Latent Epstein-Barr virus (EBV) infection is associated with nasopharyngeal carcinoma (NPC), which expresses the EBV antigens LMP1 and LMP2, both potential targets for immunotherapy. Clinical studies with EBV-specific cytotoxicT cells (EBV-CTLs) in NPC have already yielded promising results, including some complete responses, but their efficacy is limited because the EBV-CTL generated by standard methods are 1) dominated by T-cell clones not reactive to the EBV proteins LMP1 and LMP2 expressed in NPC, 2) cannot expand significantly after infusion, 3) are sensitive to immune evasion strategies employed by NPCs such as downregulation of MHC class I expression and the presence of regulatory T cells (Tregs) in the tumor environment, and 4) are dysfunctional in areas of hypoxia within NPC deposits. Our central hypothesis is that overcoming these limitations will enhance the antitumor activity of infused CTLs and improve treatment outcome. Thus, we will prepare EBV-LMP1 and LMP2-specific CTLs (LMP-CTLs) and evaluate three strategies to enhance their activity using a clinical trial or a xenograft model.
Aim 1 extends our current Phase I clinical trials in NPC by combining LMP-CTL with lymphodepleting CD45 monoclonal antibodies to augment CTL expansion in vivo and improve disease response rates.
In Aim 2, we will express a chimeric antigen receptor (CAR) specific for CD70 in LMP-CTLs. CD70 is overexpressed in EBV-positive NPCs, and the modified CTLs should thus be able to kill NPC cells through both MHC class l-restricted and unrestricted pathways, increasing their therapeutic effectiveness in our xenograft model. Moreover, we will incorporate signaling endodomains from costimulatory molecules in the CAR and test whether these modifications make the CAR-LMP-CTL resistant to Tregs present in NPC.
In Aim 3, we will exploit our previous observations showing that expression of the IL-2 gene regulated by the hypoxia inducible factor (HIF-IL2) can render CTL resistant to hypoxia. We will measure cellular persistence, proliferation and function of HIF-IL2 expressing LMP-CTL in hypoxic areas within NPC tumors, and determine, if they produce enhanced antitumor activity.
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. Lav Summary: The body's immune defenses against cancers often fail because the malignancies do not induce or actively inhibit immunity. We will try to counteract these limitations by engineering killer T cells to recognize structures on cancer cells (LMP1 and LMP2) 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).
|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 :|
|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|
|Tanaka, Miyuki; Tashiro, Haruko; Omer, Bilal et al. (2017) Vaccination Targeting Native Receptors to Enhance the Function and Proliferation of Chimeric Antigen Receptor (CAR)-Modified T Cells. Clin Cancer Res 23:3499-3509|
|Brenner, Malcolm K (2017) Next Steps in the CAR Journey of a Thousand Miles. Mol Ther 25:2226-2227|
Showing the most recent 10 out of 217 publications