Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer
© 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, iverm...
| Main Authors: | , , , , , |
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| Other Authors: | |
| Format: | Article |
| Language: | English |
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Springer Science and Business Media LLC
2022
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| Online Access: | https://hdl.handle.net/1721.1/133530.2 |
| _version_ | 1811071148257968128 |
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| author | Draganov, D Han, Z Rana, A Bennett, N Irvine, DJ Lee, PP |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Draganov, D Han, Z Rana, A Bennett, N Irvine, DJ Lee, PP |
| author_sort | Draganov, D |
| collection | MIT |
| description | © 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. |
| first_indexed | 2024-09-23T08:46:46Z |
| format | Article |
| id | mit-1721.1/133530.2 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T08:46:46Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/133530.22024-02-23T20:15:54Z Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer Draganov, D Han, Z Rana, A Bennett, N Irvine, DJ Lee, PP Massachusetts Institute of Technology. Department of Biological Engineering Koch Institute for Integrative Cancer Research at MIT © 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. 2022-01-18T19:48:36Z 2021-10-27T19:53:22Z 2022-01-18T19:48:36Z 2021-12 2020-08 2021-09-03T16:52:22Z Article http://purl.org/eprint/type/JournalArticle 2374-4677 https://hdl.handle.net/1721.1/133530.2 en http://dx.doi.org/10.1038/s41523-021-00229-5 npj Breast Cancer Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/octet-stream Springer Science and Business Media LLC Nature |
| spellingShingle | Draganov, D Han, Z Rana, A Bennett, N Irvine, DJ Lee, PP Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| title | Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| title_full | Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| title_fullStr | Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| title_full_unstemmed | Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| title_short | Ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| title_sort | ivermectin converts cold tumors hot and synergizes with immune checkpoint blockade for treatment of breast cancer |
| url | https://hdl.handle.net/1721.1/133530.2 |
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