Fueling CARs: Metabolic Strategies to Enhance CAR T-cell Therapy

Overview

Journal Exp Hematol Oncol

Publisher Biomed Central

Specialty Hematology

Date 2024 Jul 10

PMID 38987856

Authors

Arne Van der Vreken

Karin Vanderkerken

Elke de Bruyne

Kim de Veirman

Karine Breckpot

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Affiliations

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Abstract

CAR T cells are widely applied for relapsed hematological cancer patients. With six approved cell therapies, for Multiple Myeloma and other B-cell malignancies, new insights emerge. Profound evidence shows that patients who fail CAR T-cell therapy have, aside from antigen escape, a more glycolytic and weakened metabolism in their CAR T cells, accompanied by a short lifespan. Recent advances show that CAR T cells can be metabolically engineered towards oxidative phosphorylation, which increases their longevity via epigenetic and phenotypical changes. In this review we elucidate various strategies to rewire their metabolism, including the design of the CAR construct, co-stimulus choice, genetic modifications of metabolic genes, and pharmacological interventions. We discuss their potential to enhance CAR T-cell functioning and persistence through memory imprinting, thereby improving outcomes. Furthermore, we link the pharmacological treatments with their anti-cancer properties in hematological malignancies to ultimately suggest novel combination strategies.

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References

Jeon S . Regulation and function of AMPK in physiology and diseases. Exp Mol Med. 2016; 48(7):e245. PMC: 4973318. DOI: 10.1038/emm.2016.81. View

Deng Q, Han G, Puebla-Osorio N, Ma M, Strati P, Chasen B . Characteristics of anti-CD19 CAR T cell infusion products associated with efficacy and toxicity in patients with large B cell lymphomas. Nat Med. 2020; 26(12):1878-1887. PMC: 8446909. DOI: 10.1038/s41591-020-1061-7. View

Ali A, Wang M, Von Scheidt B, Dominguez P, Harrison A, Tantalo D . A Histone Deacetylase Inhibitor, Panobinostat, Enhances Chimeric Antigen Receptor T-cell Antitumor Effect Against Pancreatic Cancer. Clin Cancer Res. 2021; 27(22):6222-6234. DOI: 10.1158/1078-0432.CCR-21-1141. View

Long A, Haso W, Shern J, Wanhainen K, Murgai M, Ingaramo M . 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat Med. 2015; 21(6):581-90. PMC: 4458184. DOI: 10.1038/nm.3838. View

Saoulli K, Lee S, Cannons J, Yeh W, Santana A, Goldstein M . CD28-independent, TRAF2-dependent costimulation of resting T cells by 4-1BB ligand. J Exp Med. 1998; 187(11):1849-62. PMC: 2212301. DOI: 10.1084/jem.187.11.1849. View

Lee H, Ahn S, Maity R, Leblay N, Ziccheddu B, Truger M . Mechanisms of antigen escape from BCMA- or GPRC5D-targeted immunotherapies in multiple myeloma. Nat Med. 2023; 29(9):2295-2306. PMC: 10504087. DOI: 10.1038/s41591-023-02491-5. View

Eleutherakis-Papaiakovou E, Kanellias N, Kastritis E, Gavriatopoulou M, Terpos E, Dimopoulos M . Efficacy of Panobinostat for the Treatment of Multiple Myeloma. J Oncol. 2020; 2020:7131802. PMC: 7201625. DOI: 10.1155/2020/7131802. View

Laubach J, Moreau P, San-Miguel J, Richardson P . Panobinostat for the Treatment of Multiple Myeloma. Clin Cancer Res. 2015; 21(21):4767-73. DOI: 10.1158/1078-0432.CCR-15-0530. View

Hukelmann J, Anderson K, Sinclair L, Grzes K, Murillo A, Hawkins P . The cytotoxic T cell proteome and its shaping by the kinase mTOR. Nat Immunol. 2015; 17(1):104-12. PMC: 4685757. DOI: 10.1038/ni.3314. View

10.

Larson S, Walthers C, Ji B, Ghafouri S, Naparstek J, Trent J . CD19/CD20 Bispecific Chimeric Antigen Receptor (CAR) in Naive/Memory T Cells for the Treatment of Relapsed or Refractory Non-Hodgkin Lymphoma. Cancer Discov. 2022; 13(3):580-597. PMC: 9992104. DOI: 10.1158/2159-8290.CD-22-0964. View

11.

Soriano-Baguet L, Brenner D . Metabolism and epigenetics at the heart of T cell function. Trends Immunol. 2023; 44(3):231-244. DOI: 10.1016/j.it.2023.01.002. View

12.

Zhao Z, Shi L, Zhang W, Han J, Zhang S, Fu Z . CRISPR knock out of programmed cell death protein 1 enhances anti-tumor activity of cytotoxic T lymphocytes. Oncotarget. 2018; 9(4):5208-5215. PMC: 5797044. DOI: 10.18632/oncotarget.23730. View

13.

Goodman D, Azimi C, Kearns K, Talbot A, Garakani K, Garcia J . Pooled screening of CAR T cells identifies diverse immune signaling domains for next-generation immunotherapies. Sci Transl Med. 2022; 14(670):eabm1463. PMC: 9939256. DOI: 10.1126/scitranslmed.abm1463. View

14.

De Beck L, Awad R, Basso V, Casares N, De Ridder K, De Vlaeminck Y . Inhibiting Histone and DNA Methylation Improves Cancer Vaccination in an Experimental Model of Melanoma. Front Immunol. 2022; 13:799636. PMC: 9134079. DOI: 10.3389/fimmu.2022.799636. View

15.

Geiger R, Rieckmann J, Wolf T, Basso C, Feng Y, Fuhrer T . L-Arginine Modulates T Cell Metabolism and Enhances Survival and Anti-tumor Activity. Cell. 2016; 167(3):829-842.e13. PMC: 5075284. DOI: 10.1016/j.cell.2016.09.031. View

16.

Shen L, Xiao Y, Zhang C, Li S, Teng X, Cui L . Metabolic reprogramming by ex vivo glutamine inhibition endows CAR-T cells with less-differentiated phenotype and persistent antitumor activity. Cancer Lett. 2022; 538:215710. DOI: 10.1016/j.canlet.2022.215710. View

17.

Wang Y, Tong C, Lu Y, Wu Z, Guo Y, Liu Y . Characteristics of premanufacture CD8T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma. Signal Transduct Target Ther. 2023; 8(1):409. PMC: 10598004. DOI: 10.1038/s41392-023-01659-2. View

18.

Kallies A, Zehn D, Utzschneider D . Precursor exhausted T cells: key to successful immunotherapy?. Nat Rev Immunol. 2019; 20(2):128-136. DOI: 10.1038/s41577-019-0223-7. View

19.

Song J, So T, Croft M . Activation of NF-kappaB1 by OX40 contributes to antigen-driven T cell expansion and survival. J Immunol. 2008; 180(11):7240-8. PMC: 2410213. DOI: 10.4049/jimmunol.180.11.7240. View

20.

Zhou Y, Mu W, Wang C, Zhuo Z, Xin Y, Li H . Ray of dawn: Anti-PD-1 immunotherapy enhances the chimeric antigen receptor T-cell therapy in Lymphoma patients. BMC Cancer. 2023; 23(1):1019. PMC: 10591343. DOI: 10.1186/s12885-023-11536-4. View