- PROJECT 3 Allogeneic hematopoietic cell transplantation (HCT) provides graft-vs-tumor (GVT) reactions that may cure patients with advanced lymphoma. We developed a well tolerated, reduced intensity conditioning regimen with low-dose total body irradiation (TBI) (2 Gy) with fludarabine (FLU;30 mg/m2 ? 3) that provides reliable engraftment for allogeneic HCT from HLA-matched related or unrelated donors. This regimen allows treatment of older patients nearer the median age of presentation for these diseases or those with comorbidities unable to tolerate myeloablative HCT. Most anti-tumor activity is from GVT responses that develop as post-grafting immunosuppression is withdrawn. Nearly 90% of the causes of HCT failure are relapse and graft-vs.-host disease (GVHD) related nonrelapse mortality (NRM). Relapse risk depends on tumor histology and tumor bulk at the time of HCT with the highest risk of relapse in patients with bulky disease, aggressive NHL not in remission, and HL patients who have failed prior autologous HCT. Better treatments are needed to reduce and control disease until GVT effects emerge. Increasing the intensity of nonspecific, systemic conditioning by increasing TBI or chemotherapy in this population has been poorly tolerated and increases NRM. Radioimmunotherapy (RIT) using anti-CD20 monoclonal antibodies (mAb) conjugated with iodine-131 (131I; gamma and beta-emitter) and yttrium-90 (90Y;beta-emitter) combined with our FLU/TBI conditioning regimen has been shown to be safe;however, the long path-length, long half-life, and relatively low-energy of these radioisotopes may not provide enough targeted radiation, and may be blocked by circulating levels of rituximab from prior therapy. We propose to augment transplant conditioning with anti-CD45 mAb coupled to the alpha- emitting radionuclide astatine-211 (211At). The short path length of the alpha-emitter, high energy, and short half-life may reduce both early toxicities and late effects, such as secondary cancers, associated with conventional beta-emitter RIT. We hypothesize that alpha particle anti-CD45 RIT may provide additional anti- tumor activity, as well as lower the barriers to engraftment without greatly increasing NRM for the treatment of both B and T-cell NHL and HL at a high risk of relapse using FLU/TBI alone. Accordingly, Specific Aim 1 will evaluate 211At anti-CD45 mAb in combination with reduced intensity allogeneic HCT from HLA-matched related and unrelated donors. In order to extend the option of HCT to patients without HLA-matched donors and better serve patients from minority groups, we have developed a reduced intensity regimen using HLA-haploidentical donors. While the regimen is well tolerated with a low rate of GVHD, relapse and immunodeficiency remain high, likely due to the post HCT immunosuppression with cyclophosphamide to control GVHD.
Specific Aim 2 will address this using adoptive immunotherapy with donor NK cells and with infusions of gene modified donor T lymphocytes expressing an inducible iCaspase-9 gene that can be ablated with a dimerizing agent in the advent of severe GVHD. We hypothesize that this will reduce relapse and immunodeficiency post HCT.

Public Health Relevance

- PROJECT 3 This project is focused on reducing the risk of relapse of malignancy in patients with advanced lymphoma who have been treated with stem cell transplantation from healthy donors. We will accomplish this by using targeted radiation with an antibody to the cancer cell coupled to a short-lived radioactive isotope and with donor immune cell infusions.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Fred Hutchinson Cancer Research Center
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Walter, R B; Gyurkocza, B; Storer, B E et al. (2015) Comparison of minimal residual disease as outcome predictor for AML patients in first complete remission undergoing myeloablative or nonmyeloablative allogeneic hematopoietic cell transplantation. Leukemia 29:137-44
Walter, Roland B; Sandmaier, Brenda M; Storer, Barry E et al. (2015) Number of courses of induction therapy independently predicts outcome after allogeneic transplantation for acute myeloid leukemia in first morphological remission. Biol Blood Marrow Transplant 21:373-8
Hoffmeister, Paul A; Storer, Barry E; Baker, K Scott et al. (2014) Nephrolithiasis in pediatric hematopoietic cell transplantation with up to 40 years of follow-up. Pediatr Blood Cancer 61:417-23
Mathes, David W; Chang, Jeff; Hwang, Billanna et al. (2014) Simultaneous transplantation of hematopoietic stem cells and a vascularized composite allograft leads to tolerance. Transplantation 98:131-8
Matesan, Manuela; Rajendran, Joseph; Press, Oliver W et al. (2014) 90Y-ibritumomab tiuxetan therapy in allogeneic transplantation in B-cell lymphoma with extensive marrow involvement and chronic lymphocytic leukemia: utility of pretransplantation biodistribution. Nucl Med Commun 35:1132-42
Sorror, Mohamed L; Martin, Paul J; Storb, Rainer F et al. (2014) Pretransplant comorbidities predict severity of acute graft-versus-host disease and subsequent mortality. Blood 124:287-95
Gyurkocza, Boglarka; Sandmaier, Brenda M (2014) Conditioning regimens for hematopoietic cell transplantation: one size does not fit all. Blood 124:344-53
Bethge, W A; Kerbauy, F R; Santos, E B et al. (2014) Extracorporeal photopheresis combined with pentostatin in the conditioning regimen for canine hematopoietic cell transplantation does not prevent GVHD. Bone Marrow Transplant 49:1198-204
Sorror, Mohamed L; Storb, Rainer F; Sandmaier, Brenda M et al. (2014) Comorbidity-age index: a clinical measure of biologic age before allogeneic hematopoietic cell transplantation. J Clin Oncol 32:3249-56
Inamoto, Yoshihiro; Martin, Paul J; Storer, Barry E et al. (2014) Response endpoints and failure-free survival after initial treatment for acute graft-versus-host disease. Haematologica 99:385-91

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