St. Jude Reference #SJ-22-0002, # SJ-23-0024
Immunotherapy with immune/T cells expressing chimeric antigen receptors (CARs) revolutionized treatment approaches for patients with hematological malignancies; however, they have been less effective for solid tumors and brain tumors. While lack of efficacy is most likely multifactorial, limited persistence and an inability to function in the setting of chronic antigen exposure have emerged as major roadblocks.
Researchers have overexpressed common gamma chain cytokines, including IL-2, IL-7, IL-15, and IL-21, in CAR T cells to improve the ability of CAR T cells to remain viable without antigen exposure and to function in the setting of chronic antigen exposure. Common gamma chain cytokine-expressing CAR T cells have improved antitumor activity in preclinical models; however, secreted/membrane-bound cytokines have the potential to activate bystander immune cells, contributing to toxicity. To overcome this safety concern, the researchers designed chimeric cytokine receptors that only provide signals to the genetically modified immune cells.
Common gamma chain cytokine receptors signal as heterodimers, so to induce heterodimerization in a lignad-independent manner, the extracellular domain of the cytokine receptors was replaced with leucine zippers and called ‘Zip Cytokine Receptors’ (ZipR). An IL-2 ZipR (Zip2R) was first generated and shown to be functional as judged by activation of downstream signaling molecules (phosphorylation of STAT5). Additional ZipRs from IL-7, IL-21, IL-10, IL-22, and IL-12 receptors were also generated and have been shown to be functional. Provision of signaling from Zip2R, Zip7R, Zip21R and Zip12R can improve the antitumor activity of CAR T cells in solid tumor xenograft models.
While the preliminary data is focused on CAR T cells, the approach is applicable to other cell therapy platforms, including but not limited to, NK cells, NK92 cells, NKT cells, gamma delta T cells, and regulatory T cells. This approach has applications beyond cancer for adoptive immunotherapies of non-malignant disease including viral infections, autoimmunity, and transplant.
There is also a simplified ZipR CAR that has a homodimer rather than the heterodimer design: SJ-23-0024. In proof-of-concept studies researchers demonstrated that EpoR and GHR ZipRs activate (phosphorylate) STAT5, which is the downstream signaling molecule of IL2, IL7, and IL15, and functional studies are in progress, and that the homodimer ZipRs present a significant advance in the field since it will simplify the generation of ZipR-expressing immune cells and thus clinical translation.
Keywords
Immunotherapy, T cells, chimeric antigen receptors (CARs), hematological malignancy, solid tumor, brain tumor, gamma cytokines, IL2, IL7, IL15, IL21, antigen exposure, secreted/membrane-bound cytokines, heterodimers, Zip Cyokine Receptors (ZipR), Zip2R, Zip7R, Zip21R, Zip10R, Zip22R, Zip12R, NK cells, NK92 cells, NKT cells, gd T cells, viral infections.
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Related Scientific References
Bell, M., Lange, S., Sejdiu, B.I. et al. Modular chimeric cytokine receptors with leucine zippers enhance the antitumour activity of CAR T cells via JAK/STAT signalling. Nat. Biomed. Eng (2023). https://doi.org/10.1038/s41551-023-01143-w
Press release about the paper: Modular chimeric cytokine receptors improve CAR T–cell therapy for solid tumors https://www.stjude.org/media-resources/news-releases/2023-medicine-science-news/modular-chimeric-cytokine-receptors-improve-car-t-cell-therapy-for-solid-tumors.html
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