Interleukin 13 receptor alpha 2 (IL13Rα2): Expression, signaling pathways and therapeutic applications in cancer

Jaén, Marta; Martín‐Regalado, Ángela; Bartolomé, Rubén A.; Robles, Javier; Casal, J. Ignacio

doi:10.1016/j.bbcan.2022.188802

Cited by 22 publications

(19 citation statements)

References 148 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…IL13Rα2 is expressed by the majority of HGG, and in GBM is associated with a mesenchymal genesignature and poor prognosis 14,15 . The potential of IL13Rα2 as a CAR T target is further strengthened by the absence of expression in the normal brain tissue.…”

Section: Introductionmentioning

confidence: 99%

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Brown,

Hibbard,

Alizadeh

et al. 2023

Preprint

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T cell therapy is at early stages of clinical testing for solid tumors. We report here a completed phase I trial (NCT02208362) evaluating locoregional delivery of IL13Rα2-targeted CAR T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM; 2 + recurrences). Primary endpoints were safety and feasibility, with secondary endpoints measuring therapy-related bioactivity. Weekly intratumoral (ICT) and/or intraventricular (ICV) administration of IL13Rα2-CAR T cells was well-tolerated with clinically manageable adverse events. Stable disease or better was achieved in 50% of patients, with two partial responses, one complete response (CR), and a second CR after additional CAR T cycles off-protocol therapy. Patients with rGBM treated with dual ICT/ICV delivery and an optimized manufacturing process exhibited superior overall median survival of 10.2 months, compared to 6.1 months for other treatment arms. Central nervous system (CNS) increases in inflammatory cytokines, including IFNγ, CXCL9, and CXCL10, were associated with CAR T cell administration and bioactivity. Further, pre-treatment intratumoral CD3 T cell levels were positively associated with survival, indicating an interplay between host immunity and CAR T cells as a determinant of outcomes. These findings advance our understanding of CAR T cell immunotherapy for malignant brain tumors.

show abstract

Section: Introductionmentioning

confidence: 99%

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Brown,

Hibbard,

Alizadeh

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

“…IL-13Rα2 is a cancer-testis antigen that is expressed by the majority of HGG, and in GBM is associated with a mesenchymal gene signature and poor prognosis 14 , 15 . The potential of IL-13Rα2 as a CAR-T target is further strengthened by the absence of expression in the normal brain tissue.…”

Section: Mainmentioning

confidence: 99%

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial

Brown,

Hibbard,

Alizadeh

et al. 2024

Nat Med

View full text Add to dashboard Cite

Chimeric antigen receptor T cell (CAR-T) therapy is an emerging strategy to improve treatment outcomes for recurrent high-grade glioma, a cancer that responds poorly to current therapies. Here we report a completed phase I trial evaluating IL-13Rα2-targeted CAR-T cells in 65 patients with recurrent high-grade glioma, the majority being recurrent glioblastoma (rGBM). Primary objectives were safety and feasibility, maximum tolerated dose/maximum feasible dose and a recommended phase 2 dose plan. Secondary objectives included overall survival, disease response, cytokine dynamics and tumor immune contexture biomarkers. This trial evolved to evaluate three routes of locoregional T cell administration (intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV) and two manufacturing platforms, culminating in arm 5, which utilized dual ICT/ICV delivery and an optimized manufacturing process. Locoregional CAR-T cell administration was feasible and well tolerated, and as there were no dose-limiting toxicities across all arms, a maximum tolerated dose was not determined. Probable treatment-related grade 3+ toxicities were one grade 3 encephalopathy and one grade 3 ataxia. A clinical maximum feasible dose of 200 × 106 CAR-T cells per infusion cycle was achieved for arm 5; however, other arms either did not test or achieve this dose due to manufacturing feasibility. A recommended phase 2 dose will be refined in future studies based on data from this trial. Stable disease or better was achieved in 50% (29/58) of patients, with two partial responses, one complete response and a second complete response after additional CAR-T cycles off protocol. For rGBM, median overall survival for all patients was 7.7 months and for arm 5 was 10.2 months. Central nervous system increases in inflammatory cytokines, including IFNγ, CXCL9 and CXCL10, were associated with CAR-T cell administration and bioactivity. Pretreatment intratumoral CD3 T cell levels were positively associated with survival. These findings demonstrate that locoregional IL-13Rα2-targeted CAR-T therapy is safe with promising clinical activity in a subset of patients. ClinicalTrials.gov Identifier: NCT02208362.

show abstract

“…Also, IL-13 through the IL-13Rα2 receptor induces increased TGF-β expression, but collagen and TGF-β1 are reduced through IL-13Rα2 silencing [ 33 ]. Overexpression of IL-13Rα2 has been described in oncological pathologies like glioblastoma, adrenocortical carcinoma, head and neck cancer, melanoma, ovarian cancer, and pancreatic cancer [ 34 ], where anti-inflammatory and immunosuppressor environments are necessary for tumor survival; the M2-Th2 microenvironment in oncological pathologies is similar to that observed in helminth infections. Our data support the hypothesis that, in the absence of IL-4Rα type II and type II signaling, IL-13Rα2 could probably even play a major role in inducing compensatory mechanisms involved in the susceptibility and resistance to T. crassiceps infection.…”

Section: Discussionmentioning

confidence: 99%

A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis

Olguín,

Corano-Arredondo,

Hernández-Gómez

et al. 2024

Pathogens

View full text Add to dashboard Cite

To determine the role that the IL-4/IL13 receptor plays in the development of alternatively activated macrophages (AAM or M2) and their role in the regulation of immunity to the extraintestinal phase of the helminth parasite Taenia crassiceps, we followed the infection in a mouse strain lacking the IL-4Rα gene (IL-4Rα−/−) and in the macrophage/neutrophil-specific IL-4Rα-deficient mouse strain (LysMcreIL-4Rα-/lox or cre/LoxP). While 100% of T. crassiceps-infected IL-4Rα+/+ (WT) mice harbored large parasite loads, more than 50% of th eIL-4Rα−/− mice resolved the infection. Approximately 88% of the LysMcreIL-4Rα-/lox mice displayed a sterilizing immunity to the infection. The remaining few infected cre/LoxP mice displayed the lowest number of larvae in their peritoneal cavity. The inability of the WT mice to control the infection was associated with antigen-specific Th2-type responses with higher levels of IgG1, IL-4, IL-13, and total IgE, reduced NO production, and increased arginase activity. In contrast, IL-4Rα−/− semi-resistant mice showed a Th1/Th2 combined response. Furthermore, macrophages from the WT mice displayed higher transcripts for Arginase-1 and RELM-α, as well as increased expression of PD-L2 with robust suppressive activity over anti-CD3/CD28 stimulated T cells; all of these features are associated with the AAM or M2 macrophage phenotype. In contrast, both the IL-4Rα−/− and LysMcreIL-4Rα-/lox mice did not fully develop AAM or display suppressive activity over CD3/CD28 stimulated T cells, reducing PDL2 expression. Additionally, T-CD8+ but no T-CD4+ cells showed a suppressive phenotype with increased Tim-3 and PD1 expression in WT and IL-4Rα−/−, which were absent in T. crassiceps-infected LysMcreIL-4Rα-/lox mice. These findings demonstrate a critical role for the IL-4 signaling pathway in sustaining AAM and its suppressive activity during cysticercosis, suggesting a pivotal role for AAM in favoring susceptibility to T. crassiceps infection. Thus, the absence of these suppressor cells is one of the leading mechanisms to control experimental cysticercosis successfully.

show abstract

Interleukin 13 receptor alpha 2 (IL13Rα2): Expression, signaling pathways and therapeutic applications in cancer

Cited by 22 publications

References 148 publications

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Phase I Trial Evaluating Locoregionally-delivered IL13Rα2-targeting CAR T Cells in High-Grade Glioma

Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial

A Myeloid-Specific Lack of IL-4Rα Prevents the Development of Alternatively Activated Macrophages and Enhances Immunity to Experimental Cysticercosis

Contact Info

Product

Resources

About