Adoptive immunotherapy, which capitalizes on generating a potent immune response using genetically re- engineered T cells, represents a novel and powerful therapeutic approach to treat cancer and other diseases. Specifically, patient's T cells are modified to express a chimeric antigen receptor (CAR), which consists of a tumor antigen recognition domain fused to an activation sequence that triggers T cell cytotoxic and proliferative functions when tumor antigen is engaged. The tumor antigen recognition domain of the CAR is commonly a single chain variable fragment (scFv) excised from a monoclonal antibody (mAb) previously selected to recognize a tumor antigen epitope. Herein, we propose to replace the scFv domain with either a fragment antigen-binding domain (Fab) or a mAb that are engineered to bind a cyclic peptide called meditope. Incorporation of this meditope-binding site within the Fab/mAb uniquely marks the modified T cells and permits a highly specific, high affinity interaction with a meditope, an optimized, serum stable peptide that can be conjugated to small molecules including DOTA, biologics including scFvs, chemokines, etc., or nanoparticles. As such, the incorporation of the meditope interface offers the unique and timely opportunity to rapidly and independently add new functionality to CAR T cell therapy. The immediate goal of this application is to demonstrate that a meditope-enabled Fab or mAb can effectively replace the scFv within the CAR and can be used to image meditope-enabled CAR T cells in vivo. Successful demonstration of this novel interaction will set the stage to track meditope-enabled CAR T cells in patients, to correlate T cell distributions with clinical outcomes, and to add new functionality to improve this emerging and broadly applicable therapy.

Public Health Relevance

The objective of this application is to exploit our recent discovery and development of a unique, high affinity binding site within a monoclonal antibody (mAb) as a means to add novel functionality to chimeric antigen receptor (CAR) T cell therapies. Specifically, we will generate, characterize, and demonstrate that we can effectively replace an anti-Her2 scFv with an anti-Her2 meditope-enabled Fab or meditope-enabled mAb and to use this site for imaging CAR T cells in vivo. Successful demonstration of this technology will open up new avenues to improve adoptive immunotherapy, a highly promising and emerging treatment applicable to multiple forms of cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA193055-02
Application #
9070714
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Ossandon, Miguel
Project Start
2015-06-01
Project End
2018-05-31
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Beckman Research Institute/City of Hope
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
King, Jeremy; Bouvet, Michael; Singh, Gagandeep et al. (2017) Improving theranostics in pancreatic cancer. J Surg Oncol 116:104-113
Mirzaei, Hamid R; Rodriguez, Analiz; Shepphird, Jennifer et al. (2017) Chimeric Antigen Receptors T Cell Therapy in Solid Tumor: Challenges and Clinical Applications. Front Immunol 8:1850