The DOI matches its Crossref record; 42 of the 42 references it cites were found in a registry or an index.
A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects
Open accessAbstract
The adoptive transfer of T cells engineered with a chimeric antigen receptor (CAR) (hereafter referred to as CAR-T cells) specific for the B lymphocyte antigen CD19 has shown impressive clinical responses in patients with refractory B cell malignancies. However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit. Although inefficient tumor trafficking and various immunosuppressive mechanisms can impede CAR-T cell effector responses, the signals delivered by the current CAR constructs may still be insufficient to fully activate antitumor T cell functions. Optimal T cell activation and proliferation requires multiple signals, including T cell receptor (TCR) engagement (signal 1), co-stimulation (signal 2) and cytokine engagement (signal 3). However, CAR constructs currently being tested in the clinic contain a CD3z (TCR signaling) domain and co-stimulatory domain(s) but not a domain that transmits signal 3 (refs. 13, 14, 15, 16, 17, 18). Here we have developed a novel CAR construct capable of inducing cytokine signaling after antigen stimulation. This new-generation CD19 CAR encodes a truncated cytoplasmic domain from the interleukin (IL)-2 receptor β-chain (IL-2Rβ) and a STAT3-binding tyrosine-X-X-glutamine (YXXQ) motif, together with the TCR signaling (CD3z) and co-stimulatory (CD28) domains (hereafter referred to as 28-ΔIL2RB-z(YXXQ)). The 28-ΔIL2RB-z(YXXQ) CAR-T cells showed antigen-dependent activation of the JAK kinase and of the STAT3 and STAT5 transcription factors signaling pathways, which promoted their proliferation and prevented terminal differentiation in vitro. The 28-ΔIL2RB-z(YXXQ) CAR-T cells demonstrated superior in vivo persistence and antitumor effects in models of liquid and solid tumors as compared with CAR-T cells expressing a CD28 or 4-1BB co-stimulatory domain alone. Taken together, these results suggest that our new-generation CAR has the potential to demonstrate superior antitumor effects with minimal toxicity in the clinic and that clinical translation of this novel CAR is warranted.
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Cites
Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia
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Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
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Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection
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Targeting STAT3 in Cancer Immunotherapy
Zou, S., Tong, Q., Liu, B., Huang, W., Tian, Y., & Fu, X. (2020) · Molecular Cancer · doi:10.1186/s12943-020-01258-7 · Cited by 1,050
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Labanieh, L., & Mackall, C. L. (2023) · Nature · doi:10.1038/s41586-023-05707-3 · Cited by 658
Clinical lessons learned from the first leg of the CAR T cell journey
Majzner, R. G., & Mackall, C. L. (2019) · Nature Medicine · doi:10.1038/s41591-019-0564-6 · Cited by 636
Biology and regulation of IL-2: from molecular mechanisms to human therapy
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Metadata
- Authors
- Kagoya, Y., Tanaka, S., Guo, T., Anczurowski, M., Wang, C.-H., Saso, K., Butler, M. O., Minden, M. D., & Hirano, N.
- Venue
- Nature Medicine
- Published
- 2018-02-05
- Volume
- 24
- Issue
- 3
- Pages
- 352-359
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- OpenAlex
- W2787578932
- Cited by
- 622
- References
- 42
- FWCI
- 14.32
- Type
- journal article
- Language
- en
- Open access
- green
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- Kagoya, Y., Tanaka, S., Guo, T., Anczurowski, M., Wang, C.-H., Saso, K., Butler, M. O., Minden, M. D., & Hirano, N. (2018). A novel chimeric antigen receptor containing a JAK–STAT signaling domain mediates superior antitumor effects. Nature Medicine. https://doi.org/10.1038/nm.4478
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