic engraftment with low rates of GVHD, even in HLA-haploidentical donor/recipient pairs. With this innovation, relapse rather than GVHD is now the major cause of transplant failure. As demonstrated by mouse studies in PROJECT 2, adoptive transfer of lymphocytes from donors primed with a cancer vaccine significantly reduces relapse rates in syngeneic, tumor-bearing recipients. These results led to clinical trials testing the integration of a therapeutic leukemia vaccine into the setting of autologous BMT, which demonstrated that the response to a vaccine administered pirior to graft harvest correlated significantly with post-BMT relapse-free survival. We now propose to evaluate donor vaccination as a strategy to improve the outcome of alloBMT. However, two impediments in bringing donor vaccination into the alloBMT setting are: 1) the risk of inducing autoimmunity in the healthy donor, and 2) the potential to increase the incidence or severity of GVHD. Accordingly, we have chosen to target an antigen that is not expressed in normal tissues of healthy donors, but is aberrantly expressed in many myeloid leukemias. A collaboration between PROJECT 1 and PROJECT 2 has led to the discovery that PRAME, a cancer testis antigen, is one of the few identified LAAs that is abundantly expressed in leukemic stem cells (LSCs), but is absent from normal hematopoietic stem cells. This proposal seeks to link these three fundamental discoveries in GVHD prophylaxis (Project 4), adoptive transfer of vaccine pnmed immunity (Project 2), and LSC antigen expression (Project 1) to improve the outcome of alloBMT.

Public Health Relevance

With newer procedures for reducing the morbidity and mortality of alloBMT, the major cause of transplant failure is relapse. This proposal addresses this limitation by studying vaccination of healthy BMT donors against a leukemia-associated antigen, so as to transfer immune cells capable of killing residual leukemia in the patient. The proposal also studies shortening the duration of pharmacologic immunosuppression so as to facilitate the timely application of post-transplantation immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA015396-38
Application #
8559500
Study Section
Special Emphasis Panel (ZCA1-RPRB-B)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
38
Fiscal Year
2013
Total Cost
$416,194
Indirect Cost
$159,284
Name
Johns Hopkins University
Department
Type
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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