Maximizing response to intratumoral immunotherapy in mice by tuning local retention
<jats:title>Abstract</jats:title><jats:p>Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under developmen...
| Main Authors: | , , , , , , , , , , |
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| 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/1721.1/146810 |
| _version_ | 1811096915798917120 |
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| author | Momin, Noor Palmeri, Joseph R Lutz, Emi A Jailkhani, Noor Mak, Howard Tabet, Anthony Chinn, Magnolia M Kang, Byong H Spanoudaki, Virginia Hynes, Richard O Wittrup, K Dane |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology Momin, Noor Palmeri, Joseph R Lutz, Emi A Jailkhani, Noor Mak, Howard Tabet, Anthony Chinn, Magnolia M Kang, Byong H Spanoudaki, Virginia Hynes, Richard O Wittrup, K Dane |
| author_sort | Momin, Noor |
| collection | MIT |
| description | <jats:title>Abstract</jats:title><jats:p>Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.</jats:p> |
| first_indexed | 2024-09-23T16:51:23Z |
| format | Article |
| id | mit-1721.1/146810 |
| institution | Massachusetts Institute of Technology |
| language | English |
| last_indexed | 2024-09-23T16:51:23Z |
| publishDate | 2022 |
| publisher | Springer Science and Business Media LLC |
| record_format | dspace |
| spelling | mit-1721.1/1468102022-12-10T03:01:01Z Maximizing response to intratumoral immunotherapy in mice by tuning local retention Momin, Noor Palmeri, Joseph R Lutz, Emi A Jailkhani, Noor Mak, Howard Tabet, Anthony Chinn, Magnolia M Kang, Byong H Spanoudaki, Virginia Hynes, Richard O Wittrup, K Dane Massachusetts Institute of Technology. Department of Biology <jats:title>Abstract</jats:title><jats:p>Direct injection of therapies into tumors has emerged as an administration route capable of achieving high local drug exposure and strong anti-tumor response. A diverse array of immune agonists ranging in size and target are under development as local immunotherapies. However, due to the relatively recent adoption of intratumoral administration, the pharmacokinetics of locally-injected biologics remains poorly defined, limiting rational design of tumor-localized immunotherapies. Here we define a pharmacokinetic framework for biologics injected intratumorally that can predict tumor exposure and effectiveness. We find empirically and computationally that extending the tumor exposure of locally-injected interleukin-2 by increasing molecular size and/or improving matrix-targeting affinity improves therapeutic efficacy in mice. By tracking the distribution of intratumorally-injected proteins using positron emission tomography, we observe size-dependent enhancement in tumor exposure occurs by slowing the rate of diffusive escape from the tumor and by increasing partitioning to an apparent viscous region of the tumor. In elucidating how molecular weight and matrix binding interplay to determine tumor exposure, our model can aid in the design of intratumoral therapies to exert maximal therapeutic effect.</jats:p> 2022-12-09T17:25:17Z 2022-12-09T17:25:17Z 2022 2022-12-09T17:18:29Z Article http://purl.org/eprint/type/JournalArticle https://hdl.handle.net/1721.1/146810 Momin, Noor, Palmeri, Joseph R, Lutz, Emi A, Jailkhani, Noor, Mak, Howard et al. 2022. "Maximizing response to intratumoral immunotherapy in mice by tuning local retention." Nature Communications, 13 (1). en 10.1038/S41467-021-27390-6 Nature Communications Creative Commons Attribution 4.0 International license https://creativecommons.org/licenses/by/4.0/ application/pdf Springer Science and Business Media LLC Nature |
| spellingShingle | Momin, Noor Palmeri, Joseph R Lutz, Emi A Jailkhani, Noor Mak, Howard Tabet, Anthony Chinn, Magnolia M Kang, Byong H Spanoudaki, Virginia Hynes, Richard O Wittrup, K Dane Maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| title | Maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| title_full | Maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| title_fullStr | Maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| title_full_unstemmed | Maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| title_short | Maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| title_sort | maximizing response to intratumoral immunotherapy in mice by tuning local retention |
| url | https://hdl.handle.net/1721.1/146810 |
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