In the past year, this project has consisted of testing multiple factors that could affect the function of chimeric antigen receptors (CARs). First we compared lentiviral vector to the gammaretroviral vector that we have used in our current clinical trials. T cells transduced with the lentiviral vector had shorter duration of CAR expression;therefore, we have decided to perform future work with the gammaretroviral vector. Chimeric antigen receptors consis to several components, the antigen-recognition moiety that is usually derived from a monoclonal antibody, a hinge region that connects the antigen-recognition moiety to the transmembrane portion, costimulatory domains such as 4-1BB and CD28, and T cell activation domains such as CD3-zeta. We have constructed 10 new CARs over the past 6 months to test various components of CARs. T cells are transduced with the various CARs by using a gammaretroviral vector, and in vitro assays are carried out.
The aim i s to find CARs that impart T cells with the ability to kill cancer cells and proliferate without producing large amounts of potentially toxic inflamatory cytokines. We have found that changing the hinge region, costimulatory domains, or T cell activation domains all cause profound differences in CAR function. Following extensive in vitro testing, we will test promising CARs in a murine model within the next year. This work is all at early stages, but hopefully it will lead to improved CARs for clinical testing within the next 2-3 years.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011417-02
Application #
8553170
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2012
Total Cost
$150,681
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Magalhaes, Isabelle; Kalland, Ingrid; Kochenderfer, James N et al. (2018) CD19 Chimeric Antigen Receptor T Cells From Patients With Chronic Lymphocytic Leukemia Display an Elevated IFN-? Production Profile. J Immunother 41:73-83
Brudno, Jennifer N; Kochenderfer, James N (2018) Chimeric antigen receptor T-cell therapies for lymphoma. Nat Rev Clin Oncol 15:31-46
Ariza-Heredia, Ella J; Granwehr, Bruno P; Viola, George M et al. (2017) False-positive HIV nucleic acid amplification testing during CAR T-cell therapy. Diagn Microbiol Infect Dis 88:305-307
Kochenderfer, James N; Somerville, Robert P T; Lu, Tangying et al. (2017) Lymphoma Remissions Caused by Anti-CD19 Chimeric Antigen Receptor T Cells Are Associated With High Serum Interleukin-15 Levels. J Clin Oncol 35:1803-1813
Alabanza, Leah; Pegues, Melissa; Geldres, Claudia et al. (2017) Function of Novel Anti-CD19 Chimeric Antigen Receptors with Human Variable Regions Is Affected by Hinge and Transmembrane Domains. Mol Ther 25:2452-2465
Brudno, Jennifer N; Kochenderfer, James N (2016) Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127:3321-30
Elumogo, Comfort O; Kochenderfer, James N; Civelek, A Cahid et al. (2016) Pigmented villonodular synovitis mimics metastases on fluorine 18 fluorodeoxyglucose position emission tomography-computed tomography. Quant Imaging Med Surg 6:218-23