A Chimeric GM-CSF/IL18 Receptor to Sustain CAR T-cell Function
Open accessPublished version of a preprint
Abstract
The inability of chimeric antigen receptor (CAR) T cells to sustain their effector function after repeated exposure to tumor cells is a major obstacle to their success in patients with solid tumors. To overcome this limitation, we designed a novel chimeric cytokine receptor to create an autocrine loop that links activation-dependent GM-CSF production by CAR T cells to IL18 receptor signaling (GM18). Expression of GM18 in CAR T cells enhanced their effector function in an antigen- and activation-dependent manner. In repeat stimulation assays, which mimic chronic antigen exposure, CAR.GM18 T cells had a significantly greater ability to expand and produce cytokines in comparison with their unmodified counterparts targeting EPHA2 or HER2. In vivo, CAR.GM18 T cells induced tumor regression at cell doses at which standard CAR T cells were ineffective in two solid tumor xenograft models. Thus, our study highlights the potential of hijacking cytokines that are physiologically secreted by T cells to bolster their antitumor activity. Significance: We designed a chimeric cytokine receptor (GM18) that links CAR T-cell activation to MYD88 signaling. GM18 endows CAR T cells with sustained effector function in the setting of chronic antigen exposure, resulting in potent antitumor activity in preclinical solid tumor models. This article is highlighted in the In This Issue feature, p. 1601
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Several emerging immune-based approaches other than immune-checkpoint inhibitors have generated encouraging preclinical results in osteosarcoma.
“although several emerging immune-based approaches other than the use of ICIs have generated encouraging preclinical results 86,87,88,89,91 .”
From Osteosarcoma (2022) · cites this paper as [88]
Emerging preclinical data for chimeric antigen receptor T cell and CAR natural killer cell therapies in osteosarcoma are encouraging.
“The emerging preclinical data for chimeric antigen receptor (CAR) T and CAR natural killer cell therapies are encouraging 88,89 ,”
From Osteosarcoma (2022) · cites this paper as [88]
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“Similarly, Gottschalk and colleagues used a granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-18 ICR to sustain the functionality of CAR T cells targeting human epidermal growth factor receptor 2, a metastatic colorectal cancer target 27 .”
- Authors
- Lange, S., Sand, L. G. L., Bell, M., Patil, S. L., Langfitt, D., & Gottschalk, S.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Corresponding author
- Gottschalk, Stephen
- ORCID
- Venue
- Cancer Discovery
- Published
- 2021-02-09
- Volume
- 11
- Issue
- 7
- Pages
- 1661-1671
- ISSN
- 2159-8274 (ISSN-L)
- 2159-8290
- PMC
- PMC8292158
- OpenAlex
- W3127659431
- Cited by
- 68
- References
- 25
- Citations by year
- 2026: 4 · 2025: 14 · 2024: 16 · 2023: 20 · 2022: 8 · 2021: 6
- FWCI
- 4.55
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Discovery (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health (P01CA096832, R50CA211481)
- St. Jude and a grant from the National Cancer Institute (P30 CA021765)
- Topics
- Health Sciences › Medicine › Oncology › CAR-T cell therapy research
- Life Sciences › Immunology and Microbiology › Immunology › Immunotherapy and Immune Responses
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- chimeric antigen receptor T cells, autocrine cytokine signaling, GM-CSF, IL-18 receptor, MyD88 signaling, chronic antigen exposure, solid tumors, EphA2, HER2, tumor regression, T cell expansion
- MeSH terms
- Receptors, Chimeric Antigen, Animals, Humans, Leukocytes, Mononuclear, Neoplasms, Receptors, Granulocyte-Macrophage Colony-Stimulating Factor, Immunotherapy, Adoptive, Interleukin-18, Xenograft Model Antitumor Assays, Cell Line, Tumor, Mice
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