Suppression of Human Glioma Xenografts with Second-Generation IL13R-Specific Chimeric Antigen Receptor–Modified T Cells
| Autor: | Anthony Bais, Sadhak Sengupta, Jinyuan Zhou, Richard P. Junghans, Henry Brem, Qiangzhong Ma, Saryn Doucette, Betty Tyler, Bob S. Carter, Seogkyoung Kong, Ayguen Sahin, Prakash Sampath |
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| Rok vydání: | 2012 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty T-Lymphocytes medicine.medical_treatment T cell Receptors Antigen T-Cell Biology Immunotherapy Adoptive CD28 Antigens Antigen Cell Line Tumor Gene Order medicine Animals Humans Interleukin-13 CD28 Immunotherapy Xenograft Model Antitumor Assays Chimeric antigen receptor Disease Models Animal medicine.anatomical_structure Oncology Mutation Interleukin 13 Interleukin-13 Receptor alpha2 Subunit Cancer research Stereotactic injection Systemic administration Protein Multimerization Glioblastoma Signal Transduction |
| Zdroj: | Clinical Cancer Research. 18:5949-5960 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-12-0319 |
| Popis: | Purpose: Glioblastoma multiforme (GBM) remains highly incurable, with frequent recurrences after standard therapies of maximal surgical resection, radiation, and chemotherapy. To address the need for new treatments, we have undertaken a chimeric antigen receptor (CAR) “designer T cell” (dTc) immunotherapeutic strategy by exploiting interleukin (IL)13 receptor α-2 (IL13Rα2) as a GBM-selective target. Experimental Design: We tested a second-generation IL13 “zetakine” CAR composed of a mutated IL13 extracellular domain linked to intracellular signaling elements of the CD28 costimulatory molecule and CD3ζ. The aim of the mutation (IL13.E13K.R109K) was to enhance selectivity of the CAR for recognition and killing of IL13Rα2+ GBMs while sparing normal cells bearing the composite IL13Rα1/IL4Rα receptor. Results: Our aim was partially realized with improved recognition of tumor and reduced but persisting activity against normal tissue IL13Rα1+ cells by the IL13.E13K.R109K CAR. We show that these IL13 dTcs were efficient in killing IL13Rα2+ glioma cell targets with abundant secretion of cytokines IL2 and IFNγ, and they displayed enhanced tumor-induced expansion versus control unmodified T cells in vitro. In an in vivo test with a human glioma xenograft model, single intracranial injections of IL13 dTc into tumor sites resulted in marked increases in animal survivals. Conclusions: These data raise the possibility of immune targeting of diffusely invasive GBM cells either via dTc infusion into resection cavities to prevent GBM recurrence or via direct stereotactic injection of dTcs to suppress inoperable or recurrent tumors. Systemic administration of these IL13 dTc could be complicated by reaction against normal tissues expressing IL13Ra1. Clin Cancer Res; 18(21); 5949–60. ©2012 AACR. |
| Databáze: | OpenAIRE |
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