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

• DOI: 10.1073/pnas.2306782120
• Publication Date: 2023-08-22T17:59:29Z
• Authors: Jeffrey L. Wong; Patrick Smith; Juan Angulo-Lozano; Daniel Ranti; Bernard H. Bochner; John P. Sfakianos; Amir Horowitz; Jeffrey V. Ravetch; David A. Knorr
• Keywords: Interleukin-15; 0301 basic medicine; Urinary Bladder; Antibodies, Monoclonal; Biological Sciences; Combined Modality Therapy; Article; 3. Good health; Immunoglobulin Fc Fragments; 03 medical and health sciences; Urinary Bladder Neoplasms; Humans; CD40 Antigens

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 pathway has demonstrated dose-limiting toxicities with minimal clinical activity, emphasizing an important need for optimized CD40-targeted approaches, rational combination therapy strategies. Here, we describe role endogenous IL-15 contributing to activity agonism orthotopic tumors, upregulation transpresented IL-15/IL-15Rα surface complexes, particularly by cross-presenting conventional type 1 DCs (Dendritic Cells), and associated enrichment activated CD8 T cells. In cancer patient samples, identify as primary source IL-15, although they lack high levels IL-15Rα at baseline. Using humanized immunocompetent tumor models, demonstrate ability therapeutically augment this interaction through combined treatment anti-CD40 agonist exogenous fully-human Fc-optimized antibody 2141-V11 currently development Collectively, these data reveal mediating provide key proof-of-concept use agents pathway. These support expansion ongoing studies evaluating IL-15-based approaches develop combinations promising therapeutics patients