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Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
Name
s41523-021-00229-5.pdf
Description
Published version
Size
2.18 MB
Format
Adobe PDF
Checksum (MD5)
818645ae5f67e73a09d158438b7ac4c9
Author(s)
Draganov, D
Han, Z
Rana, A
Bennett, N
Irvine, DJ
Lee, PP
Date Issued
December 1, 2021
Journal
npj Breast Cancer
Publisher
Springer Science and Business Media LLC
Version
Final published version
Abstract
© 2021, The Author(s). We show that treatment with the FDA-approved anti-parasitic drug ivermectin induces immunogenic cancer cell death (ICD) and robust T cell infiltration into breast tumors. As an allosteric modulator of the ATP/P2X4/P2X7 axis which operates in both cancer and immune cells, ivermectin also selectively targets immunosuppressive populations including myeloid cells and Tregs, resulting in enhanced Teff/Tregs ratio. While neither agent alone showed efficacy in vivo, combination therapy with ivermectin and checkpoint inhibitor anti-PD1 antibody achieved synergy in limiting tumor growth (p = 0.03) and promoted complete responses (p < 0.01), also leading to immunity against contralateral re-challenge with demonstrated anti-tumor immune responses. Going beyond primary tumors, this combination achieved significant reduction in relapse after neoadjuvant (p = 0.03) and adjuvant treatment (p < 0.001), and potential cures in metastatic disease (p < 0.001). Statistical modeling confirmed bona fide synergistic activity in both the adjuvant (p = 0.007) and metastatic settings (p < 0.001). Ivermectin has dual immunomodulatory and ICD-inducing effects in breast cancer, converting cold tumors hot, thus represents a rational mechanistic partner with checkpoint blockade.
Terms of Use
Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1038/s41523-021-00229-5
