CAR T Cell Therapy Becomes CHIC: "cytokine Help Intensified CAR" T Cells

Overview

Journal Front Immunol

Specialty Allergy & Immunology

Date 2023 Jan 26

PMID 36700225

Authors

Simone Thomas

Hinrich Abken

Affiliations

Soon will be listed here.

Abstract

Chimeric antigen receptors (CARs) in the canonical "second generation" format provide two signals for inducing T cell effector functions; the primary "signal-1" is provided through the TCR CD3ζ chain and the "signal-2" through a linked costimulatory domain to augment activation. While therapy with second generation CAR T cells can induce remissions of leukemia/lymphoma in a spectacular fashion, CAR T cell persistence is frequently limited which is thought to be due to timely limited activation. Following the "three-signal" dogma for inducing a sustained T cell response, cytokines were supplemented to provide "signal-3" to CAR T cells. Recent progress in the understanding of structural biology and receptor signaling has allowed to engineer cytokines for more selective, fine-tuned stimulation of CAR T cells including an artificial autocrine loop of a transgenic cytokine, a cytokine anchored to the CAR T cell membrane or inserted into the extracellular CAR domain, and a cytokine receptor signaling moiety co-expressed with the CAR or inserted into the CAR endodomain. Here we discuss the recent strategies and options for engineering such "cytokine help intensified CAR" (CHIC) T cells for use in adoptive cell therapy.

Citing Articles

From promise to practice: CAR T and Treg cell therapies in autoimmunity and other immune-mediated diseases.

Bulliard Y, Freeborn R, Uyeda M, Humes D, Bjordahl R, de Vries D Front Immunol. 2024; 15:1509956.

PMID: 39697333 PMC: 11653210. DOI: 10.3389/fimmu.2024.1509956.

Application of novel CAR technologies to improve treatment of autoimmune disease.

Cheever A, Kang C, ONeill K, Weber K Front Immunol. 2024; 15:1465191.

PMID: 39445021 PMC: 11496059. DOI: 10.3389/fimmu.2024.1465191.

Several factors that predict the outcome of large B-cell lymphoma patients who relapse/progress after chimeric antigen receptor (CAR) T-cell therapy can be identified before cell administration.

Sykorova A, Folber F, Polgarova K, Mocikova H, Duras J, Steinerova K Cancer Med. 2024; 13(17):e70138.

PMID: 39248284 PMC: 11382134. DOI: 10.1002/cam4.70138.

Immune modulatory microRNAs in tumors, their clinical relevance in diagnosis and therapy.

Vaxevanis C, Bachmann M, Seliger B J Immunother Cancer. 2024; 12(8).

PMID: 39209767 PMC: 11367391. DOI: 10.1136/jitc-2024-009774.

UniCAR T-Cell Potency-A Matter of Affinity between Adaptor Molecules and Adaptor CAR T-Cells?.

Boutier H, Loureiro L, Hoffmann L, Arndt C, Bartsch T, Feldmann A Int J Mol Sci. 2024; 25(13).

PMID: 39000348 PMC: 11241561. DOI: 10.3390/ijms25137242.

References

Hombach A, Barden M, Hannappel L, Chmielewski M, Rappl G, Sachinidis A . IL12 integrated into the CAR exodomain converts CD8 T cells to poly-functional NK-like cells with superior killing of antigen-loss tumors. Mol Ther. 2021; 30(2):593-605. PMC: 8821972. DOI: 10.1016/j.ymthe.2021.10.011. View

Imamura M, Shook D, Kamiya T, Shimasaki N, Chai S, Coustan-Smith E . Autonomous growth and increased cytotoxicity of natural killer cells expressing membrane-bound interleukin-15. Blood. 2014; 124(7):1081-8. DOI: 10.1182/blood-2014-02-556837. View

Lange S, Sand L, Bell M, Patil S, Langfitt D, Gottschalk S . A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function. Cancer Discov. 2021; 11(7):1661-1671. PMC: 8292158. DOI: 10.1158/2159-8290.CD-20-0896. View

Adachi K, Kano Y, Nagai T, Okuyama N, Sakoda Y, Tamada K . IL-7 and CCL19 expression in CAR-T cells improves immune cell infiltration and CAR-T cell survival in the tumor. Nat Biotechnol. 2018; 36(4):346-351. DOI: 10.1038/nbt.4086. View

Saxton R, Glassman C, Garcia K . Emerging principles of cytokine pharmacology and therapeutics. Nat Rev Drug Discov. 2022; 22(1):21-37. PMC: 10292932. DOI: 10.1038/s41573-022-00557-6. View

Alizadeh D, Wong R, Yang X, Wang D, Pecoraro J, Kuo C . IL15 Enhances CAR-T Cell Antitumor Activity by Reducing mTORC1 Activity and Preserving Their Stem Cell Memory Phenotype. Cancer Immunol Res. 2019; 7(5):759-772. PMC: 6687561. DOI: 10.1158/2326-6066.CIR-18-0466. View

Zhang Q, Hresko M, Picton L, Su L, Hollander M, Nunez-Cruz S . A human orthogonal IL-2 and IL-2Rβ system enhances CAR T cell expansion and antitumor activity in a murine model of leukemia. Sci Transl Med. 2021; 13(625):eabg6986. PMC: 9116279. DOI: 10.1126/scitranslmed.abg6986. View

Bajgain P, Tawinwung S, DElia L, Sukumaran S, Watanabe N, Hoyos V . CAR T cell therapy for breast cancer: harnessing the tumor milieu to drive T cell activation. J Immunother Cancer. 2018; 6(1):34. PMC: 5944113. DOI: 10.1186/s40425-018-0347-5. View

Chmielewski M, Abken H . CAR T cells transform to trucks: chimeric antigen receptor-redirected T cells engineered to deliver inducible IL-12 modulate the tumour stroma to combat cancer. Cancer Immunol Immunother. 2012; 61(8):1269-77. PMC: 11029721. DOI: 10.1007/s00262-012-1202-z. View

10.

Hurton L, Singh H, Najjar A, Switzer K, Mi T, Maiti S . Tethered IL-15 augments antitumor activity and promotes a stem-cell memory subset in tumor-specific T cells. Proc Natl Acad Sci U S A. 2016; 113(48):E7788-E7797. PMC: 5137758. DOI: 10.1073/pnas.1610544113. View

11.

Reppel L, Tsahouridis O, Akulian J, Davis I, Lee H, Fuca G . Targeting disialoganglioside GD2 with chimeric antigen receptor-redirected T cells in lung cancer. J Immunother Cancer. 2022; 10(1). PMC: 8756261. DOI: 10.1136/jitc-2021-003897. View

12.

Chmielewski M, Hombach A, Abken H . Of CARs and TRUCKs: chimeric antigen receptor (CAR) T cells engineered with an inducible cytokine to modulate the tumor stroma. Immunol Rev. 2013; 257(1):83-90. DOI: 10.1111/imr.12125. View

13.

Hunter M, Prosser M, Mahadev V, Wang X, Aguilar B, Brown C . Chimeric γc cytokine receptors confer cytokine independent engraftment of human T lymphocytes. Mol Immunol. 2013; 56(1-2):1-11. DOI: 10.1016/j.molimm.2013.03.021. View

14.

Sato N, Patel H, Waldmann T, Tagaya Y . The IL-15/IL-15Ralpha on cell surfaces enables sustained IL-15 activity and contributes to the long survival of CD8 memory T cells. Proc Natl Acad Sci U S A. 2007; 104(2):588-93. PMC: 1766429. DOI: 10.1073/pnas.0610115104. View

15.

Markley J, Sadelain M . IL-7 and IL-21 are superior to IL-2 and IL-15 in promoting human T cell-mediated rejection of systemic lymphoma in immunodeficient mice. Blood. 2010; 115(17):3508-19. PMC: 2867264. DOI: 10.1182/blood-2009-09-241398. View

16.

Wang Y, Jiang H, Luo H, Sun Y, Shi B, Sun R . An IL-4/21 Inverted Cytokine Receptor Improving CAR-T Cell Potency in Immunosuppressive Solid-Tumor Microenvironment. Front Immunol. 2019; 10:1691. PMC: 6658891. DOI: 10.3389/fimmu.2019.01691. View

17.

Curtsinger J, Mescher M . Inflammatory cytokines as a third signal for T cell activation. Curr Opin Immunol. 2010; 22(3):333-40. PMC: 2891062. DOI: 10.1016/j.coi.2010.02.013. View

18.

Sockolosky J, Trotta E, Parisi G, Picton L, Su L, Le A . Selective targeting of engineered T cells using orthogonal IL-2 cytokine-receptor complexes. Science. 2018; 359(6379):1037-1042. PMC: 5947856. DOI: 10.1126/science.aar3246. View

19.

Yeku O, Brentjens R . Armored CAR T-cells: utilizing cytokines and pro-inflammatory ligands to enhance CAR T-cell anti-tumour efficacy. Biochem Soc Trans. 2016; 44(2):412-8. PMC: 5529098. DOI: 10.1042/BST20150291. View

20.

Gargett T, Ebert L, Truong N, Kollis P, Sedivakova K, Yu W . GD2-targeting CAR-T cells enhanced by transgenic IL-15 expression are an effective and clinically feasible therapy for glioblastoma. J Immunother Cancer. 2022; 10(9). PMC: 9516307. DOI: 10.1136/jitc-2022-005187. View