دورية أكاديمية
Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models.
العنوان: | Inducible expression of interleukin-12 augments the efficacy of affinity-tuned chimeric antigen receptors in murine solid tumor models. |
---|---|
المؤلفون: | Yang Y; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Yang H; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Alcaina Y; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Puc J; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Birt A; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Vedvyas Y; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Gallagher M; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Alla S; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Riascos MC; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA.; Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA., McCloskey JE; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Du K; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Gonzalez-Valdivieso J; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA., Min IM; Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA., de Stanchina E; Antitumor Assessment Core Facility, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA., Britz M; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., von Hofe E; AffyImmune Therapeutics, Inc., Natick, MA, 01760, USA., Jin MM; Molecular Imaging Innovations Institute, Department of Radiology, Weill Cornell Medicine, New York, NY, 10065, USA. moj2005@med.cornell.edu.; Department of Surgery, Weill Cornell Medicine, New York, NY, 10065, USA. moj2005@med.cornell.edu. |
المصدر: | Nature communications [Nat Commun] 2023 Apr 12; Vol. 14 (1), pp. 2068. Date of Electronic Publication: 2023 Apr 12. |
نوع المنشور: | Journal Article; Research Support, Non-U.S. Gov't; Research Support, N.I.H., Extramural |
اللغة: | English |
بيانات الدورية: | Publisher: Nature Pub. Group Country of Publication: England NLM ID: 101528555 Publication Model: Electronic Cited Medium: Internet ISSN: 2041-1723 (Electronic) Linking ISSN: 20411723 NLM ISO Abbreviation: Nat Commun Subsets: MEDLINE |
أسماء مطبوعة: | Original Publication: [London] : Nature Pub. Group |
مواضيع طبية MeSH: | Receptors, Chimeric Antigen* , Neoplasms*/genetics , Neoplasms*/therapy, Humans ; Animals ; Mice ; Interleukin-12/genetics ; Epithelial Cell Adhesion Molecule ; Immunotherapy, Adoptive ; Antigens, Neoplasm/genetics ; Receptors, Antigen, T-Cell/genetics ; Receptors, Antigen, T-Cell/metabolism ; Xenograft Model Antitumor Assays ; Cell Line, Tumor ; Tumor Microenvironment |
مستخلص: | The limited number of targetable tumor-specific antigens and the immunosuppressive nature of the microenvironment within solid malignancies represent major barriers to the success of chimeric antigen receptor (CAR)-T cell therapies. Here, using epithelial cell adhesion molecule (EpCAM) as a model antigen, we used alanine scanning of the complementarity-determining region to fine-tune CAR affinity. This allowed us to identify CARs that could spare primary epithelial cells while still effectively targeting EpCAM high tumors. Although affinity-tuned CARs showed suboptimal antitumor activity in vivo, we found that inducible secretion of interleukin-12 (IL-12), under the control of the NFAT promoter, can restore CAR activity to levels close to that of the parental CAR. This strategy was further validated with another affinity-tuned CAR specific for intercellular adhesion molecule-1 (ICAM-1). Only in affinity-tuned CAR-T cells was NFAT activity stringently controlled and restricted to tumors expressing the antigen of interest at high levels. Our study demonstrates the feasibility of specifically gearing CAR-T cells towards recognition of solid tumors by combining inducible IL-12 expression and affinity-tuned CAR. (© 2023. The Author(s).) |
References: | J Immunol. 2004 Dec 15;173(12):7647-53. (PMID: 15585893) Nat Med. 2022 Apr;28(4):724-734. (PMID: 35314843) Biotechnology (N Y). 1992 Oct;10(10):1128-32. (PMID: 1369487) Cancer Res. 2015 Sep 1;75(17):3505-18. (PMID: 26330164) Mol Ther Oncolytics. 2017 Dec 19;8:41-51. (PMID: 29367945) Cancer Immunol Res. 2021 Oct;9(10):1158-1174. (PMID: 34341066) Hum Pathol. 2004 Jan;35(1):122-8. (PMID: 14745734) Proc Natl Acad Sci U S A. 1992 May 15;89(10):4285-9. (PMID: 1350088) Eur J Immunol. 1996 Mar;26(3):659-68. (PMID: 8605935) Clin Cancer Res. 2015 May 15;21(10):2278-88. (PMID: 25695689) Nat Biotechnol. 1999 Mar;17(3):276-81. (PMID: 10096296) Oncoimmunology. 2012 Sep 1;1(6):863-873. (PMID: 23162754) Sci Rep. 2017 Oct 30;7(1):14366. (PMID: 29085043) Cancer Res. 1987 Jun 1;47(11):2883-91. (PMID: 3552208) Immunology. 2009 Feb;126(2):165-76. (PMID: 19125887) Nat Rev Immunol. 2003 Feb;3(2):133-46. (PMID: 12563297) Cancer Cell. 2019 Dec 9;36(6):613-629.e7. (PMID: 31761658) Lancet Oncol. 2021 Jul;22(7):893. (PMID: 34197740) Nat Med. 2022 Jun;28(6):1189-1198. (PMID: 35534566) Sci Transl Med. 2019 Aug 14;11(505):. (PMID: 31413142) Science. 1995 Nov 10;270(5238):908. (PMID: 7481785) Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14145-50. (PMID: 14610278) Mol Ther. 2010 Apr;18(4):843-51. (PMID: 20179677) J Biol Chem. 1993 Nov 15;268(32):24232-41. (PMID: 7693697) Clin Cancer Res. 2012 Mar 15;18(6):1672-83. (PMID: 22291136) Nat Med. 2019 Sep;25(9):1408-1414. (PMID: 31477906) Leuk Res. 2009 Nov;33(11):1485-9. (PMID: 19243818) Sci Rep. 2019 Jul 23;9(1):10634. (PMID: 31337787) Mol Ther. 2013 Apr;21(4):904-12. (PMID: 23423337) Oncoimmunology. 2020 Aug 15;9(1):1806009. (PMID: 32923168) Mol Ther Oncolytics. 2020 Aug 21;18:587-601. (PMID: 32995483) Proc Natl Acad Sci U S A. 2006 Apr 11;103(15):5758-63. (PMID: 16595626) Cancer Res. 2011 Sep 1;71(17):5697-706. (PMID: 21742772) J Clin Invest. 2011 Dec;121(12):4746-57. (PMID: 22056381) Nat Rev Drug Discov. 2021 Jul;20(7):531-550. (PMID: 33972771) Cancer Immunol Immunother. 2017 Nov;66(11):1425-1436. (PMID: 28660319) JCI Insight. 2016 Nov 17;1(19):e90064. (PMID: 27882353) Cancer Res. 2015 Sep 1;75(17):3596-607. (PMID: 26330166) Front Oncol. 2018 Feb 19;8:19. (PMID: 29515970) |
معلومات مُعتمدة: | P30 CA008748 United States CA NCI NIH HHS; R01 CA217059 United States CA NCI NIH HHS; R01 CA254035 United States CA NCI NIH HHS |
المشرفين على المادة: | 0 (Receptors, Chimeric Antigen) 187348-17-0 (Interleukin-12) 0 (Epithelial Cell Adhesion Molecule) 0 (Antigens, Neoplasm) 0 (Receptors, Antigen, T-Cell) |
تواريخ الأحداث: | Date Created: 20230412 Date Completed: 20230414 Latest Revision: 20230719 |
رمز التحديث: | 20231215 |
مُعرف محوري في PubMed: | PMC10097865 |
DOI: | 10.1038/s41467-023-37646-y |
PMID: | 37045815 |
قاعدة البيانات: | MEDLINE |
تدمد: | 2041-1723 |
---|---|
DOI: | 10.1038/s41467-023-37646-y |