{"id":{"repo_id":"mit","oai_identifier":"oai:dspace.mit.edu:1721.1/153465"},"canonical_url":"https://search.dev.ndltd.org/etd/mit/oai:dspace.mit.edu:1721.1/153465","repository":{"repo_id":"mit","name":"MIT","base_url":"https://dspace.mit.edu/oai/request"},"display":{"title":"A materials-based approach for localized delivery of cancer immunotherapy","abstract":"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.","abstract_html":"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.","abstract_has_math":false,"creators":["Agarwal, Yash"],"institution":"Massachusetts Institute of Technology","degree_name":"Doctoral","degree_level":null,"degree_discipline":null,"degree_department":"Massachusetts Institute of Technology. Department of Biological Engineering","school":null,"contributors":[],"advisors":["Irvine, Darrell J.","Wittrup, K. Dane"],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-05","date_published":"2022-05","updated_at":"2026-07-22T22:21:43Z","subjects":[],"languages":[],"rights":["In Copyright - Educational Use Permitted","Copyright MIT"],"rights_urls":["http://rightsstatements.org/page/InC-EDU/1.0/"],"identifier_entries":[]},"links":{"outbound_url":"https://hdl.handle.net/1721.1/153465","outbound_label":"Handle","outbound_source":"dc:identifier.uri"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor.advisor","label":"Advisor","values":["Irvine, Darrell J.","Wittrup, K. Dane"]},{"key":"dc:contributor.department","label":"Department","values":["Massachusetts Institute of Technology. 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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."]},{"key":"dc:description.degree","label":"Dc Description Degree","values":["Ph.D."]},{"key":"dc:title","label":"Title","values":["A materials-based approach for localized delivery of cancer immunotherapy"]}]}],"canonical_facts":{"dc:contributor.advisor":["Irvine, Darrell J.","Wittrup, K. Dane"],"dc:contributor.department":["Massachusetts Institute of Technology. Department of Biological Engineering"],"dc:creator":["Agarwal, Yash"],"dc:date.accessioned":["2024-02-08T15:11:19Z"],"dc:date.available":["2024-02-08T15:11:19Z"],"dc:date.issued":["2022-05"],"dc:description.abstract":["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. 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