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.
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.
|Zerboni, Leigh; Sung, Phillip; Sommer, Marvin et al. (2018) The C-terminus of varicella-zoster virus glycoprotein M contains trafficking motifs that mediate skin virulence in the SCID-human model of VZV pathogenesis. Virology 523:110-120|
|Muffly, Lori; Sheehan, Kevin; Armstrong, Randall et al. (2018) Infusion of donor-derived CD8+ memory T cells for relapse following allogeneic hematopoietic cell transplantation. Blood Adv 2:681-690|
|Tavallaee, Mahkam; Steiner, David F; Zehnder, James L et al. (2018) Coexistence of BRAF V600E and TERT Promoter Mutations in Low-grade Serous Carcinoma of Ovary Recurring as Carcinosarcoma in a Lymph Node: Report of a Case. Int J Gynecol Pathol :|
|Du, Jing; Paz, Katelyn; Thangavelu, Govindarajan et al. (2017) Invariant natural killer T cells ameliorate murine chronic GVHD by expanding donor regulatory T cells. Blood 129:3121-3125|
|Spinner, Michael A; Fernández-Viña, Marcelo; Creary, Lisa E et al. (2017) HLA-mismatched unrelated donor transplantation using TLI-ATG conditioning has a low risk of GVHD and potent antitumor activity. Blood Adv 1:1347-1357|
|Costa, Helio A; Neal, Joel W; Bustamante, Carlos D et al. (2017) Identification of a Novel Somatic Mutation Leading to Allele Dropout for EGFR L858R Genotyping in Non-Small Cell Lung Cancer. Mol Diagn Ther 21:431-436|
|Chen, Yi-Bin; Efebera, Yvonne A; Johnston, Laura et al. (2017) Increased Foxp3+Helios+Regulatory T Cells and Decreased Acute Graft-versus-Host Disease after Allogeneic Bone Marrow Transplantation in Patients Receiving Sirolimus and RGI-2001, an Activator of Invariant Natural Killer T Cells. Biol Blood Marrow Transplant 23:625-634|
|Xu, Liwen; You, Xiaoqing; Zheng, PingPing et al. (2017) Methodologic Considerations in the Application of Next-Generation Sequencing of Human TRB Repertoires for Clinical Use. J Mol Diagn 19:72-83|
|Paul, Jed; Sahaf, Bita; Perloff, Spenser et al. (2016) High-throughput allogeneic antibody detection using protein microarrays. J Immunol Methods 432:57-64|
|Pierini, Antonio; Strober, William; Moffett, Caitlin et al. (2016) TNF-? priming enhances CD4+FoxP3+ regulatory T-cell suppressive function in murine GVHD prevention and treatment. Blood 128:866-71|
Showing the most recent 10 out of 307 publications