Abstract
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Objectives: ytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a checkpoint inhibitor expressed on the surface of activated T-cells which interacts with tumor antigen-presenting cells to suppress the activation of T-cells in tumor draining lymph nodes (LNs). Systemic intravenous administration of anti-CTLA-4 antibody has been shown to have modest to minimal anti-tumor activity in several non-immunogenic tumor models. Clinically, anti-CTLA-4 alone or in combination with other therapeutic agents is effective in patients with Stage III and IV melanoma. However, systemic administration of anti-CTLA-4 is associated with frequent and severe immune-related adverse events (irAEs) making it cost-ineffective (Oh et al., J Manag Care Spec Pharm, 2017). Previously, we have shown that a nanotopography microneedle device (termed SOFUSATM) can effectively deliver therapeutic antibodies into the lymphatics with significant benefit over systemic administration (Aldrich, et al., Arthritis. Res. Ther., 2017). In this study, we hypothesized that lymphatic delivery can maximize drug exposure to anti-CTLA-4 in tumor-draining LNs and improve anti-tumor response, especially in non-immunogenic cancers. Herein, we employed near-infrared fluorescence (NIRF) imaging of lymphatics and bioluminescence imaging of cancer metastasis in the orthotopic non-immunogenic model of 4T1-luc to investigate the anti-tumor response associated with lymphatic delivery. While mouse models fail to predict irAEs, our goal is to show tumor response to formulate a pathway for translation of lymphatically delivered immunotherapeutics that could mitigate irAEs in humans. Results show that lymphatic delivery of 10 mg/kg anti-CTLA-4 as a monotherapy on days 11, 15, 19, and 23 post-implant significantly decreased tumor growth after 19 days and ameliorated LN metastases in a 4T1 tumor that is otherwise nonresponsive to systemic administration of anti-CTLA-4. While further studies are underway, these initial imaging results suggest that lymphatic delivery of anti-CTLA-4 to tumor draining LNs could improve anti-tumor efficacy and potentially mitigate irAEs associated with systemic administration which induces non-tumor antigen activation of T-cells. Furthermore, these studies suggest that if irAEs could be mitigated, immunotherapeutics could be used at earlier stages of disease to arrest metastasis and improve cancer survival. Supported by Kimberly-Clark Corporation. Figure Caption: Example mouse with orthotopic 4T1-luc (A) 16 days p.i. and (B) after 30 days p.i. and SOFUSATM delivered anti-CTLA-4 therapy. (C) Corresponding control animal shows large primary tumor size and LN metastases (arrow). Accumulated data shows significant reduction (after day 15) in tumor volume with SOFUSATM delivered anti-CTLA-4.