More widespread reports of complete tumor responses to cell therapies are paralleled by increasing clinical, scientific and public interest in, therapies that can produce antitumor effects without the devastating consequences of standard chemo-radiotherapies. However, much remains to be achieved before these eariy phase therapies become a standard of clinical practice. During our prior SPORE funding , we demonstrated, that EBV antigen-specific T cells produced over 60% complete remission rate without toxicity, in 21 patients with relapsed EBV-positive lymphoma. Our complex T cell generation process was, however, identified as a critical regulatory barrier to the progress of this study to pivotal clinical studies and a biologies licensing application (BLA). The manufacturing process required live virus (EBV) and (adeno)viral vectors, as well as B cells for the generation of autologous antigen-presenting cells (APCs) - a severe limitation now that most patients receive the B cell depleting antibody rituxan upon diagnosis. We therefore developed a strategy for the production of EBV-specific T cells that does not require live virus or viral vectors and reduces both complexity and the manufacturing time (from >3 riionths to <4 weeks);increases the number of viral tumor antigens recognized from 2 to 4;and is effective for any patient regardless of HLA type or prior treatment with rituxan. In the current application, we plan a phase 1 trial to validate the biological and clinical equivalency of T cells made with the new manufacturing strategies, which will enable us to proceed to a pivotal trial (outside the scope of the SPORE) and then a BLA. In the second part of our proposal, we plan to further improve upon our 60% CR rate in relapsed disease, by combining ithe tumor-directed T cells with small molecule histone deacetylase inhibitors (HDAC-ls). These drugs have both direct anti-lymphoma activity and multiple proimmune effects that should increase the efficacy of tumor-specific T cells. Since HDAC-ls can also inhibit T cells, we will use mouse lymphoma models to evaluate how HDAC-ls and adoptive T cell transfer can best be used in combination, by identifying the mechanisms of tumor immuneresistance that can be effectively altered by HDAC-I to augment T cell persistence, proliferation and antitumor activity.

Public Health Relevance

There is increasing excitement over the use of cellular immunotherapies in the treatment of cancer, but many of the current approaches are overiy complex or pose excessive risks for the patient. The modifications proposed in the application are designed to bring virus-specific T cell therapy for lymphoma to the bedside, in a manner that is straightfonward, reproducible and cost effective.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA126752-08
Application #
8724177
Study Section
Special Emphasis Panel (ZCA1-RPRB-7)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-08-31
Support Year
8
Fiscal Year
2014
Total Cost
$214,762
Indirect Cost
$67,179
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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