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.