A novel chimeric antigen receptor containing a JAK-STAT signaling domain mediates superior antitumor effects

Nat Med. 2018 Mar;24(3):352-359. doi: 10.1038/nm.4478. Epub 2018 Feb 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD19 / genetics*
  • Antigens, CD19 / therapeutic use
  • CD28 Antigens / genetics
  • CD28 Antigens / therapeutic use
  • Cell Differentiation / genetics
  • Cell Line, Tumor
  • Cell Proliferation / genetics
  • Humans
  • Immunotherapy, Adoptive
  • Interleukin-2 Receptor beta Subunit / genetics*
  • Interleukin-2 Receptor beta Subunit / therapeutic use
  • Janus Kinases / genetics
  • Lymphocyte Activation / genetics
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Neoplasms / therapy*
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / therapeutic use
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / therapeutic use
  • STAT3 Transcription Factor / genetics*
  • STAT3 Transcription Factor / therapeutic use
  • Signal Transduction
  • T-Lymphocytes / metabolism
  • Xenograft Model Antitumor Assays


  • Antigens, CD19
  • CD28 Antigens
  • Interleukin-2 Receptor beta Subunit
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • STAT3 Transcription Factor
  • Janus Kinases