TY - JOUR
T1 - A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects
AU - Kagoya, Yuki
AU - Tanaka, Shinya
AU - Guo, Tingxi
AU - Anczurowski, Mark
AU - Wang, Chung Hsi
AU - Saso, Kayoko
AU - Butler, Marcus O.
AU - Minden, Mark D.
AU - Hirano, Naoto
N1 - Funding Information:
This work was supported by CIHR Project Grant 362860 (N.H.), Ontario Institute for Cancer Research Clinical Investigator Award IA-039 (N.H.), BioCanRX Catalyst Program grant FY17CAT7 (N.H.), the Princess Margaret Cancer Foundation (M.O.B. and N.H.), a Japan Society for the Promotion of Science Postdoctoral Fellowship for Overseas Researchers (Y.K.), a Guglietti Fellowship Award (Y.K.), a Canadian Institutes of Health Research Canada Graduate Scholarship (T.G.), the Province of Ontario (T.G. and M.A.) and a Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship (T.G.). This study was partly sponsored by Takara Bio, Inc.
Publisher Copyright:
© 2018 Nature America, Inc., part of Springer Nature. All rights reserved.
PY - 2018/3/1
Y1 - 2018/3/1
N2 - 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-Δ IL2RB-z(YXXQ)). The 28-Δ IL2RB-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-Δ IL2RB-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.
AB - 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-Δ IL2RB-z(YXXQ)). The 28-Δ IL2RB-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-Δ IL2RB-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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U2 - 10.1038/nm.4478
DO - 10.1038/nm.4478
M3 - Article
C2 - 29400710
AN - SCOPUS:85042615352
SN - 1078-8956
VL - 24
SP - 352
EP - 359
JO - Nature Medicine
JF - Nature Medicine
IS - 3
ER -