CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

Beatty, Gregory L.; Chiorean, E. Gabriela; Fishman, Matthew P.; Saboury, Babak; Teitelbaum, Ursina R.; Sun, Weijing; Huhn, Richard D.; Song, Wenru; Li, Dongguang; Sharp, Leslie L.; Torigian, Drew A.; O’Dwyer, Peter J.; Vonderheide, Robert H.

doi:10.1126/science.1198443

Cited by 1,412 publications

(1,390 citation statements)

References 23 publications

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“…22 As has been reported for other sites, 41-43 we observed that the peritoneal administration of IL-33 was able to promote an allergic like macrophage activation in the peritoneal tumor-associated macrophages. As reported previously for CD40 activated CD86 + activated macrophages in the microenvironment of pancreatic cancer, 44 or activated peritoneal macrophages were able to promote tumor cytotoxicity in vitro and delay tumor progression in vivo. Additionally, IL-33 activated macrophages significantly decreased the expression of IL-10, an immunosuppressive cytokine that is normally high in tumor-associated ascites and associated with unfavorable prognoses.…”

Section: Discusionsupporting

confidence: 78%

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

et al. 2018

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Ovarian cancer is frequently diagnosed as peritoneal carcinomatosis. Unlike other tumor locations, the peritoneal cavity is commonly exposed to gut-breaching and ascending genital microorganisms and has a unique immune environment. IL-33 is a local cytokine that can activate innate and adaptive immunity. We studied the effectiveness of local IL-33 delivery in the treatment of cancer that has metastasized to the peritoneal cavity. Direct peritoneal administration of IL-33 delayed the progression of metastatic peritoneal cancer. Prolongation in survival was not associated with a direct effect of IL-33 on tumor cells, but with major changes in the immune microenvironment of the tumor. IL-33 promoted a significant increase in the leukocyte compartment of the tumor immunoenvironment and an allergic cytokine profile. We observed a substantial increase in the number of activated CD4+ T-cells accompanied by peritoneal eosinophil infiltration, B-cell activation and activation of peritoneal macrophages which displayed tumoricidal capacity. Depletion of CD4+ cells, eosinophils or macrophages reduced the anti-tumor effects of IL-33 but none of these alone were sufficient to completely abrogate its positive benefit. In conclusion, local administration of IL-33 generates an allergic tumor environment resulting in a novel approach for treatment of metastatic peritoneal malignancies, such as advanced ovarian cancer.

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Section: Discusionsupporting

confidence: 78%

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

et al. 2018

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“…Prior clinical trials of single-agent agonistic CD40 mAb, or CD40 mAb in combination with chemotherapy, have demonstrated clinical activity. 7,11–13,15,21 In a previous trial, 4 patients among 15 with advanced melanoma had a PR to a single dose of the CD40 mAb CP-870,893. 7 Potential synergy of CD40 activation and CTLA-4 blockade has been established in mouse tumor models, 6 but this study is the first to test this hypothesis in patients.…”

Section: Discussionmentioning

confidence: 99%

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

et al. 2018

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We report long-term clinical outcomes and immune responses observed from a phase 1 trial of agonist CD40 monoclonal antibody (mAb) and blocking CTLA-4 mAb in patients with metastatic melanoma. Twenty-four patients previously untreated with checkpoint blockade were enrolled. The agonistic CD40 mAb CP-870,893 and the CTLA-4 blocking mAb tremelimumab were dosed concomitantly every 3 weeks and 12 weeks, respectively, across four dose combinations. Two patients developed dose-limiting grade 3 immune-mediated colitis that led to the definition of the maximum tolerated dose (MTD). Other immune-mediated toxicity included uveitis (n = 1), hypophysitis (n = 1), hypothyroidism (n = 2), and grade 3 cytokine release syndrome (CRS) (n = 1). The estimated MTD was 0.2 mg/kg of CP-870,893 and 10 mg/kg of tremelimumab. In 22 evaluable patients, the objective response rate (ORR) was 27.3%: two patients (9.1%) had complete responses (CR) and four (18.2%) patients had partial responses (PR). With a median follow-up of 45 months, the median progression-free survival (PFS) was 3.2 months (95% CI, 1.3–5.1 months) and median overall survival (OS) was 23.6 months (95% CI, 11.7–35.5 months). Nine patients are long-term survivors (> 3 years), 8 of whom subsequently received other therapy including PD-1 mAb, surgery, or radiation therapy. Elevated baseline soluble CD25 was associated with shorter OS. Immunologically, treatment was associated with evidence of T cell activation and increased tumor T cell infiltration that was accomplished without therapeutic PD-1/PD-L1 blockade. These results suggest opportunities for immune activation and cancer immunotherapy beyond PD-1.

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“…The TAM phenotype is reversible and these cells can be re-educated to exert antitumor activity [41][42][43]. In a recent study [44], anti-CD40 antibodies with agonist activity have been shown to have antitumor potential in both murine and human carcinoma of the pancreas. Circumstantial evidence suggests that the anti-tumor activity of CD40 agonist antibodies is mediated by macrophage activation.…”

Section: Therapeutic Targetingmentioning

confidence: 99%

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

et al. 2011

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Tumor‐associated macrophages (TAMs) are key components of the tumor macroenvironment. Cancer‐ and host cell‐derived signals generally drive the functions of TAMs towards an M2‐like polarized, tumor‐propelling mode; however, when appropriately re‐educated. TAMs also have the potential to elicit tumor destructive reactions. Here, we discuss recent advances regarding the immunobiology of TAMs and highlight open questions including the mechanisms of their accumulation (recruitment versus proliferation), their diversity and how to best therapeutically target these cells.

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CD40 Agonists Alter Tumor Stroma and Show Efficacy Against Pancreatic Carcinoma in Mice and Humans

Cited by 1,412 publications

References 23 publications

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

IL-33 delays metastatic peritoneal cancer progression inducing an allergic microenvironment

Long-term outcomes of a phase I study of agonist CD40 antibody and CTLA-4 blockade in patients with metastatic melanoma

Cancer‐promoting tumor‐associated macrophages: New vistas and open questions

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