The long-term goal of Project 4 is to develop an effective, clinically feasible approach to targeting chemoresistant tumor-initiating cells in chronic lymphocytic leukemia (CLL). In the preceding SPORE funding period, we showed that a small subset of circulating or marrow-resident CLL cells within the side population (SP) of tumor cells are drug resistant and have properties associated with cancer initiation. After demonstrating that a tumor vaccine consisting of autologous tumor cells modified to express IL-2 and CD40L could generate a T cell response (vaccine-induced cytotoxic T cells, or VICTs), directed primarily against the SP subset of CLL cells, we now propose to use this information to prepare T cells directed against the SP-associated antigens we previously identified, using ex vivo peptide immunization (Peptide-induced Cytotxic T cells- PICTs). We will also test a strategy for enhancing these T cell responses against the drug resistant and putative tumor initiating SP cells, by genetically modifying the SP-directed T cells to express IL-21, thus rendering them resistant to Treg cell inhibition. We will also administer the modified T cells together with continued

Public Health Relevance

An overriding goal of targeted cancer therapy is to eliminate all malignant cells that can initiate the formation of new tumors, rather than simply the obvious general population of tumor cells. The studies outlined here could provide a specific method for eradicating a small drug-resistant group of leukemic stem cells in an otherwise incurable disease.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Baylor College of Medicine
United States
Zip Code
Iwahori, Kota; Kakarla, Sunitha; Velasquez, Mireya P et al. (2015) Engager T cells: a new class of antigen-specific T cells that redirect bystander T cells. Mol Ther 23:171-8
Ngo, Minhtran Charlotte; Ando, Jun; Leen, Ann M et al. (2014) Complementation of antigen-presenting cells to generate T lymphocytes with broad target specificity. J Immunother 37:193-203
Ok, Chi Young; Li, Ling; Xu-Monette, Zijun Y et al. (2014) Prevalence and clinical implications of epstein-barr virus infection in de novo diffuse large B-cell lymphoma in Western countries. Clin Cancer Res 20:2338-49
Bollard, Catherine M; Gottschalk, Stephen; Torrano, Vicky et al. (2014) Sustained complete responses in patients with lymphoma receiving autologous cytotoxic T lymphocytes targeting Epstein-Barr virus latent membrane proteins. J Clin Oncol 32:798-808
Rouce, Rayne H; Louis, Chrystal U; Heslop, Helen E (2014) Epstein-Barr virus lymphoproliferative disease after hematopoietic stem cell transplant. Curr Opin Hematol 21:476-81
Leen, Ann M; Heslop, Helen E; Brenner, Malcolm K (2014) Antiviral T-cell therapy. Immunol Rev 258:12-29
Xu, Xin; Hegazy, Wael A H; Guo, Linjie et al. (2014) Effective cancer vaccine platform based on attenuated salmonella and a type III secretion system. Cancer Res 74:6260-70
Zhou, Xiaoou; Di Stasi, Antonio; Tey, Siok-Keen et al. (2014) Long-term outcome after haploidentical stem cell transplant and infusion of T cells expressing the inducible caspase 9 safety transgene. Blood 123:3895-905
Papadopoulou, Anastasia; Krance, Robert A; Allen, Carl E et al. (2014) Systemic inflammatory response syndrome after administration of unmodified T lymphocytes. Mol Ther 22:1134-8
Anurathapan, Usanarat; Leen, Ann M; Brenner, Malcolm K et al. (2014) Engineered T cells for cancer treatment. Cytotherapy 16:713-33

Showing the most recent 10 out of 121 publications