Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy
Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical us...
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| Format: | Article |
| Language: | en_US |
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Elsevier
2015
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| Online Access: | http://hdl.handle.net/1721.1/99424 https://orcid.org/0000-0002-4267-237X |
| _version_ | 1826194229302394880 |
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| author | Kwong, Brandon Liu, Haipeng Irvine, Darrell J |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Kwong, Brandon Liu, Haipeng Irvine, Darrell J |
| author_sort | Kwong, Brandon |
| collection | MIT |
| description | Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bioactivity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immuno-agonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpG-liposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40 + CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally-administered soluble immunotherapy, anti-CD40/CpG-liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation. |
| first_indexed | 2024-09-23T09:52:54Z |
| format | Article |
| id | mit-1721.1/99424 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T09:52:54Z |
| publishDate | 2015 |
| publisher | Elsevier |
| record_format | dspace |
| spelling | mit-1721.1/994242022-09-26T14:15:17Z Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy Kwong, Brandon Liu, Haipeng Irvine, Darrell J Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Department of Materials Science and Engineering Ragon Institute of MGH, MIT and Harvard Koch Institute for Integrative Cancer Research at MIT Kwong, Brandon Liu, Haipeng Irvine, Darrell J. Immunostimulatory therapies that activate immune response pathways are of great interest for overcoming the immunosuppression present in advanced tumors. Agonistic anti-CD40 antibodies and CpG oligonucleotides have previously demonstrated potent, synergistic anti-tumor effects, but their clinical use even as monotherapies is hampered by dose-limiting inflammatory toxicity provoked upon systemic exposure. We hypothesized that by anchoring immuno-agonist compounds to lipid nanoparticles we could retain the bioactivity of therapeutics in the local tumor tissue and tumor-draining lymph node, but limit systemic exposure to these potent molecules. We prepared PEGylated liposomes bearing surface-conjugated anti-CD40 and CpG and assessed their therapeutic efficacy and systemic toxicity compared to soluble versions of the same immuno-agonists, injected intratumorally in the B16F10 murine model of melanoma. Anti-CD40/CpG-liposomes significantly inhibited tumor growth and induced a survival benefit similar to locally injected soluble anti-CD40 + CpG. Biodistribution analyses following local delivery showed that the liposomal carriers successfully sequestered anti-CD40 and CpG in vivo, reducing leakage into systemic circulation while allowing draining to the tumor-proximal lymph node. Contrary to locally-administered soluble immunotherapy, anti-CD40/CpG-liposomes did not elicit significant increases in serum levels of ALT enzyme, systemic inflammatory cytokines, or overall weight loss, confirming that off-target inflammatory effects had been minimized. The development of a delivery strategy capable of inducing robust anti-tumor responses concurrent with minimal systemic side effects is crucial for the continued progress of potent immunotherapies toward widespread clinical translation. Dana-Farber/Harvard Cancer Center (MIT Bridge Project Fund) 2015-10-23T13:34:45Z 2015-10-23T13:34:45Z 2011-04 2011-02 Article http://purl.org/eprint/type/JournalArticle 01429612 1878-5905 http://hdl.handle.net/1721.1/99424 Kwong, Brandon, Haipeng Liu, and Darrell J. Irvine. “Induction of Potent Anti-Tumor Responses While Eliminating Systemic Side Effects via Liposome-Anchored Combinatorial Immunotherapy.” Biomaterials 32, no. 22 (August 2011): 5134–5147. https://orcid.org/0000-0002-4267-237X en_US http://dx.doi.org/10.1016/j.biomaterials.2011.03.067 Biomaterials Creative Commons Attribution-Noncommercial-NoDerivatives http://creativecommons.org/licenses/by-nc-nd/4.0/ application/pdf Elsevier PMC |
| spellingShingle | Kwong, Brandon Liu, Haipeng Irvine, Darrell J Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy |
| title | Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy |
| title_full | Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy |
| title_fullStr | Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy |
| title_full_unstemmed | Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy |
| title_short | Induction of potent anti-tumor responses while eliminating systemic side effects via liposome-anchored combinatorial immunotherapy |
| title_sort | induction of potent anti tumor responses while eliminating systemic side effects via liposome anchored combinatorial immunotherapy |
| url | http://hdl.handle.net/1721.1/99424 https://orcid.org/0000-0002-4267-237X |
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