Research ArticleCancer

Dendritic cell targeting with Fc-enhanced CD40 antibody agonists induces durable antitumor immunity in humanized mouse models of bladder cancer

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Science Translational Medicine  19 May 2021:
Vol. 13, Issue 594, eabd1346
DOI: 10.1126/scitranslmed.abd1346

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Anti-CD40 against bladder cancer

Patients with high-risk non–muscle-invasive bladder cancer can be given intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally, but this treatment is associated with high rates of resistance and recurrence. Garris et al. show that dendritic cells (DCs) in the bladder tumor microenvironment express high levels of CD40 in orthotopic mouse tumor models, consistent with human DCs. Intravesical treatment with an anti-CD40 agonist Ab induces a potent antitumor response in these mouse models that requires conventional DCs and CD8+ T cells. In addition, orthotopic mouse models expressing human CD40 and Fcγ receptors treated with a fully humanized Fc-enhanced anti-CD40 Ab showed potent antitumor responses under naïve and BCG-refractory treatment conditions, suggesting the potential for this treatment to be used clinically.

Abstract

Intravesical immunotherapy using Bacille Calmette-Guérin (BCG) attenuated bacteria delivered transurethrally to the bladder has been the standard of care for patients with high-risk non–muscle-invasive bladder cancer (NMIBC) for several decades. BCG therapy continues to be limited by high rates of disease recurrence and progression, and patients with BCG-unresponsive disease have few effective salvage therapy options besides radical cystectomy, highlighting a need for new therapies. We report that the immune-stimulatory receptor CD40 is highly expressed on dendritic cells (DCs) within the bladder tumor microenvironment of orthotopic bladder cancer mouse models, recapitulating CD40 expression by DCs found in human disease. We demonstrate that local CD40 agonism in mice with orthotopic bladder cancer through intravesical delivery of anti-CD40 agonist antibodies drives potent antitumor immunity and induces pharmacodynamic effects in the bladder tumor microenvironment, including a reduction in CD8+ T cells with an exhausted phenotype. We further show that type 1 conventional DCs (cDC1) and CD8+ T cells are required for both bladder cancer immune surveillance and anti-CD40 agonist antibody responses. Using orthotopic murine models humanized for CD40 and Fcγ receptors, we demonstrate that intravesical treatment with a fully human, Fc-enhanced anti-CD40 agonist antibody (2141-V11) induces robust antitumor activity in both treatment-naïve and treatment-refractory settings, driving long-term systemic antitumor immunity with no evidence of systemic toxicity. These findings support targeting CD40-expressing DCs in the bladder cancer microenvironment through an intravesical agonistic antibody approach for the treatment of NMIBC.

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