These results indicate that IL-13/IL-13Rα2 axis can mediate signal transduction in situ via AP-1 pathway in GBM and astrocytoma and may serve as a new target for GBM immunotherapy.
Here, we investigated the differential antitumor effect of CD4+ and CD8+ CAR T cells targeting glioblastoma-associated (GBM-associated) antigen IL-13 receptor α2 (IL13Rα2).
No association between IL-4/IL-13 pathway genetic polymorphisms and glioma risk was observed in the overall population, although a significant association was found between rs2234248 and glioblastoma when stratified by histological subtype (log-additive model, OR 1.57, 95 % CI 1.11-2.24).
In the genetic model analysis, the genotype "TC" of rs20541 in IL-13 gene showed an increased risk of GBM in over-dominant model (OR = 2.00; 95% CI, 1.13-3.54, p = 0.015); the genotype "CT" of rs1800871 in the IL-10 gene showed a decrease risk in the over-dominant model (OR = 0.57; 95% CI, 0.33 - 0.97; p = 0.037).
Targeted toxins approaches against glioblastoma were under investigation in phase I and II clinical trials with several immunotoxins (IT)/ligand toxins such as IL4-Pseudomonas aeruginosa exotoxin A (IL4-PE, NBI-3001), tumour growth factor fused to PE38, a shorter PE variant, (TGF)alpha-TP-38, IL13-PE38, and a transferrin-C diphtheriae toxin mutant (Tf-CRM107).
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.
We developed a regulatable adenoviral vector (Ad.mhIL-4.TRE.mhIL-13-PE) encoding a mutated human IL-13 fused to Pseudomonas exotoxin (mhIL-13-PE) that specifically binds to IL13Rα2 to provide sustained expression, effective anti-GBM cytotoxicity, and minimal neurotoxicity.
A bispecific ligand-directed toxin (BLT) consisting of human interleukin-13, epithelial growth factor, and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma.
Recent studies show that interleukin-13 receptor [alpha]2 chain (IL-13Ra2), a brain tumor-associated receptor for IL-13, may play a role in immunotherapy for glioblastoma.
The IL-13 receptor remains an important potential target in GBM, and preliminary experience with the IL-13-PE38QQR cytotoxin (also called cintredekin besudotox) has helped to pave the way for study of CED as an important means of drug delivery to malignant gliomas.
Based on this finding, a recombinant cytotoxin composed of IL13 ligand and a truncated form of Pseudomonas aeruginosa exotoxin A (IL13-PE38QQR) was developed for the targeted treatment of glioblastoma multiforme tumors.
The lack of support for a link between four IL-4Ralpha and IL-13 SNPs and glioblastoma may reflect the absence of associations or may result from uncontrolled confounding by haplotypes related both to those that we examined and glioblastoma.
A fusion protein consisting of human interleukin-13 and the first 389 amino acids of diphtheria toxin was assembled in order to target human glioblastoma cell lines in a murine intracranial model.
These results indicate that IL-4/IL-13 receptor-mediated Stat3 signaling may contribute to the pathogenesis of GBM cells by modulating the expression of the Bcl-2 family of antiapoptotic proteins.
These results indicate that IL-13R alpha2 chain in GBM cells is essential for IL-13 cytotoxin-induced cytotoxicity and that IL-13R alpha2 chain plays a critical biologic role in IL-13 cytotoxin-mediated therapy for GBM.
To identify target genes of cell death and other cellular genes with IL-13 receptors in glioblastoma cells, we utilized the cDNA microarrays to analyze global gene expression profiles after IL-13 cytotoxin and IL-13 treatment.
Diphtheria toxin-epidermal growth factor fusion protein and Pseudomonas exotoxin-interleukin 13 fusion protein exert synergistic toxicity against human glioblastoma multiforme cells.
A bispecific immunotoxin (IT) called DTAT13 was synthesized in order to target simultaneously the urokinase-type plasminogen activator receptor (uPAR)-expressing tumor neovasculature and IL-13 receptor expressing glioblastoma cells with the goal of intratumoral administration for brain tumors.
Pilot clinical trials have been initiated to evaluate the feasibility and safety of local-regional delivery of autologous IL13-zetakine redirected CTL clones in patients with recurrent GBM.