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• W2330572955 abstract "Pancreatic ductal adenocarcinoma (PDA) is an almost uniformly lethal disease for which novel effective therapies are critically needed. Although immunotherapy offers a distinct and promising therapeutic approach, the ability of pancreas carcinoma to orchestrate immune suppression represents a significant clinical obstacle. Previous studies to model pancreatic tumor immune responses in mice have been limited by the use of implantable tumor models or non-PDA tumors of islet cells. To circumvent these obstacles, we have evaluated immune surveillance in PDA using a genetically engineered mouse (GEM) model of this disease in which endogenous expression of Kras G12D and Trp53 R172H is targeted to the pancreas of immune competent mice and for which the salient clinical, histopathologic, and molecular features of the human disease are strikingly recapitulated. In this ‘KPC’ model, progression to PDA is intimately associated with a suppressive immune reaction, particularly in the myeloid compartment, such that adaptive anti-tumor immunity is essentially non-existent. Because CD40 activation can reverse immune suppression and drive potent anti-tumor T cell responses, we tested the combination of an agonist CD40 antibody with gemcitabine chemotherapy in the KPC model. We observed tumor regression in 30% of mice and found further 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. T cells, as expected, were activated following CD40 therapy but never infiltrate the tumor. Based on these preclinical findings, we performed a clinical study to test the hypothesis that CD40 activation in humans can cooperate with chemotherapy for the treatment of chemotherapy-naive, surgically incurable PDA. Twenty-one patients (90% with metastatic disease) received gemcitabine weekly on days 1, 8, and 15 with the agonist CD40 mAb CP-870,893 (Pfizer) administered on day 3 of each 28 day cycle. Treatment was well-tolerated overall, and the most common side effect was mild-to-moderate cytokine release syndrome managed in the outpatient clinic. Metabolic responses were observed by FDG-PET/CT in both the primary and metastatic lesions in 88% of patients evaluated after 2 cycles of therapy. By RECIST, 5 of 21 patients developed a partial response. Thus, productive cancer immune surveillance does not necessarily depend on T cells; rather, our findings demonstrate a CD40-dependent mechanism for targeting cancer-associated inflammation in the treatment of cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr SY40-01. doi:1538-7445.AM2012-SY40-01" @default.
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• W2330572955 date "2012-04-15" @default.
• W2330572955 modified "2023-09-27" @default.
• W2330572955 title "Abstract SY40-01: Anti-CD40 as an anticancer agent" @default.
• W2330572955 doi "https://doi.org/10.1158/1538-7445.am2012-sy40-01" @default.
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