Abstract
Immunotherapy against tumors with anti-CD40 agonistic antibodies has been extensively studied in preclinical animal models and recently also in clinical trials. Although promising results have been obtained, antibody (Ab)-related toxicity has been a limiting factor. We reasoned that strict local activation of tumor-specific CD8 T cells through stimulation of CD40 on the dendritic cells (DC) in the tumor area while excluding systemic stimulation might be sufficient for effective tumor eradication and can limit systemic toxicity. Preclinical in vivo models for immunogenic tumors were used to investigate the potential of delivering a nontoxic dose of agonistic anti-CD40 Ab to the tumor region, including draining lymph node, in a slow-release formulation (montanide). The delivery of anti-CD40 monoclonal Ab, formulated in slow-release Montanide ISA-51, reprograms CTLs by inducing local but not systemic DC activation, resulting in effective tumor-specific CTL responses that eradicate local and distant tumors. Adverse side effects, assayed by organ histology and liver enzymes in the blood, were much lower after local anti-CD40 Ab delivery than systemic administration. The local delivery of anti-CD40 Ab activates only CTLs against antigens presented in the tumor-draining area, because unrelated distant tumors expressing different tumor antigens were not eradicated. These results establish a novel therapeutic principle that local delivery and slow release of agonistic anti-CD40 Ab to the tumor-draining area effectively activates local tumor-specific CD8 T cells to become systemic effectors without causing systemic toxicity or nonspecific CTL activation. These findings have important implications for the use of anti-CD40 therapies in patients.
Highlights
CD8þ T cells (CTLs) recognize and kill specific target cells on the basis of their T-cell receptors that are selected to recognize antigens presented by MHC class I molecules [1]
The local delivery of anti-CD40 Ab activates only CTLs against antigens presented in the tumor-draining area, because unrelated distant tumors expressing different tumor antigens were not eradicated
One of the reasons for this phenomenon is that dendritic cells (DC), which cross-present the tumor antigens in tumor-draining lymph nodes (LN), are poorly activated because of a lack of danger signals and insufficient
Summary
CD8þ T cells (CTLs) recognize and kill specific target cells on the basis of their T-cell receptors that are selected to recognize antigens presented by MHC class I molecules [1]. Since many tumors express aberrant antigens, CD8þ T cells have the potential to eradicate these tumors [2,3,4]. One of the reasons for this phenomenon is that dendritic cells (DC), which cross-present the tumor antigens in tumor-draining lymph nodes (LN), are poorly activated because of a lack of danger signals and insufficient. Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). Methods to effectively activate those DCs and thereby enhance the antitumor CTL response may provide significant improvement for the treatment of cancer
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