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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Texas MD Anderson Cancer Center
United States
Zip Code
Cruz, Conrad R Y; Bollard, Catherine M (2017) Adoptive Immunotherapy For Leukemia With Ex vivo Expanded T Cells. Curr Drug Targets 18:271-280
Kerros, Celine; Tripathi, Satyendra C; Zha, Dongxing et al. (2017) Neuropilin-1 mediates neutrophil elastase uptake and cross-presentation in breast cancer cells. J Biol Chem 292:10295-10305
Kolonin, Mikhail G; Sergeeva, Anna; Staquicini, Daniela I et al. (2017) Interaction between Tumor Cell Surface Receptor RAGE and Proteinase 3 Mediates Prostate Cancer Metastasis to Bone. Cancer Res 77:3144-3150
Alsuliman, Abdullah; Muftuoglu, Muharrem; Khoder, Ahmad et al. (2017) A subset of virus-specific CD161+ T cells selectively express the multidrug transporter MDR1 and are resistant to chemotherapy in AML. Blood 129:740-758
Peters, Haley L; Tripathi, Satyendra C; Kerros, Celine et al. (2017) Serine Proteases Enhance Immunogenic Antigen Presentation on Lung Cancer Cells. Cancer Immunol Res 5:319-329
Houghtelin, Amy; Bollard, Catherine M (2017) Virus-Specific T Cells for the Immunocompromised Patient. Front Immunol 8:1272
Robinson, Simon N; Thomas, Michael W; Simmons, Paul J et al. (2017) Non-fucosylated CB CD34+ cells represent a good target for enforced fucosylation to improve engraftment following cord blood transplantation. Cytotherapy 19:285-292
Dave, Hema; Luo, Min; Blaney, J W et al. (2017) Toward a Rapid Production of Multivirus-Specific T Cells Targeting BKV, Adenovirus, CMV, and EBV from Umbilical Cord Blood. Mol Ther Methods Clin Dev 5:13-21
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
Nesher, Lior; Shah, Dimpy P; Ariza-Heredia, Ella J et al. (2016) Utility of the Enzyme-Linked Immunospot Interferon-?-Release Assay to Predict the Risk of Cytomegalovirus Infection in Hematopoietic Cell Transplant Recipients. J Infect Dis 213:1701-7

Showing the most recent 10 out of 95 publications