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Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer

Dobrin Draganov, Zhen Han, Nitasha Bennett, Darrell J. Irvine, Peter P. Lee
doi: https://doi.org/10.1101/2020.08.21.261511
Dobrin Draganov
1Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
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Zhen Han
1Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
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Nitasha Bennett
2Koch Institute for Integrative Cancer Research and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
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Darrell J. Irvine
2Koch Institute for Integrative Cancer Research and Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA
3Howard Hughes Medical Institute, Chevy Chase, MD
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Peter P. Lee
1Department of Immuno-Oncology, Beckman Research Institute, City of Hope, Duarte, CA
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  • For correspondence: plee@coh.org
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Abstract

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/P2×4/P2×7 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.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted August 24, 2020.
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Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer
Dobrin Draganov, Zhen Han, Nitasha Bennett, Darrell J. Irvine, Peter P. Lee
bioRxiv 2020.08.21.261511; doi: https://doi.org/10.1101/2020.08.21.261511
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Ivermectin converts cold tumors hot and synergies with immune checkpoint blockade for treatment of breast cancer
Dobrin Draganov, Zhen Han, Nitasha Bennett, Darrell J. Irvine, Peter P. Lee
bioRxiv 2020.08.21.261511; doi: https://doi.org/10.1101/2020.08.21.261511

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