CD40 agonists alter tumor stroma and show efficacy against pancreatic carcinoma in mice and humans

GL Beatty, EG Chiorean, MP Fishman, B Saboury… - Science, 2011 - science.org
GL Beatty, EG Chiorean, MP Fishman, B Saboury, UR Teitelbaum, W Sun, RD Huhn…
Science, 2011science.org
Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly
in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune
suppression and drive antitumor T cell responses, we tested the combination of an agonist
CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically
incurable PDA and observed tumor regressions in some patients. We reproduced this
treatment effect in a genetically engineered mouse model of PDA and found unexpectedly …
Immunosuppressive tumor microenvironments can restrain antitumor immunity, particularly in pancreatic ductal adenocarcinoma (PDA). Because CD40 activation can reverse immune suppression and drive antitumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in a small cohort of patients with surgically incurable PDA and observed tumor regressions in some patients. We reproduced this treatment effect in a genetically engineered mouse model of PDA and found unexpectedly that tumor regression required macrophages but not T cells or gemcitabine. CD40-activated macrophages rapidly infiltrated tumors, became tumoricidal, and facilitated the depletion of tumor stroma. Thus, cancer immune surveillance does not necessarily depend on therapy-induced T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting tumor stroma in the treatment of cancer.
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