Latent Epstein-Barr virus (EBV) infection is associated with nasopharyngeal carcinoma (NPC), which expresses the EBV antigens LMP1, LMP2, EBNA1 and BARF1, all potential targets for immunotherapy. Investigators in Project 4 (S. Gottschalk and H. Heslop) and elsewhere have shown that administration of EBV-specific cytotoxic T cells (EBV-CTLs) is safe and has antitumor activity, and that clinical responses correlate with the presence of LMP2-specific T cells in the CTL product. Nonetheless, the anti-NFC activity of the CTL lines generated by the applicants'cun-ent methods is limited by several factors: (1) variability in the presence of CTL populations with specificity to the major EBV-derived tumor-associated antigen LMP2 and low frequency of T cells reactive to the other EBV-associated tumor antigens - LMP1, EBNA1 and BARF1;(2) the sensitivity of infused CTLs to the immunosuppressive tumor microenvironment;and (3) the inability of CTLs to attack the reactive stroma present in head and neck cancers, including NPC. The central hypothesis underiying this project is that eliminating two or more of the above obstacles will enhance the antitumor activity of infused CTLs, and improve the outcome in NPC patients. Thus, the investigators plan to implement a new T-cell manufacturing strategy that consistently produces T cells specific for LMP2 and at least one of the other three NPC-associated EBV antigens (NPC-specific CTLs). They will also genetically modify T cells with a dominant-negative receptor (DNR) to render them resistant to TGF-beta, the production of which is a common immune evasion strategy used by tumors including NPC. The safety and antitumor activity of these modified T cells will be evaluated in a phase I trial (Aim 1) with further investigations to monitor their in vivo fate (Aim 2).
Aim 3 will ask if CTLs expressing a chimeric antigen receptor (CAR) specific for tumor stroma and having the capacity to target tumor cells through their native receptors will show enhanced antitumor activity in a murine xenograft model.
These aims complement but do not overlap with those in Projects 1-3, such that advances emerging from our research could be rapidly assimilated into strategies being tested In other tumors within this program and vice versa.

Public Health Relevance

The body's Immune defenses against cancers often fail because the malignancies do not induce or actively inhibit immunity. Investigators in this project will try to counteract these limitations by engineering killer T cells to recognize structures on cancer cells and to resist the defenses Imposed by the tumor cell environment. The effects ofthe T cells will then be tested in patients with nasopharyngeal carcinoma (NPC).

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Baylor College of Medicine
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Rouce, Rayne H; Heslop, Helen E (2016) Forecasting Cytokine Storms with New Predictive Biomarkers. Cancer Discov 6:579-80
Yagyu, Shigeki; Hoyos, Valentina; Del Bufalo, Francesca et al. (2016) Multiple mechanisms determine the sensitivity of human-induced pluripotent stem cells to the inducible caspase-9 safety switch. Mol Ther Methods Clin Dev 3:16003
Bollard, Catherine M; Heslop, Helen E (2016) T cells for viral infections after allogeneic hematopoietic stem cell transplant. Blood 127:3331-40
Rouce, Rayne H; Sharma, Sandhya; Huynh, Mai et al. (2016) Recent advances in T-cell immunotherapy for haematological malignancies. Br J Haematol :
Ramos, Carlos A; Heslop, Helen E; Brenner, Malcolm K (2016) CAR-T Cell Therapy for Lymphoma. Annu Rev Med 67:165-83
Hegde, Meenakshi; Mukherjee, Malini; Grada, Zakaria et al. (2016) Tandem CAR T cells targeting HER2 and IL13Rα2 mitigate tumor antigen escape. J Clin Invest 126:3036-52
DeRenzo, Christopher; Gottschalk, Stephen (2016) Genetically Modified T-cell Therapy for the Treatment of Osteosarcoma: An Update. J Clin Cell Immunol 7:
Zhou, Xiaoou; Naik, Swati; Dakhova, Olga et al. (2016) Serial Activation of the Inducible Caspase 9 Safety Switch After Human Stem Cell Transplantation. Mol Ther 24:823-31
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
Chang, Edmund C; Liu, Hao; West, John A et al. (2016) Clonal Dynamics In Vivo of Virus Integration Sites of T Cells Expressing a Safety Switch. Mol Ther 24:736-45

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