Inclusion of 4-1BB Costimulation Enhances Selectivity and Functionality of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells

Overview

Journal Cancer Res Commun

Specialty Oncology

Date 2023 Mar 27

PMID 36968221

Authors

Renate Starr

Brenda Aguilar

Diana Gumber

Madeleine Maker

Stephanie Huard

Dongrui Wang

Wen-Chung Chang

Alfonso Brito

Vivian Chiu

Julie R Ostberg

Benham Badie

Stephen J Forman

Darya Alizadeh

Leo D Wang

Christine E Brown

Affiliations

Soon will be listed here.

Abstract

Significance: This study reveals how modulating CAR design outside the antigen targeting domain improves selective tumor recognition. Specifically, this work shows improved specificity, persistence, and efficacy of 4-1BB-based IL13-ligand CARs. Human clinical trials evaluating IL13-41BB-CAR T cells are ongoing, supporting the clinical significance of these findings.

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References

Kahlon K, Brown C, Cooper L, Raubitschek A, Forman S, Jensen M . Specific recognition and killing of glioblastoma multiforme by interleukin 13-zetakine redirected cytolytic T cells. Cancer Res. 2004; 64(24):9160-6. DOI: 10.1158/0008-5472.CAN-04-0454. View

Brown C, Alizadeh D, Starr R, Weng L, Wagner J, Naranjo A . Regression of Glioblastoma after Chimeric Antigen Receptor T-Cell Therapy. N Engl J Med. 2016; 375(26):2561-9. PMC: 5390684. DOI: 10.1056/NEJMoa1610497. View

Debinski W, Gibo D, Slagle B, Powers S, Gillespie G . Receptor for interleukin 13 is abundantly and specifically over-expressed in patients with glioblastoma multiforme. Int J Oncol. 1999; 15(3):481-6. DOI: 10.3892/ijo.15.3.481. View

Kong S, Sengupta S, Tyler B, Bais A, Ma Q, Doucette S . Suppression of human glioma xenografts with second-generation IL13R-specific chimeric antigen receptor-modified T cells. Clin Cancer Res. 2012; 18(21):5949-60. PMC: 4337849. DOI: 10.1158/1078-0432.CCR-12-0319. View

Philipson B, OConnor R, May M, June C, Albelda S, Milone M . 4-1BB costimulation promotes CAR T cell survival through noncanonical NF-κB signaling. Sci Signal. 2020; 13(625). PMC: 7883633. DOI: 10.1126/scisignal.aay8248. View

Reilly K, Loisel D, Bronson R, McLaughlin M, Jacks T . Nf1;Trp53 mutant mice develop glioblastoma with evidence of strain-specific effects. Nat Genet. 2000; 26(1):109-13. DOI: 10.1038/79075. View

Lai E, Joshi B, Martiniova L, Dogra R, Fujisawa T, Leland P . Overexpression of interleukin-13 receptor-alpha2 in neuroendocrine malignant pheochromocytoma: a novel target for receptor directed anti-cancer therapy. J Clin Endocrinol Metab. 2009; 94(8):2952-7. PMC: 2730867. DOI: 10.1210/jc.2009-0309. View

Brown C, Badie B, Barish M, Weng L, Ostberg J, Chang W . Bioactivity and Safety of IL13Rα2-Redirected Chimeric Antigen Receptor CD8+ T Cells in Patients with Recurrent Glioblastoma. Clin Cancer Res. 2015; 21(18):4062-72. PMC: 4632968. DOI: 10.1158/1078-0432.CCR-15-0428. View

Majzner R, Rietberg S, Sotillo E, Dong R, Vachharajani V, Labanieh L . Tuning the Antigen Density Requirement for CAR T-cell Activity. Cancer Discov. 2020; 10(5):702-723. PMC: 7939454. DOI: 10.1158/2159-8290.CD-19-0945. View

10.

Dudley M, Yang J, Sherry R, Hughes M, Royal R, Kammula U . Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens. J Clin Oncol. 2008; 26(32):5233-9. PMC: 2652090. DOI: 10.1200/JCO.2008.16.5449. View

11.

Krebs S, Chow K, Yi Z, Rodriguez-Cruz T, Hegde M, Gerken C . T cells redirected to interleukin-13Rα2 with interleukin-13 mutein--chimeric antigen receptors have anti-glioma activity but also recognize interleukin-13Rα1. Cytotherapy. 2014; 16(8):1121-31. PMC: 4087074. DOI: 10.1016/j.jcyt.2014.02.012. View

12.

Brown C, Starr R, Aguilar B, Shami A, Martinez C, DApuzzo M . Stem-like tumor-initiating cells isolated from IL13Rα2 expressing gliomas are targeted and killed by IL13-zetakine-redirected T Cells. Clin Cancer Res. 2012; 18(8):2199-209. PMC: 3578382. DOI: 10.1158/1078-0432.CCR-11-1669. View

13.

Alizadeh D, Wong R, Gholamin S, Maker M, Aftabizadeh M, Yang X . IFNγ Is Critical for CAR T Cell-Mediated Myeloid Activation and Induction of Endogenous Immunity. Cancer Discov. 2021; 11(9):2248-2265. PMC: 8561746. DOI: 10.1158/2159-8290.CD-20-1661. View

14.

Maude S, Laetsch T, Buechner J, Rives S, Boyer M, Bittencourt H . Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018; 378(5):439-448. PMC: 5996391. DOI: 10.1056/NEJMoa1709866. View

15.

Wang D, Aguilar B, Starr R, Alizadeh D, Brito A, Sarkissian A . Glioblastoma-targeted CD4+ CAR T cells mediate superior antitumor activity. JCI Insight. 2018; 3(10). PMC: 6012522. DOI: 10.1172/jci.insight.99048. View

16.

Suryadevara C, Desai R, Abel M, Riccione K, Batich K, Shen S . Temozolomide lymphodepletion enhances CAR abundance and correlates with antitumor efficacy against established glioblastoma. Oncoimmunology. 2018; 7(6):e1434464. PMC: 5980382. DOI: 10.1080/2162402X.2018.1434464. View

17.

Brentjens R, Riviere I, Park J, Davila M, Wang X, Stefanski J . Safety and persistence of adoptively transferred autologous CD19-targeted T cells in patients with relapsed or chemotherapy refractory B-cell leukemias. Blood. 2011; 118(18):4817-28. PMC: 3208293. DOI: 10.1182/blood-2011-04-348540. View

18.

Brown C, Aguilar B, Starr R, Yang X, Chang W, Weng L . Optimization of IL13Rα2-Targeted Chimeric Antigen Receptor T Cells for Improved Anti-tumor Efficacy against Glioblastoma. Mol Ther. 2017; 26(1):31-44. PMC: 5763077. DOI: 10.1016/j.ymthe.2017.10.002. View

19.

Wang D, Starr R, Alizadeh D, Yang X, Forman S, Brown C . In Vitro Tumor Cell Rechallenge For Predictive Evaluation of Chimeric Antigen Receptor T Cell Antitumor Function. J Vis Exp. 2019; (144). PMC: 6719706. DOI: 10.3791/59275. View

20.

Priceman S, Gerdts E, Tilakawardane D, Kennewick K, Murad J, Park A . Co-stimulatory signaling determines tumor antigen sensitivity and persistence of CAR T cells targeting PSCA+ metastatic prostate cancer. Oncoimmunology. 2018; 7(2):e1380764. PMC: 5749625. DOI: 10.1080/2162402X.2017.1380764. View