The long-term goal of Project 1, led by C. Rooney, is to improve the outcome of immunotherapy for lymphomas associated with Epstein-Barr virus (EBV), especially Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Although studies during the previous funding cycle showed that cytotoxic T lymphocytes (CTLs) specific for the LMP2 protein of EBV home to tumor sites and produce antitumor effects (complete responses in 4 of 6 patients with relapsed disease), such therapy had clear shortcomings that would limit its effectiveness in future protocols for HD and NHL patients, and for other malignancies. Most prominent were the short-lived increases in the frequency and function of tumor-specific CTLs, particularly in patients with bulky disease. These observations suggested that optimal immune responses were being suppressed by the tumor microenvironment and by the tumor cells themselves, leading the investigators to propose (i) that LMP1- and LMP2-specific CTLs resistant to TGF-B, an immune inhibitory molecule produced by HD tumors, will have prolonged persistence and function in patients with relapsed disease, (ii) tumor antigen (TA)- specific CTLs expressing IL-12 will reverse the Th2 and negative immunoregulatory phenotype/function of tumor-infiltrating mononuclear cells, and (iii) TA-specific CTLs expressing IL-12 or constitutive T-bet, the master regulator of Tc1/Th1 functions and an inhibitor of GATA-3 , will have enhanced resistance to and efficacy against Th2 and Treg containing tumors. These predictions will be tested in three specific aims: to determine the safety and clinical efficacy of adoptively transferred LMP1- and LMP2-specific CTLs genetically modified to express a transdominant-negative TGF-beta type II receptor (DNR) in patients with EBV-positive HD or NHL (Aim 1);to evaluate the functional persistence of adoptively transferred DNR gene-modified EBV-CTLs in these patients (Aim 2);and to compare the safety and antitumor efficacy of TA-specific CTLs expressing IL-12 or T-bet in a model that mimics the regulatory environment of human HD. If the DNR, IL-12 or T-bet gene modifications of CTLs prove safe and enhance the survival and function of CTLs at tumor sites, this strategy could be introduced into the T-cell therapies evaluated in Projects 3 and 4. Lay summary - In many patients with Hodgkin disease and non-Hodgkin lymphoma, the cancer cells are infected with Epstein-Barr virus. The viral proteins in the lymphoma cells are attractive targets for immunotherapy. The investigators in this project are taking advantage of these viral targets by engineering a specific type of T cell to express proteins that should improve the ability of the modified cells to find and destroy EBV-positive tumors without producing toxic effects in the patient.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA094237-10
Application #
8378610
Study Section
Special Emphasis Panel (ZCA1-RPRB-J)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
10
Fiscal Year
2012
Total Cost
$271,113
Indirect Cost
$93,131
Name
Baylor College of Medicine
Department
Type
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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