Locally delivered CD40 agonist antibody accumulates in secondary lymphoid organs and eradicates experimental disseminated bladder cancer
2014 (English)In: Cancer Immunology Research, ISSN 2326-6066, Vol. 2, no 1, 80-90 p.Article in journal (Refereed) Published
Immunotherapy with intratumoral injection of adenoviral vectors expressing CD40L has yielded positive results in experimental and clinical bladder cancer. We therefore hypothesized that anti-CD40 antibody would be effective in this setting. Agonistic CD40 antibodies were developed as vaccine adjuvants but have later been used as treatment for advanced solid tumors and hematological cancers. Systemic anti-CD40 therapy has been associated with immune-related adverse events such as cytokine release syndrome and liver toxicity and local delivery is an attractive approach that could reduce toxicity. Herein, we compared local and systemic anti-CD40 antibody delivery to evaluate efficacy, toxicity and biodistribution in the experimental MB49 bladder cancer model. Anti-tumor effects were confirmed in the B16 model. In terms of anti-tumor efficacy, local anti-CD40 antibody stimulation was superior to systemic therapy at an equivalent dose and CD8 T-cells were crucial for tumor growth inhibition. Both administration routes were dependent on host CD40 expression for therapeutic efficacy. In vivo biodistribution studies revealed CD40-specific antibody accumulation in tumor-draining lymph nodes and spleen, most likely reflecting organs with frequent target antigen-expressing immune cells. Systemic administration led to higher antibody concentrations in liver and blood compared to local delivery, and was associated with elevated levels of serum haptoglobin. Despite the lack of a slow-release system, local anti-CD40 therapy was dependent on tumor antigen at the injection site for clearance of distant tumors. To summarize, local low-dose administration of anti-CD40 antibody mediates anti-tumor effects in murine models with reduced toxicity and may represent an attractive treatment alternative in the clinic.
Place, publisher, year, edition, pages
2014. Vol. 2, no 1, 80-90 p.
Immunology in the medical area
IdentifiersURN: urn:nbn:se:uu:diva-209738DOI: 10.1158/2326-6066.CIR-13-0067ISI: 000340030900010PubMedID: 24778163OAI: oai:DiVA.org:uu-209738DiVA: diva2:659313