Preventing relapse after allogeneic hematopoietic cell transplantation (alloHCT) requires novel approaches to identify and augment beneficial GVL alloimmunity. We propose that chronic lymphocytic leukemia (CLL) is the human """"""""model disease"""""""" to achieve these goals and lessons learned focusing on CLL will improve all transplantation outcomes. Studying CLL patients enables sensitive measurement of minimal residual disease (MRD) which has emerged as the most important predictor of CLL disease free survival following alloHCT. Our innovative research proposal employs massively parallel sequencing of the B and T cell receptor genes to sensitively quantify CLL minimal residual disease MRD while identifying the unique T cell clones providing GVL benefit. We have already demonstrated the feasibility of high-throughput sequencing (HTS) the immunoglobulin heavy chain (IGH) for quantifying CLL MRD. In order to identify beneficial donor T cell clones, ex vivo CLL stimulated donor T cell clones will be isolated by flow cytometry and their unique V T cell receptors (TCR) will be determined by HTS. Following graft infusion, we will quantify these """"""""marked"""""""" anti-CLL TCR clonotypes proliferation and persistence in relation to CLL MRD. Our second innovative application of HTS will assess the overall breadth and depth of donor T and B cell reconstitution following alloHCT. In the final aim, we will test the therapeutic benefit of human allogeneic cytokine induced killer cells (alloCIK) that were successfully translated through human phase I studies supported by our current PPG demonstrating feasibility and low GVHD risk. Overall, we hypothesize that impaired post-transplant donor immune reconstitution with limited T and B cell repertoire diversity limits beneficial GVL alloimmunity and associates with disease relapse. In project 4, we will pioneer massively parallel sequencing of B and T cell receptors to test this hypothesis in CLL patients undergoing alloHCT. We will: 1) quantify CLL MRD, 2) identify beneficial GVL T cell responses, 3) quantify overall immune reconstitution.

Public Health Relevance

Allogeneic hematopoietic cell transplantation can cure many hematologic malignancies through beneficial graft-versus-leukemia (GVL) immune responses. However, relapse remains the major cause of death. Chronic Lymphocytic leukemia (CLL) is the most common blood cancer, can be frequently cured following alloHCT via GVL benefit, and CLL MRD response predicts cure. Our novel approaches to identify and augment CLL GVL will improve all transplantation outcomes.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Stanford University
United States
Zip Code
Sen, Nandini; Arvin, Ann M (2016) Dissecting the Molecular Mechanisms of the Tropism of Varicella-Zoster Virus for Human T Cells. J Virol 90:3284-7
Pierini, Antonio; Alvarez, Maite; Negrin, Robert S (2016) NK Cell and CD4+FoxP3+ Regulatory T Cell Based Therapies for Hematopoietic Stem Cell Engraftment. Stem Cells Int 2016:9025835
Khodadoust, M S; Luo, B; Medeiros, B C et al. (2016) Clinical activity of ponatinib in a patient with FGFR1-rearranged mixed-phenotype acute leukemia. Leukemia 30:947-50
Xu, Lian; Hunter, Zachary R; Tsakmaklis, Nicholas et al. (2016) Clonal architecture of CXCR4 WHIM-like mutations in Waldenström Macroglobulinaemia. Br J Haematol 172:735-44
Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-α priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71
Nakasone, Hideki; Sahaf, Bita; Tian, Lu et al. (2016) Presensitization to HY antigens in female donors prior to transplant is not associated with male recipient post-transplant HY antibody development nor with clinical outcomes. Haematologica 101:e30-3
Pierini, Antonio; Colonna, Lucrezia; Alvarez, Maite et al. (2015) Donor Requirements for Regulatory T Cell Suppression of Murine Graft-versus-Host Disease. J Immunol 195:347-55
Ohgami, Robert S; Ma, Lisa; Merker, Jason D et al. (2015) Next-generation sequencing of acute myeloid leukemia identifies the significance of TP53, U2AF1, ASXL1, and TET2 mutations. Mod Pathol 28:706-14
Nakasone, Hideki; Remberger, Mats; Tian, Lu et al. (2015) Risks and benefits of sex-mismatched hematopoietic cell transplantation differ according to conditioning strategy. Haematologica 100:1477-85
Kelley, Todd W; Arber, Daniel A; Gibson, Christine et al. (2015) Template for Reporting Results of Monitoring Tests for Patients With Chronic Myelogenous Leukemia (BCR-ABL1(+)). Arch Pathol Lab Med :

Showing the most recent 10 out of 292 publications