Journal
NATURE MEDICINE
Volume 24, Issue 3, Pages 352-+Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.4478
Keywords
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Funding
- CIHR Project [362860]
- Ontario Institute for Cancer Research Clinical Investigator Award [IA-039]
- BioCanRX Catalyst Program [FY17CAT7]
- Princess Margaret Cancer Foundation
- Japan Society for the Promotion of Science Postdoctoral Fellowship for Overseas Researchers
- Guglietti Fellowship Award
- Canadian Institutes of Health Research Canada Graduate Scholarship
- Province of Ontario
- Natural Sciences and Engineering Research Council of Canada Postgraduate Scholarship
- Takara Bio, Inc.
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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(1-7). However, the therapeutic effects of CAR-T cells that target other malignancies have not yet resulted in significant clinical benefit(8-11). 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)(12). 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. 13-18). 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 beta-chain (IL-2R beta) 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-Delta IL2RB-z(YXXQ)). The 28-Delta IL2RBz(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-Delta 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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