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).
|Bollard, Catherine M; Tripic, Tamara; Cruz, Conrad Russell et al. (2018) Tumor-Specific T-Cells Engineered to Overcome Tumor Immune Evasion Induce Clinical Responses in Patients With Relapsed Hodgkin Lymphoma. J Clin Oncol 36:1128-1139|
|Lyon, Deborah; Lapteva, Natasha; Gee, Adrian P (2018) Absence of Replication-Competent Retrovirus in Vectors, T Cell Products, and Patient Follow-Up Samples. Mol Ther 26:6-7|
|Shum, Thomas; Kruse, Robert L; Rooney, Cliona M (2018) Strategies for enhancing adoptive T-cell immunotherapy against solid tumors using engineered cytokine signaling and other modalities. Expert Opin Biol Ther 18:653-664|
|Bajgain, Pradip; Tawinwung, Supannikar; D'Elia, Lindsey et al. (2018) CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation. J Immunother Cancer 6:34|
|McLaughlin, Lauren P; Rouce, Rayne; Gottschalk, Stephen et al. (2018) EBV/LMP-specific T cells maintain remissions of T- and B-cell EBV lymphomas after allogeneic bone marrow transplantation. Blood 132:2351-2361|
|Heslop, Helen E; Brenner, Malcolm K (2018) Seek and You Will Not Find: Ending the Hunt for Replication-Competent Retroviruses during Human Gene Therapy. Mol Ther 26:1-2|
|Mamonkin, Maksim; Mukherjee, Malini; Srinivasan, Madhuwanti et al. (2018) Reversible Transgene Expression Reduces Fratricide and Permits 4-1BB Costimulation of CAR T Cells Directed to T-cell Malignancies. Cancer Immunol Res 6:47-58|
|Kalra, Mamta; Gerdemann, Ulrike; Luu, Jessica D et al. (2018) Epstein-Barr Virus (EBV)-derived BARF1 encodes CD4- and CD8-restricted epitopes as targets for T-cell immunotherapy. Cytotherapy :|
|Mata, Melinda; Gerken, Claudia; Nguyen, Phuong et al. (2017) Inducible Activation of MyD88 and CD40 in CAR T Cells Results in Controllable and Potent Antitumor Activity in Preclinical Solid Tumor Models. Cancer Discov 7:1306-1319|
|Tzannou, Ifigeneia; Papadopoulou, Anastasia; Naik, Swati et al. (2017) Off-the-Shelf Virus-Specific T Cells to Treat BK Virus, Human Herpesvirus 6, Cytomegalovirus, Epstein-Barr Virus, and Adenovirus Infections After Allogeneic Hematopoietic Stem-Cell Transplantation. J Clin Oncol 35:3547-3557|
Showing the most recent 10 out of 217 publications