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.
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 of the T cells will then be tested in patients with nasopharyngeal carcinoma (NPC).
|DeRenzo, Christopher; Gottschalk, Stephen (2014) Genetically modified T-cell therapy for osteosarcoma. Adv Exp Med Biol 804:323-40|
|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|
|Perna, Serena K; Pagliara, Daria; Mahendravada, Aruna et al. (2014) Interleukin-7 mediates selective expansion of tumor-redirected cytotoxic T lymphocytes (CTLs) without enhancement of regulatory T-cell inhibition. Clin Cancer Res 20:131-9|
|Leen, Ann M; Heslop, Helen E; Brenner, Malcolm K (2014) Antiviral T-cell therapy. Immunol Rev 258:12-29|
|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|
|Chia, Whay-Kuang; Teo, Marissa; Wang, Who-Whong et al. (2014) Adoptive T-cell transfer and chemotherapy in the first-line treatment of metastatic and/or locally recurrent nasopharyngeal carcinoma. Mol Ther 22:132-9|
|Anurathapan, Usanarat; Leen, Ann M; Brenner, Malcolm K et al. (2014) Engineered T cells for cancer treatment. Cytotherapy 16:713-33|
|Anurathapan, Usanarat; Chan, Robert C; Hindi, Hakeem F et al. (2014) Kinetics of tumor destruction by chimeric antigen receptor-modified T cells. Mol Ther 22:623-33|
|Heslop, Helen E (2014) Combining drugs and biologics to treat nasopharyngeal cancer. Mol Ther 22:8-9|
|Lee, Daniel W; Gardner, Rebecca; Porter, David L et al. (2014) Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124:188-95|
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