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Updated: May 18, 2026
Stereotactic Adoptive Transfer of Cytotoxic Immune Cells in Murine Models of Orthotopic Human Glioblastoma Multiforme Xenografts
Published on: September 1, 2018
Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T
Seogkyoung Kong1, Sadhak Sengupta, Betty Tyler
1Brain Tumor Lab, Department of Neurosurgery, Biotherapeutics Development Lab, Boston University School of Medicine, Roger Williams Medical Center, Providence, Rhode Island02908, USA.
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.
Insights
Chimeric antigen receptor (CAR) designer T cells (dTcs) targeting IL13Rα2 show promise for treating glioblastoma multiforme (GBM). These engineered T cells effectively kill GBM cells and improve survival in preclinical models.
Area of Science:
- Immunotherapy
- Oncology
- Cellular Biology
Background:
- Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with poor prognosis.
- Recurrence is common after standard treatments like surgery, radiation, and chemotherapy.
- Novel therapeutic strategies are urgently needed to improve GBM treatment outcomes.
Purpose of the Study:
- To develop and evaluate a chimeric antigen receptor (CAR) "designer T cell" (dTc) immunotherapy targeting IL13 receptor α-2 (IL13Rα2) for glioblastoma multiforme (GBM).
- To engineer a mutated IL13-based CAR (IL13.E13K.R109K) for enhanced selectivity towards IL13Rα2-expressing GBM cells while minimizing off-target effects on normal tissues.
Main Methods:
- Constructed a second-generation IL13 "zetakine" CAR incorporating mutated IL13 and CD28/CD3ζ signaling domains.
- Tested the engineered CAR's specificity and efficacy against IL13Rα2(+) GBM cells and IL13Rα1(+) normal cells in vitro.
- Evaluated the therapeutic potential of IL13 dTcs in a human glioma xenograft model using intracranial injections.
Main Results:
- The IL13.E13K.R109K CAR demonstrated improved recognition of GBM targets and reduced, though persistent, activity against normal IL13Rα1(+) cells.
- Engineered IL13 dTcs efficiently killed IL13Rα2(+) glioma cells, secreting IL2 and IFNγ, and showed enhanced tumor-specific expansion in vitro.
- Single intracranial injections of IL13 dTcs significantly increased survival rates in a human glioma xenograft model.
Conclusions:
- IL13 dTcs represent a potential immunotherapy for GBM, capable of targeting diffusely invasive cells.
- dTc infusion into resection cavities or direct stereotactic injection may prevent recurrence or treat inoperable/recurrent GBM.
- Systemic administration requires careful consideration due to potential reactions against normal tissues expressing IL13Rα1.
