The successful application of adoptive cell transfer (ACT) using chimeric antigen receptor (CAR)-transduced T- cells (CAR-T-cells) in solid tumors, such as GBM, will require improved tumor-homing ability by the T-cells. Recent studies of autoimmune conditions in the central nervous system (CNS) show that interleukin-17 (IL-17)- producing Type17 T-cells, which are reactive to CNS autoantigens, have a higher migratory capability to the CNS parenchyma than other T-cell subpopulations due to their ability to penetrate the blood brain barrier (BBB) via expression of IL-17/IL-22. Moreover, a chemokine receptor, CCR6, on Type17 T-cells allows them to infiltrate the CNS by interacting with its ligand, CCL20. Although the induction of CNS autoimmunity should be avoided, these data led us to hypothesize that Type17 T-cells engineered to direct glioblastoma (GBM) antigens will safely demonstrate superior anti-glioma activity compared with Type1 T-cells. To evaluate our hypothesis in preclinical studies, we will employ both a syngeneic mouse glioma model (Aim 1) and a human xenograft model and ACT with human GBM patient-derived CAR-T-cells (Aim 2).
Aim 1. Mouse Type17 T-cells will demonstrate superior in vivo persistence, tumor-homing, and anti- tumor effects without CNS autoimmunity in syngeneic glioma models compared with Type1 T-cells. In our preliminary data, Type17 T-cells showed a more sustained anti-tumor immune response in vitro than did Type1 counterparts. Furthermore, our Type17 T-cells express both CXCR3 and CCR6 and induce glioma cells to produce their cognate ligands, CXCL10 and CCL20, respectively. Based on these data, we hypothesize that Type17 T-cells will demonstrate superior therapeutic efficacy against intra-cerebral gliomas compared with Type1 cells due to their greater in vivo persistence and their ability to traffic to CNS tumors. Using a C57BL/6 mouse syngeneic model, we will determine whether the CXCL10-CXCR3 and CCL20-CCR6 chemokine axes promote Type17 cell infiltration of CNS gliomas. We will also ensure the absence of CNS autoimmunity.
Aim 2. Human GBM patient-derived Type17 T-cells transduced with CAR will safely mediate anti-tumor effects against human GBM xenograft in vivo. We will evaluate whether we can propagate Type17 CAR-T cells using GBM patient-derived T-cells, and whether the critical phenotype (e.g., chemokine receptor expression) observed in the syngeneic model in Aim 1 can be recapitulated in human GBM patient-derived Type17 T-cells that are transduced with the CAR. Finally, using immunocompromised NOD/scid/?c(-/-) (NSG) mice bearing human GBM patient-derived xenografts in the brain, we will determine whether intravenous (i.v.) administration of human Type17 CAR-T-cells, especially both EGFRvIII- and EphA2-CARs compared with the single antigen-targeting approach, achieves effective and long-lasting therapeutic response against the human GBM xenografts without causing significant CNS toxicity.

Public Health Relevance

We have created lentiviral Chimeric Antigen Receptor (CAR) vectors that target glioblastoma (GBM) antigens, such as epidermal growth factor receptor variant III and EphA2. We will evaluate our hypothesis that Type17 T-cells engineered to direct GBM antigens by CAR gene-transduction will demonstrate superior ability to migrate to CNS glioma sites and have greater anti-GBM activity compared with other T-cell types. If successful, our studies will lay the foundation for developing clinical trials of adoptive cell transfer therap with Type17 T-cells, which has not been reported before in patients with GBM.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21NS083171-01A1
Application #
8641010
Study Section
National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
Program Officer
Fountain, Jane W
Project Start
2014-09-15
Project End
2016-08-31
Budget Start
2014-09-15
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$395,208
Indirect Cost
$145,208
Name
University of California San Francisco
Department
Neurosurgery
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143