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

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.

Imaging peripheral lymphatic dysfunction in chronic conditions

“…With systemic administration, the immune system may be over-stimulated and dosing can result in autoimmunity and subsequent autoimmune disease. Indeed, in studies involving microneedle delivery of anti-CTLA-4 in an orthotopic mouse model of head and neck cancer, Gutkind and coworkers ( Gilardi et al, 2022 ) showed anti-tumor responses at doses significantly lower than that needed using systemic administration. Additionally, the lower lymphatic dose reduced the lymphocyte infiltration of normal tissues that characterizes the immune related adverse events (irAEs) often suffered by cancer patients.…”

Microneedle-mediated treatment for superficial tumors by combining multiple strategies

“…MN-assisted delivery of DNA vaccines [ 89 , 128 , 129 ], tumor cell lysates [ 130 , 131 ], immune adjuvants required for immunotherapy, or immune checkpoint inhibitors [ 71 , 132 ] has also been developed for the treatment of superficial tumors. Subunit vaccines are an ideal choice for immunotherapy due to their good biosafety.…”

PD-1 inhibitor therapy causes multisystem immune adverse reactions: a case report and literature review

“…Using a mouse model of HNSCC, Gilardi M team developed a novel, local delivery strategy based upon an array of soluble microneedles (MN). Local-MN delivery of anti-CTLA-4 in vivo can protect animals from irAEs observed, but this process relies on CD8 T cells and conventional dendritic cell type 1 (cDC1) (64). Additionally, the 3D culture models of the tumorpromoting microenvironment in vitro will contribute to a comprehensive understanding of the mechanisms of malignant metastasis in vivo and facilitate the development of novel anti-tumour drugs (65,66).…”