RESUMO
High-grade gliomas are aggressive cancers that often become rapidly fatal. Immunotherapy using CD8+ cytotoxic T lymphocytes (CTLs), engineered to express both herpes simplex virus type 1 thymidine kinase (HSV1-TK) and interleukin-13 (IL-13) zetakine chimeric antigen receptor (CAR), is a treatment strategy with considerable potential. To optimize this and related immunotherapies, it would be helpful to monitor CTL viability and trafficking to glioma cells. We show that noninvasive positron emission tomography (PET) imaging with 9-[4-[18F]fluoro-3-(hydroxymethyl)butyl]guanine ([18F]FHBG) can track HSV1-tk reporter gene expression present in CAR-engineered CTLs. [18F]FHBG imaging was safe and enabled the longitudinal imaging of T cells stably transfected with a PET reporter gene in patients. Further optimization of this imaging approach for monitoring in vivo cell trafficking should greatly benefit various cell-based therapies for cancer.
Assuntos
Neoplasias Encefálicas/diagnóstico por imagem , Genes Reporter , Glioma/diagnóstico por imagem , Imunoterapia/métodos , Receptores de Antígenos de Linfócitos T/metabolismo , Linfócitos T Citotóxicos/citologia , Idoso , Neoplasias Encefálicas/terapia , Feminino , Expressão Gênica , Terapia Genética/métodos , Glioma/terapia , Humanos , Interleucina-13/metabolismo , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Tomografia por Emissão de Pósitrons , Estudos Prospectivos , Timidina Quinase/metabolismoRESUMO
A patient with recurrent multifocal glioblastoma received chimeric antigen receptor (CAR)-engineered T cells targeting the tumor-associated antigen interleukin-13 receptor alpha 2 (IL13Rα2). Multiple infusions of CAR T cells were administered over 220 days through two intracranial delivery routes - infusions into the resected tumor cavity followed by infusions into the ventricular system. Intracranial infusions of IL13Rα2-targeted CAR T cells were not associated with any toxic effects of grade 3 or higher. After CAR T-cell treatment, regression of all intracranial and spinal tumors was observed, along with corresponding increases in levels of cytokines and immune cells in the cerebrospinal fluid. This clinical response continued for 7.5 months after the initiation of CAR T-cell therapy. (Funded by Gateway for Cancer Research and others; ClinicalTrials.gov number, NCT02208362 .).