Effects of direct lymphatic delivery of anti-CTLA-4 on tumor growth and metastases of murine breast cancer
Sunkuk Kwon1, Christian Fred Velasquez1, Russell F. Ross2, Eva M. Sevick-Muraca1*
1Brown Foundation of Institute of Molecular Medicine, University of Texas Health Science Center at Houston; 2Kimberly Clark Cooperation, Atlanta, GA
Despite important clinical benefits, systemic administration of immune checkpoint blocking antibodies often result in off-target toxicities (i.e., severe immune-related adverse events, iRAes) by inappropriately activating naïve-T cells in distant lymph nodes (LNs) and other lymphoid tissues where non-tumor, self-antigens rather than tumor antigens are presented. Efficient direct delivery of checkpoint inhibitors into the regional lymphatics could provide maximal drug exposure to targets within tumor-draining LN basins and their efferent lymphatic vessels before emptying into the blood vasculature for systemic delivery to the tumor.
In this study, we used a novel, infusion device, SOFUSATM, consisting of a 66 mm2 microneedle array with a 6 micron polyether ketone nanotopographical film heat-formed over each microneedle to infuse therapeutic doses into the lymphatics in mice. 4T1 mouse mammary tumor cells transfected with luciferase (4T1-luc) were injected into the mammary fat pad of BALB/C mice. Anti-(cytotoxic T-lymphocyte-associated protein-4 (CTLA-4) antibody (10mg/kg) was administered on days 9, 13, 17, and 21 via SOFUSATM. SOFUSATM infusion occurred on the right dorsal back. Results show that when anti-mCTLA-4 was delivered lymphatically via SOFUSATM, significant tumor shrinkage occurred when compared to the untreated group and the group of mice treated with conventional intraperitoneal administrations. Bioluminescence imaging data showed no lymph node and distant organ metastases in mice dosed with SOFUSATM as compared to the untreated mice and mice with intraperitoneal treatment, both of which showed LNs, lung, or liver metastases. Whether regional lymphatic delivery can more effectively treat metastatic disease and reduce immune related events will need further investigation. If proven true, then regionally delivered immunotherapies with limited or reduced iRAes, could be moved to “first-line” loco-regional, cancer treatment.
Supported in parts by Kimberly-Clark Corporation and the National Institutes of Health (R21 - Sunkuk's past grant).