Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Concise Communication
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
Sitravatinib potentiates immune checkpoint blockade in refractory cancer models
Wenting Du, … , Noah Sorrelle, Rolf A. Brekken
Wenting Du, … , Noah Sorrelle, Rolf A. Brekken
Published November 2, 2018
Citation Information: JCI Insight. 2018;3(21):e124184. https://doi.org/10.1172/jci.insight.124184.
View: Text | PDF
Research Article Oncology Therapeutics

Sitravatinib potentiates immune checkpoint blockade in refractory cancer models

  • Text
  • PDF
Abstract

Immune checkpoint blockade has achieved significant therapeutic success for a subset of cancer patients; however, a large portion of cancer patients do not respond. Unresponsive tumors are characterized as being immunologically “cold,” indicating that these tumors lack tumor antigen-specific primed cytotoxic T cells. Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MerTK) and split tyrosine-kinase domain–containing receptors (VEGFR and PDGFR families and KIT) plus RET and MET, targets that contribute to the immunosuppressive tumor microenvironment. We report that sitravatinib has potent antitumor activity by targeting the tumor microenvironment, resulting in innate and adaptive immune cell changes that augment immune checkpoint blockade. These results suggest that sitravatinib has the potential to combat resistance to immune checkpoint blockade and expand the number of cancer patients that are responsive to immune therapy.

Authors

Wenting Du, Huocong Huang, Noah Sorrelle, Rolf A. Brekken

×

Figure 6

Sitravatinib enhances the efficacy of PD-1 blockade.

Options: View larger image (or click on image) Download as PowerPoint
Sitravatinib enhances the efficacy of PD-1 blockade.
(A and B) In vivo a...
(A and B) In vivo assessment of treatment response of subcutaneously or orthotopically implanted tumors (n = 12–14/group) in combination with PD-1 blockade. We injected 0.5 × 106 KLN205 cells (A) subcutaneously into 6-week-old DBA/2 mice, and 0.5 × 106 E0771 cells (B) were injected orthotopically into the mammary fat pads of 6-week-old female C57BL/6 mice. Therapy was initiated in mice with a tumor volume of 300 mm3 (KLN205) or 500 mm3 (E0771) and included control (Ctrl, vehicle, once per day), anti–PD-1 (PD-1, i.p. 10 mg/kg, every 3 days), sitravatinib (sitra, p.o. 20 mg/kg, once per day), or anti–PD-1 in combination with sitravatinib at the indicated dose. Mice were treated for 2.5 weeks. **P < 0.01 anti–PD-1 in combination with sitravatinib vs. sitravatinib alone by t test. Two of fourteen mice bearing E0771 tumors treated with the combination therapy showed complete remission and stayed tumor free for 50 days. (C) Rechallenge growth curve of the 2 tumor-free animals from B. We injected 0.5 × 106 E0771 cells orthotopically into the mammary fat pads of 6-week-old female C57BL/6 mice (Ctrl, n = 4) and on the contralateral side from the original injection of the 2 tumor-free animals.

Copyright © 2022 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts