American Association for Cancer Research
Browse
mct-21-0234_supplementary_data_supp0.pdf (776.83 kB)

Supplementary Data from Microneedle-mediated Intratumoral Delivery of Anti-CTLA-4 Promotes cDC1-dependent Eradication of Oral Squamous Cell Carcinoma with Limited irAEs

Download (776.83 kB)
journal contribution
posted on 2023-04-03, 18:44 authored by Mara Gilardi, Robert Saddawi-Konefka, Victoria H. Wu, Miguel Angel Lopez-Ramirez, Zhiyong Wang, Fernando Soto, Dana J. Ramms, Marco Proietto, Zbigniew Mikulski, Haruka Miki, Andrew Sharabi, Daniel Kupor, Ricardo Rueda, Daniel P. Hollern, Joseph Wang, J. Silvio Gutkind
Supplementary Data from Microneedle-mediated Intratumoral Delivery of Anti-CTLA-4 Promotes cDC1-dependent Eradication of Oral Squamous Cell Carcinoma with Limited irAEs

Funding

NCI

NIDCR

NIH

Salk Cancer center pilot award

History

ARTICLE ABSTRACT

Head and neck squamous cell carcinoma (HNSCC) ranks sixth in cancer incidence worldwide and has a 5-year survival rate of only 63%. Immunotherapies—principally immune checkpoint inhibitors (ICI), such as anti-PD-1 and anti-CTLA-4 antibodies that restore endogenous antitumor T-cell immunity—offer the greatest promise for HNSCC treatment. Anti-PD-1 has been recently approved for first-line treatment of recurrent and metastatic HNSCC; however, less than 20% of patients show clinical benefit and durable responses. In addition, the clinical application of ICI has been limited by immune-related adverse events (irAE) consequent to compromised peripheral immune tolerance. Although irAEs are often reversible, they can become severe, prompting premature therapy termination or becoming life threatening. To address the irAEs inherent to systemic ICI therapy, we developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Using our recently reported syngeneic, tobacco-signature murine HNSCC model, we found that both systemic and local-MN anti-CTLA-4 therapy lead to >90% tumor response, which is dependent on CD8 T cells and conventional dendritic cell type 1 (cDC1). However, local-MN delivery limited the distribution of anti-CTLA-4 antibody from areas distal to draining lymphatic basins. Employing Foxp3-GFPDTR transgenic mice to interrogate irAEs in vivo, we found that local-MN delivery of anti-CTLA-4 protects animals from irAEs observed with systemic therapy. Taken together, our findings support the exploration of MN-intratumoral ICI delivery as a viable strategy for HNSCC treatment with reduced irAEs, and the opportunity to target cDC1s as part of multimodal treatment options to boost ICI therapy.

Usage metrics

    Molecular Cancer Therapeutics

    Categories

    Keywords

    Licence

    Exports

    RefWorks
    BibTeX
    Ref. manager
    Endnote
    DataCite
    NLM
    DC