A materials-based approach for localized delivery of cancer immunotherapy
Cancer immunotherapy provides a promising new alternative to traditional cancer treatment modalities such as chemotherapy and radiation. However, even the most effective therapies only show benefit in a subset of patients when used alone and so, combination therapy may be critical to maximizing anti...
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| Format: | Thesis |
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Massachusetts Institute of Technology
2024
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| Online Access: | https://hdl.handle.net/1721.1/153465 https://orcid.org/0000-0001-7785-7828 |
| _version_ | 1811084483879763968 |
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| author | Agarwal, Yash |
| author2 | Irvine, Darrell J. |
| author_facet | Irvine, Darrell J. Agarwal, Yash |
| author_sort | Agarwal, Yash |
| collection | MIT |
| description | Cancer immunotherapy provides a promising new alternative to traditional cancer treatment modalities such as chemotherapy and radiation. However, even the most effective therapies only show benefit in a subset of patients when used alone and so, combination therapy may be critical to maximizing anti-tumor responses in the clinic. Inflammatory cytokines such as interleukins-2, 12 and 15 promote potent anti-tumor immunity, but systemically administered cytokines are also highly toxic.
In this thesis, we engineered cytokines with a peptide tag containing multiple phosphoserine (pSer) residues, through in-cell phosphorylation during recombinant expression. Cytokines with pSer tags bind tightly to the common vaccine adjuvant aluminum hydroxide (alum) via ligand exchange. Intratumoral injection of pSer-cytokine-loaded alum led to prolonged retention of the proteins in tumors (>weeks) with minimal side effects. A single dose of alum-tethered interleukin-12 (IL-12) induced significant interferon-γ-mediated T-cell and NK-cell activity in tumors, increased tumor-antigen accumulation in draining lymph nodes, and elicited robust tumor-specific T cell priming. Intratumoral alum/cytokine therapy enhanced responses to checkpoint blockade, promoting cures in distinct poorly immunogenic syngeneic tumors while eliciting control over distant, untreated lesions and metastases. Thus, intratumoral treatment with alum-anchored cytokines presents a safe, tumor-agnostic approach to improve local and systemic anti-cancer immunity.
This thesis also contains abundant discussion about the potential disadvantages of persistently-retained IL-12 along with solutions to circumvent the obstacles while maintaining the high therapeutic-index benefits seen with local delivery of alum-bound cytokines. Overall, our work presents strong proof-of-concept for alum as a powerful delivery vehicle for cancer immunotherapy and further work could help unlock the true potential for precise spatiotemporal control after local drug delivery. |
| first_indexed | 2024-09-23T12:51:31Z |
| format | Thesis |
| id | mit-1721.1/153465 |
| institution | Massachusetts Institute of Technology |
| last_indexed | 2024-09-23T12:51:31Z |
| publishDate | 2024 |
| publisher | Massachusetts Institute of Technology |
| record_format | dspace |
| spelling | mit-1721.1/1534652024-02-09T03:34:06Z A materials-based approach for localized delivery of cancer immunotherapy Agarwal, Yash Irvine, Darrell J. Wittrup, K. Dane Massachusetts Institute of Technology. Department of Biological Engineering Cancer immunotherapy provides a promising new alternative to traditional cancer treatment modalities such as chemotherapy and radiation. However, even the most effective therapies only show benefit in a subset of patients when used alone and so, combination therapy may be critical to maximizing anti-tumor responses in the clinic. Inflammatory cytokines such as interleukins-2, 12 and 15 promote potent anti-tumor immunity, but systemically administered cytokines are also highly toxic. In this thesis, we engineered cytokines with a peptide tag containing multiple phosphoserine (pSer) residues, through in-cell phosphorylation during recombinant expression. Cytokines with pSer tags bind tightly to the common vaccine adjuvant aluminum hydroxide (alum) via ligand exchange. Intratumoral injection of pSer-cytokine-loaded alum led to prolonged retention of the proteins in tumors (>weeks) with minimal side effects. A single dose of alum-tethered interleukin-12 (IL-12) induced significant interferon-γ-mediated T-cell and NK-cell activity in tumors, increased tumor-antigen accumulation in draining lymph nodes, and elicited robust tumor-specific T cell priming. Intratumoral alum/cytokine therapy enhanced responses to checkpoint blockade, promoting cures in distinct poorly immunogenic syngeneic tumors while eliciting control over distant, untreated lesions and metastases. Thus, intratumoral treatment with alum-anchored cytokines presents a safe, tumor-agnostic approach to improve local and systemic anti-cancer immunity. This thesis also contains abundant discussion about the potential disadvantages of persistently-retained IL-12 along with solutions to circumvent the obstacles while maintaining the high therapeutic-index benefits seen with local delivery of alum-bound cytokines. Overall, our work presents strong proof-of-concept for alum as a powerful delivery vehicle for cancer immunotherapy and further work could help unlock the true potential for precise spatiotemporal control after local drug delivery. Ph.D. 2024-02-08T15:11:19Z 2024-02-08T15:11:19Z 2022-05 2024-02-02T20:56:19.076Z Thesis https://hdl.handle.net/1721.1/153465 https://orcid.org/0000-0001-7785-7828 In Copyright - Educational Use Permitted Copyright MIT http://rightsstatements.org/page/InC-EDU/1.0/ application/pdf Massachusetts Institute of Technology |
| spellingShingle | Agarwal, Yash A materials-based approach for localized delivery of cancer immunotherapy |
| title | A materials-based approach for localized delivery of cancer immunotherapy |
| title_full | A materials-based approach for localized delivery of cancer immunotherapy |
| title_fullStr | A materials-based approach for localized delivery of cancer immunotherapy |
| title_full_unstemmed | A materials-based approach for localized delivery of cancer immunotherapy |
| title_short | A materials-based approach for localized delivery of cancer immunotherapy |
| title_sort | materials based approach for localized delivery of cancer immunotherapy |
| url | https://hdl.handle.net/1721.1/153465 https://orcid.org/0000-0001-7785-7828 |
| work_keys_str_mv | AT agarwalyash amaterialsbasedapproachforlocalizeddeliveryofcancerimmunotherapy AT agarwalyash materialsbasedapproachforlocalizeddeliveryofcancerimmunotherapy |