Harnessing T-cells to treat cancer more effectively remains a leading biomedical research goal, yet this pursuit is often thwarted by multiple obstacles, including poor antigen presentation and negative immunoregulatory mechanisms within the tumor and its microenvironment. This program project grant (PPG) renewal builds on successes during the past funding period to address several persistent problems that impede the use of T cells as Immunotherapy for poor-prognosis solid tumors: (I) abbreviated expansion and persistence of activated T cells, (ii) negative impact of the tumor microenvironment, and (iii) lack of an adequate molecular safety switch to destroy aberrantly proliferating T cells. Thus, investigators with exemplary records of interactive research have designed first-in-man studies that would each address one or more of these issues. Project 1 tests the use of VZV vaccination to boost the expansion and antitumor activity of VZV-specific cytotoxic T lymphocytes (CTLs) engrafted with a GD2-directed chimeric antigen receptor (CAR) in patients with relapsed/refractory sarcomas. Project 2 seeks to develop effective targeted T-cell therapy for pancreatic cancer by using T cells that are specific for the tumor antigen mesothelin and express a hovel chimeric cytokine receptor (1L4/7), which is expected to promote T-cell expansion and persistence when engaged by inhibitory IL4 signal from the tumor. Project 3 will take advantage of recent successes with the use of CAR.GD2+ T cells in treatment of advanced neuroblastoma to produce a new generation of modified T cells. The investigators will engineer two costimulatory endodomains, CD28 and OX40, as well as an inducible suicide gene {iC9), into the CAR construct and analyze the consequent effects on T-cell proliferation and tumor killing in patients with relapsed/refractory neuroblastoma. Project 4 asks whether targeting multiple antigens on nasopharyngeal cancer cells and expressing a dominant-negative TGF-beta receptor will broaden the specificity and enhance the durability of EBV-specific CTLs directed to this tumor. Besides initial clinical testing of promising therapeutic strategies, these projects will also assess newly emerging concepts in a range of model systems, in preparation for subsequent phase I testing. A major strength of this proposal resides in the GMP Core, where improvements in the T-cell manufacturing process will enable all planned studies to be completed in a timelier and less costly manner. This series of iterative laboratory and linked clinical studies is expected to yield strategies with the potential to increase cure rates and reduce treatment-related toxicity in patients with a spectrum of resistant solid tumors.

Public Health Relevance

Treatment with tumor-specific T cells has clear advantages over other contemporary forms of immunotherapy, but further progress appears uncertain without innovative strategies to overcome existing negative influences on T-cell expansion and killing of tumor targets. This PPG renewal combines recent advances in T-cell-based therapies with promising new experimental approaches to meet this challenge.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA094237-15
Application #
9201305
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Program Officer
Song, Min-Kyung H
Project Start
2001-12-01
Project End
2018-01-31
Budget Start
2017-02-01
Budget End
2018-01-31
Support Year
15
Fiscal Year
2017
Total Cost
$1,739,056
Indirect Cost
$626,076
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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 :
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
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