Cord blood transplantation (CBT) is an increasingly effective treatment for patients with hematological malignancies for whom suitable HLA-matched donors are not available. If T cells that mediate graft verus leukemia (GVL) could be distinguished from those that mediate graft versus host disease (GVHD), more effective immunotherapy strategies could be developed. Our long-term goal is to improve the outcome of CBT for patients with AML by engineering donor T cells to increase GVL without increasing GVHD. We hypothesize that donor T-cells targeting leukemia-associated antigens (LAA), such as the HLA-A2-restricted PR1 peptide on AML, preferentially mediate GVL activity over GVHD and that cord blood (CB) donor-derived PR1-specific cytotoxic T lymphocytes (PR1-CTL) can be elicited and expanded ex vivo for clinical use to selectively induce GVL in CBT recipients. Thus, we have cloned high- and low-affinity PR1-specific T cell receptor-alphaBeta (TCR) heterodimers from PR1 vaccine clinical responders, which can be transduced into polyclonal T-cells to redirect antigen specificity and mediate antileukemic effects. We have also produced a monoclonal antibody with high affinity for a specific conformational epitope of PR1/HLA-A2 (8F4) that mediates potent and specific cytotoxicity against acute myeloid leukemia (AML), and a single chain Fv of 8F4 fused with CD3zeta + CD28 as a chimeric antigen receptor (CAR) will be used to gene modify T-cells to study GVL effects. In addition, the number of precursor PR1-CTL is ~1000-fold higher in CB compared to adult peripheral blood and CB PRI-CTL can be activated and expanded more than 5-fold in vitro. On the strength of these advances, we propose to (1) identify an optimal method to elicit and expand potent CB-derived PR1-CTL ex vivo by comparing (a) cell expansion from single CB units, (b) cell purification from multiple donors, (c) PR1-TCR-alphaBeta gene modification, and (d) 8F4-CAR gene modification;(2) use a xenogeneic mouse model to validate the potency of PR1-CTL against human AML in vivo to study the persistence and possible tolerance induction of PR1-CTL by AML, and to determine the spatial and temporal GVL effects, persistence, and possible tolerance of CB-derived PR1-CTL using bioluminescence and PET/CT imaging. Finally, based on the method identified to optimally obtain PR1-CTL, we will (3) test the clinical feasibility and safety of CB-derived PR1-CTL as adoptive cell therapy for AML patients after CBT.

Public Health Relevance

While CBT is potentially an effective treatment alternative for leukemia, poor immune reconstitution, GVHD, and disease relapse continue to be significant obstacles to successful outcomes. We will determine methods to improve the GVL effect, decrease the risk of relapse, and mitigate GVHD by adoptively transferring donor-derived antigen-specific T-cells to CBT recipients. Thus, combining targeted T-cell therapy with CBT may provide an effective alternative to leukemia patients at high risk for treatment failure.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA148600-04
Application #
8730463
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
4
Fiscal Year
2014
Total Cost
$115,490
Indirect Cost
$27,838
Name
University of Texas MD Anderson Cancer Center
Department
Type
DUNS #
800772139
City
Houston
State
TX
Country
United States
Zip Code
77030
Sekine, Takuya; Marin, David; Cao, Kai et al. (2016) Specific combinations of donor and recipient KIR-HLA genotypes predict for large differences in outcome after cord blood transplantation. Blood 128:297-312
Patel, Shabnum; Lam, Sharon; Cruz, Conrad Russell et al. (2016) Functionally Active HIV-Specific T Cells that Target Gag and Nef Can Be Expanded from Virus-Naïve Donors and Target a Range of Viral Epitopes: Implications for a Cure Strategy after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 22:536-41
Torikai, Hiroki; Mi, Tiejuan; Gragert, Loren et al. (2016) Genetic editing of HLA expression in hematopoietic stem cells to broaden their human application. Sci Rep 6:21757
Tripathi, Satyendra C; Peters, Haley L; Taguchi, Ayumu et al. (2016) Immunoproteasome deficiency is a feature of non-small cell lung cancer with a mesenchymal phenotype and is associated with a poor outcome. Proc Natl Acad Sci U S A 113:E1555-64
Patel, Shabnum; Jones, R Brad; Nixon, Douglas F et al. (2016) T-cell therapies for HIV: Preclinical successes and current clinical strategies. Cytotherapy 18:931-42
Bollard, Catherine M; Heslop, Helen E (2016) T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127:3331-40
Thompson, Philip A; Perera, Travis; Marin, David et al. (2016) Double umbilical cord blood transplant is effective therapy for relapsed or refractory Hodgkin lymphoma. Leuk Lymphoma 57:1607-15
Naik, Swati; Nicholas, Sarah K; Martinez, Caridad A et al. (2016) Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J Allergy Clin Immunol 137:1498-1505.e1
Kebriaei, Partow; Singh, Harjeet; Huls, M Helen et al. (2016) Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest 126:3363-76
Spielmann, Guillaume; Bollard, Catherine M; Kunz, Hawley et al. (2016) A single exercise bout enhances the manufacture of viral-specific T-cells from healthy donors: implications for allogeneic adoptive transfer immunotherapy. Sci Rep 6:25852

Showing the most recent 10 out of 86 publications