IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer

Sep 24, 2026

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CD40 costimulation is a promising immunotherapy route, yet systemic CD40 agonist antibodies have shown dose-limiting toxicities and limited clinical activity. This research identifies an endogenous IL-15 contribution to CD40-mediated antitumor efficacy in orthotopic bladder tumors, driven by transpresented IL-15/IL-15Rα surface complexes enriched with activated CD8 T cells. In patient samples, dendritic cells provide IL-15 while lacking IL-15Rα baseline expression. Humanized orthotopic bladder tumor models show that combining anti-CD40 agonist antibodies with exogenous IL-15, including the clinical Fc-optimized antibody 2141-V11, therapeutically augments this interaction, supporting IL-15-based rational combinations for bladder cancer patients.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Introduction

Significance

Methods and Data Sources

Author Contributions and Affiliations

RESEARCH ARTICLE IMMUNOLOGY AND INFLAMMATION OPEN ACCESS IL-15 synergizes with CD40 agonist antibodies to induce durable immunity against bladder cancer Jeffrey L. Wonga, b,1, Patrick Smitha, Juan Angulo-Lozanoa, Daniel Rantic,d, Bernard H. Bochnere, John P. Sfakianosf, Amir Horowitzc,d, Jeffrey V. Ravetcha,2, and David A. Knorra, b,2,3 Contributed by Jeffrey V. Ravetch; received April 26, 2023; accepted July 14, 2023; reviewed by Alan J. Korman and Diane Mathis CD40 is a central costimulatory receptor implicated in productive antitumor immune responses across multiple cancers, including bladder cancer. Despite strong preclinical rationale, systemic administration of therapeutic agonistic antibodies targeting the CD40 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, including rational combination therapy strategies. Here, we describe a role for the endogenous IL-15 pathway in contributing to the therapeutic activity of CD40 agonism in orthotopic bladder tumors, with upregulation of transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment of activated CD8 T cells. In bladder cancer patient samples, we identify DCs as the primary source of IL-15, although they lack high levels of IL-15Rα at baseline. Using humanized immunocompetent orthotopic bladder tumor models, we demonstrate the ability to therapeutically augment this interaction through combined treatment with anti-CD40 agonist antibodies and exogenous IL-15, includingthe fully-human Fc-optimized antibody 2141-V11 currently in clinical development for the treatment of bladder cancer. Collectively, these data reveal an important role for IL-15 in mediating antitumor CD40 agonist responses in bladder cancer and provide key proof-of-concept for combined use ofFc-optimized anti-CD40 agonist antibodies and agents targeting the IL-15 pathway. These data support expansion of ongoing clinical studies evaluating anti-CD40 agonist antibodies and IL-15-based approaches to develop combinations of these promising therapeutics for the treatment of patients with bladder cancer. CD40 | FcγRIIB inhibitory receptor | nonmuscle invasive bladder cancer | immunotherapy | dendritic cells CD40, a member of the tumor necrosis factor superfamily of receptors, plays a central costimulatory role in both innate and adaptive immunity, serving as a proximal regulator of the adaptive immune cascade driving the development of antigen-specific T cell responses (1) . Evidence across multiple preclinical models for the ability of CD40 activation to induce robust antitumor responses (2), as well as the association of CD40 expression with improved clinical outcomes and markers of type I immunity in pan-cancer human tumor analyses (3), have provided strong rationale for the clinical development of CD40 agonist approaches for cancer therapy, including agonistic anti-CD40 antibodies. Despite this promise, however, the clinical activity reported to date for these agents, particularly as systemic monotherapy, has been disappointing (2, 4), with transaminitis and thrombocytopenia reported at doses of 0.2 mg/kg, thus limiting the ability to achieve therapeutic doses for evaluation. These prior studies highlight an important need for continued optimization of current CD40-targeted therapies. We and others have previously implicated CD40 as an important pathway in the context of bladder cancer (5–9), a disease area of significant unmet clinical need with an estimated 550,000 new cases and nearly 200,000 disease-associated deaths annually worldwide (10). Using humanized orthotopic bladder cancer murine models, we have also recently identified the ability to substantially enhance therapeutic antitumor immune responses through the use of novel agonistic anti-CD40 antibodies engineered for optimal engagement of

FAQs

Why are CD40 agonist antibodies challenging in clinical use?

Systemic administration has shown dose-limiting toxicities and minimal clinical activity, including reports such as transaminitis and thrombocytopenia that limit achievable therapeutic dosing.

How does IL-15 contribute to CD40 agonist responses in bladder cancer?

The study links the endogenous IL-15 pathway to CD40-mediated antitumor activity via upregulated transpresented IL-15/IL-15Rα surface complexes and enrichment of activated CD8 T cells.

What combination strategy does the research support for patients?

It supports rational combination use of Fc-optimized anti-CD40 agonist antibodies (including 2141-V11) with IL-15-based approaches to enhance efficacy in nonmuscle invasive bladder cancer.

Sep 24, 2026

Uploaded by Bintang