The goal of this project is to increase access to normal donor hematopoietic stem cell transplants for patients who lack an HLA- identical sibling donor, and to improve the safety and efficacy of these transplants as therapy for patients with hematological malignancy. Transplants from alternative donors with variable and sometimes undetected HLA mismatching have a higher risk of morbidity and transplant-related mortality (TRM) due to more severe graft- versus-host-disease (GVHD) than HLA identical sibling transplants. Studies outlined in the four specific aims of this project are directed to improving methods and criteria for donor matching, reducing GVHD and TRM, and understanding the nature of the prolonged immune deficiency that frequently occurs in HLA mismatched and unrelated donor transplants. Advances in DNA-based typing technology has allowed us to identify previously unrecognized HLA genetic variations that occur between patients and their haploidentical or unrelated donor. In the studies proposed here we will determine the degree of mismatching for HLA-A,B,C,DQ and DP alleles that can be safely tolerated without significantly increasing the risk of severe GVHD, and we will better define the situations where HLA mismatching and the potential for a stronger graft-versus-leukemia (GVL) effect may be beneficial. A clinical trail will be undertaken to determine if TRM might be reduced by improving the rate and quality of engraftment using growth factor-mobilized peripheral blood stem cells (PBSC). New methods for selected T-cell depletion (TCD) of HLA mismatched marrow or PBSC grafts from haploidentical related and unrelated donors will be examined to determine if this approach to GVHD prevention will allow us to safely undertake these kind of transplants for patients unable to find an optimal HLA match. Laboratory studies are proposed to examine the kinetics and diversity of posttransplant T- cell reconstitution especially in patients receiving TCD stem cell grafts by analyzing the expression of T-cell receptor (TCR) VB gene families using reverse-transcriptase (RT) and the polymerase chain reaction (PCR) to amplify individual TCR transcripts. The size variation of the CDR3 region of the TCR encoded by recombinant VDJ segments will be analyzed by spectratyping to identify individual TCR clonotypes as a means for estimating clonal diversity and identifying host-reactive T- cell clones that may be involved in GVHD. This method may provide an objective means for monitoring the effectiveness of immunosuppression therapy in the prevention and treatment of GVHD, and may help determine when tolerance has occurred and patients can be safely withdrawn from immunosuppression therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA018029-26
Application #
6420501
Study Section
Project Start
2001-02-13
Project End
2001-11-30
Budget Start
Budget End
Support Year
26
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109
Salter, Alexander I; Pont, Margot J; Riddell, Stanley R (2018) Chimeric antigen receptor-modified T cells: CD19 and the road beyond. Blood 131:2621-2629
Lee, Stephanie J; Nguyen, Tam D; Onstad, Lynn et al. (2018) Success of Immunosuppressive Treatments in Patients with Chronic Graft-versus-Host Disease. Biol Blood Marrow Transplant 24:555-562
Bar, Merav; Flowers, Mary E D; Storer, Barry E et al. (2018) Reversal of Low Donor Chimerism after Hematopoietic Cell Transplantation Using Pentostatin and Donor Lymphocyte Infusion: A Prospective Phase II Multicenter Trial. Biol Blood Marrow Transplant 24:308-313
Armenian, Saro H; Yang, Dongyun; Teh, Jennifer Berano et al. (2018) Prediction of cardiovascular disease among hematopoietic cell transplantation survivors. Blood Adv 2:1756-1764
Petersdorf, Effie W; Stevenson, Philip; Malkki, Mari et al. (2018) Patient HLA Germline Variation and Transplant Survivorship. J Clin Oncol 36:2524-2531
Yeung, Cecilia C S; McElhone, Scott; Chen, Xue Yan et al. (2018) Impact of copy neutral loss of heterozygosity and total genome aberrations on survival in myelodysplastic syndrome. Mod Pathol 31:569-580
Lee, Stephanie J; Onstad, Lynn; Chow, Eric J et al. (2018) Patient-reported outcomes and health status associated with chronic graft-versus-host disease. Haematologica 103:1535-1541
McCune, Jeannine S; Storer, Barry; Thomas, Sushma et al. (2018) Inosine Monophosphate Dehydrogenase Pharmacogenetics in Hematopoietic Cell Transplantation Patients. Biol Blood Marrow Transplant 24:1802-1807
Deegan, Anthony J; Talebi-Liasi, Faezeh; Song, Shaozhen et al. (2018) Optical coherence tomography angiography of normal skin and inflammatory dermatologic conditions. Lasers Surg Med 50:183-193
Leger, Kasey J; Baker, K Scott; Cushing-Haugen, Kara L et al. (2018) Lifestyle factors and subsequent ischemic heart disease risk after hematopoietic cell transplantation. Cancer 124:1507-1515

Showing the most recent 10 out of 1845 publications