A materials-based approach for localized delivery of cancer immunotherapy
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agarwal-yashag-phd-be-2022-thesis copy.pdf
Description
Thesis PDF
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16.72 MB
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Adobe PDF
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Author(s)
Agarwal, Yash
Advisor(s)
Irvine, Darrell J.
Wittrup, K. Dane
Date Issued
May 2022
Publisher
Massachusetts Institute of Technology
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.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
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