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 #
5P01CA094237-12
Application #
8613463
Study Section
Special Emphasis Panel (ZCA1-RPRB-B (O1))
Program Officer
Merritt, William D
Project Start
2001-12-01
Project End
2018-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
12
Fiscal Year
2014
Total Cost
$1,739,059
Indirect Cost
$626,079
Name
Baylor College of Medicine
Department
Pediatrics
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
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Heczey, Andras; Louis, Chrystal U; Savoldo, Barbara et al. (2017) CAR T Cells Administered in Combination with Lymphodepletion and PD-1 Inhibition to Patients with Neuroblastoma. Mol Ther 25:2214-2224
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Shum, Thomas; Omer, Bilal; Tashiro, Haruko et al. (2017) Constitutive Signaling from an Engineered IL7 Receptor Promotes Durable Tumor Elimination by Tumor-Redirected T Cells. Cancer Discov 7:1238-1247
Tashiro, Haruko; Sauer, Tim; Shum, Thomas et al. (2017) Treatment of Acute Myeloid Leukemia with T Cells Expressing Chimeric Antigen Receptors Directed to C-type Lectin-like Molecule 1. Mol Ther 25:2202-2213
Gomes-Silva, Diogo; Mukherjee, Malini; Srinivasan, Madhuwanti et al. (2017) Tonic 4-1BB Costimulation in Chimeric Antigen Receptors Impedes T Cell Survival and Is Vector-Dependent. Cell Rep 21:17-26
Szoor, Arpad; Vaidya, Abishek; Velasquez, Mireya Paulina et al. (2017) T Cell-Activating Mesenchymal Stem Cells as a Biotherapeutic for HCC. Mol Ther Oncolytics 6:69-79
Yagyu, Shigeki; Hoyos, Valentina; Del Bufalo, Francesca et al. (2016) Multiple mechanisms determine the sensitivity of human-induced pluripotent stem cells to the inducible caspase-9 safety switch. Mol Ther Methods Clin Dev 3:16003

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