Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity
Immunostimulatory agents such as agonistic anti-CD137 and interleukin (IL)-2 generate effective anti-tumor immunity but also elicit serious toxicities, hampering their clinical application. Here we show that combination therapy with anti-CD137 and an IL-2-Fc fusion achieves significant initial anti-...
| Main Authors: | , , , |
|---|---|
| Other Authors: | |
| Format: | Article |
| Published: |
Nature Publishing Group
2018
|
| Online Access: | http://hdl.handle.net/1721.1/115183 https://orcid.org/0000-0002-2931-7592 https://orcid.org/0000-0003-0787-298X |
| _version_ | 1811077460750499840 |
|---|---|
| author | Zhang, Yuan Li, Na Suh, Heikyung Irvine, Darrell J |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Zhang, Yuan Li, Na Suh, Heikyung Irvine, Darrell J |
| author_sort | Zhang, Yuan |
| collection | MIT |
| description | Immunostimulatory agents such as agonistic anti-CD137 and interleukin (IL)-2 generate effective anti-tumor immunity but also elicit serious toxicities, hampering their clinical application. Here we show that combination therapy with anti-CD137 and an IL-2-Fc fusion achieves significant initial anti-tumor activity, but also lethal immunotoxicity deriving from stimulation of circulating leukocytes. To overcome this toxicity, we demonstrate that anchoring IL-2 and anti-CD137 on the surface of liposomes allows these immune agonists to rapidly accumulate in tumors while lowering systemic exposure. In multiple tumor models, immunoliposome delivery achieves anti-tumor activity equivalent to free IL-2/anti-CD137 but with the complete absence of systemic toxicity. Immunoliposomes stimulated tumor infiltration by cytotoxic lymphocytes, cytokine production, and granzyme expression, demonstrating equivalent immunostimulatory effects to the free drugs in the local tumor microenvironment. Thus, surface-anchored particle delivery may provide a general approach to exploit the potent stimulatory activity of immune agonists without debilitating systemic toxicities. |
| first_indexed | 2024-09-23T10:43:23Z |
| format | Article |
| id | mit-1721.1/115183 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T10:43:23Z |
| publishDate | 2018 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1151832022-09-30T22:32:14Z Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity Zhang, Yuan Li, Na Suh, Heikyung Irvine, Darrell J Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Materials Science and Engineering Koch Institute for Integrative Cancer Research at MIT Zhang, Yuan Li, Na Suh, Heikyung Irvine, Darrell J Immunostimulatory agents such as agonistic anti-CD137 and interleukin (IL)-2 generate effective anti-tumor immunity but also elicit serious toxicities, hampering their clinical application. Here we show that combination therapy with anti-CD137 and an IL-2-Fc fusion achieves significant initial anti-tumor activity, but also lethal immunotoxicity deriving from stimulation of circulating leukocytes. To overcome this toxicity, we demonstrate that anchoring IL-2 and anti-CD137 on the surface of liposomes allows these immune agonists to rapidly accumulate in tumors while lowering systemic exposure. In multiple tumor models, immunoliposome delivery achieves anti-tumor activity equivalent to free IL-2/anti-CD137 but with the complete absence of systemic toxicity. Immunoliposomes stimulated tumor infiltration by cytotoxic lymphocytes, cytokine production, and granzyme expression, demonstrating equivalent immunostimulatory effects to the free drugs in the local tumor microenvironment. Thus, surface-anchored particle delivery may provide a general approach to exploit the potent stimulatory activity of immune agonists without debilitating systemic toxicities. 2018-05-02T18:13:15Z 2018-05-02T18:13:15Z 2018-01 2017-04 2018-04-27T14:41:26Z Article http://purl.org/eprint/type/JournalArticle 2041-1723 http://hdl.handle.net/1721.1/115183 Zhang, Yuan et al. “Nanoparticle Anchoring Targets Immune Agonists to Tumors Enabling Anti-Cancer Immunity Without Systemic Toxicity.” Nature Communications 9, 1 (January 2018) © 2018 The Author(s) https://orcid.org/0000-0002-2931-7592 https://orcid.org/0000-0003-0787-298X http://dx.doi.org/10.1038/S41467-017-02251-3 Nature Communications Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/ application/pdf Nature Publishing Group Nature Communications |
| spellingShingle | Zhang, Yuan Li, Na Suh, Heikyung Irvine, Darrell J Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity |
| title | Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity |
| title_full | Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity |
| title_fullStr | Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity |
| title_full_unstemmed | Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity |
| title_short | Nanoparticle anchoring targets immune agonists to tumors enabling anti-cancer immunity without systemic toxicity |
| title_sort | nanoparticle anchoring targets immune agonists to tumors enabling anti cancer immunity without systemic toxicity |
| url | http://hdl.handle.net/1721.1/115183 https://orcid.org/0000-0002-2931-7592 https://orcid.org/0000-0003-0787-298X |
| work_keys_str_mv | AT zhangyuan nanoparticleanchoringtargetsimmuneagoniststotumorsenablinganticancerimmunitywithoutsystemictoxicity AT lina nanoparticleanchoringtargetsimmuneagoniststotumorsenablinganticancerimmunitywithoutsystemictoxicity AT suhheikyung nanoparticleanchoringtargetsimmuneagoniststotumorsenablinganticancerimmunitywithoutsystemictoxicity AT irvinedarrellj nanoparticleanchoringtargetsimmuneagoniststotumorsenablinganticancerimmunitywithoutsystemictoxicity |