Abstract B103: Intralesional administration of CTLA-4 blocking monoclonal antibodies as a means to optimize bladder cancer therapy
Authors: Hooren Luuk van , Sandin Linda , Moskalev Igor , Ellmark Peter , Dimberg Anna , Black Peter , Tötterman Thomas H. , Mangsbo Sara M. 
Published: November 2016

Abstract
CTLA-4 blockade as well as CD40 agonistic therapy comes with adverse events when administrated systemically to patients. Whereas anti-CD40 therapy is associated with both cytokine release and liver toxicity, CTLA-4 blockade leads to auto-immune manifestations. Cytokine release affects the maximum tolerated dose (MTD) for anti-CD40, thereby hampering anti-tumor responses. Whereas patients with localized bladder cancer respond to immunotherapy in the form of BCG, they suffer high relapse frequencies and toxicity. Patients with a more advanced disease have a poor prognosis due to relapses, and not all patients are fit to undergo radical cystectomy, mainly due to age, underlying diseases and health status. There is also a high tumor recurrence (50% of cystectomy patients relapse with local or metastatic tumor growth). We believe these patients could benefit from local immunotherapy similar to BCG instillations, but focusing on strengthening the adaptive immune response rather than the innate. In solid cancer where an accessible tumor lesion is available, monoclonal antibody therapies targeting our immune cells can be administrated intralesionally (1). In a preclinical bladder cancer model we show that both anti-CD40 and anti-CTLA-4 therapy can be used in a lower dose with a peritumoral injection route (2, 3 and current work). Local anti-CD40 therapy partly limits systemic spread of the antibody and the efficacy is dependent on the presence of tumor antigens at the site of the location. CD8+ T cells are the main effectors cells causing tumor regression (3). Herein we initially assessed standard orthotopic instillation of CTLA-4 directed antibody therapy, but drug uptake was poor despite pre-conditioning with clorpactin. As an alternative we slightly modified our existing MB49 syngeneic tumor model based (by injecting tumor cells into the submucosal space of the anterior bladder wall), and made use of ultrasound-guided intratumoral anti-CTLA-4 antibody treatment. The results show tumor regression followed by a more than 10-fold reduction in systemic antibody levels as compared to intravenous administration, in line with the compartmentally restrained nature of the bladder. In addition, local anti-CTLA-4 therapy, when complemented by systemic anti-PD1 therapy for subcutaneously growing tumors, demonstrated CR in 7/8 animals, superior to each therapy alone. Our results demonstrate that local anti-CTLA-4 antibody therapy is equally effective as systemic administration, but reduces systemic antibody levels and that its combination with anti-PD1 therapy displays superior outcome. The clinical use of spasm-relieving injections in the bladder illustrates the feasibility to perform injections in clinical routine, and intralesional injections of a check-point inhibitor prior to surgery could boost the adaptive immune response and decrease relapse frequencies without the risk of adverse events delaying a planned surgery. 1. NCT02379741 (clinicaltrials.gov June 2016) 2. Sandin et al. Cancer Immunol Res. 2014 Jan;2(1) 3. Mangsbo et al. Clin Cancer Res. 2015 Mar 1;21(5)
Citation Format: Luuk van Hooren, Linda Sandin, Igor Moskalev, Peter Ellmark, Anna Dimberg, Peter Black, Thomas H. Tötterman, Sara M. Mangsbo. Intralesional administration of CTLA-4 blocking monoclonal antibodies as a means to optimize bladder cancer therapy [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr B103.