Long-lasting Complete Regression of Established Mouse Tumors by Counteracting Th2 Inflammation

Dai, Min; Wei, Huafeng; Yip, Yuen Yee; Feng, Qinghua; He, Kecheng; Popov, Viorica; Hellström, Ingegerd; Hellström, Karl Erik

doi:10.1097/cji.0b013e3182943549

Cited by 41 publications

(85 citation statements)

References 47 publications

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“…1). The combination of anti-4-1BB with anti-PD-1 was also more efficacious than dual combinations of anti-CLTA-4/anti-PD-1 and anti-4-1BB/anti-CTLA-4 in the ID8 model (16,17). Therefore, in at least two of the most aggressive and poorly immunogenic tumor models (ID8 and B16), anti-4-1BB/ anti-PD-1 combination appears to exhibit the strongest antitumor effect among the dual-agent combinations of several widely studied pathways (CTLA-4, PD-1, LAG-3, and 4-1BB).…”

Section: Discussionmentioning

confidence: 95%

“…Synergistic antitumor effects have been observed for combinations of anti-4-1BB with anti-TIM-3 (15) or with anti-PD-1 (16,17) in the ID8 murine ovarian cancer model. Studies on ID8 ovarian carcinoma also indicated that the anti-4-1BB/anti-PD-L1 combination had moderate impact on survival, which could be further improved with additional vaccination (18).…”

Section: Introductionmentioning

confidence: 94%

“…Modulation of stimulatory signals by 4-1BB, OX40, or GITR pathway is still in the early stages of clinical evaluation (30). In preclinical studies, combinations of immunomodulators as well as in combination with chemotherapy, targeted agents, vaccination or irradiation, have been evaluated in various models (15)(16)(17)(18)(31)(32)(33). Here, we show that the combination of anti-4-1BB with anti-PD-1 synergistically inhibited the growth of B16F10 melanoma and MC38 colon carcinoma in syngeneic C57BL/6 mice, and that the combination was reasonably well tolerated, supporting the clinical development of an anti-4-1BB/anti-PD-1 combination immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

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Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Chen

Lee

Fisher

et al. 2015

Cancer Immunology Research

236

167

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Immunotherapies targeting the programmed death 1 (PD-1) coinhibitory receptor have shown great promise for a subset of patients with cancer. However, robust and safe combination therapies are still needed to bring the benefit of cancer immunotherapy to broader patient populations. To search for an optimal strategy of combinatorial immunotherapy, we have compared the antitumor activity of the anti-4-1BB/anti-PD-1 combination with that of the anti-PD-1/anti-LAG-3 combination in the poorly immunogenic B16F10 melanoma model. Pronounced tumor inhibition occurred only in animals receiving anti-PD-1 and anti-4-1BB concomitantly, while combining anti-PD-1 with anti-LAG-3 led to a modest degree of tumor suppression. The activity of the anti-4-1BB/anti-PD-1 combination was dependent on IFNg and CD8 þ T cells. Both 4-1BB and PD-1 proteins were elevated on the surface of CD8 þ T cells by anti-4-1BB/anti-PD-1 cotreatment. In the tumor microenvironment, an effective antitumor immune response was induced as indicated by the increased CD8 þ /Treg ratio and the enrichment of genes such as Cd3e, Cd8a, Ifng, and Eomes. In the spleen, the combination treatment shaped the immune system to an effector/memory phenotype and increased the overall activity of tumor-specific CD8 þ CTLs, reflecting a long-lasting systemic antitumor response. Furthermore, combination treatment in C57BL/6 mice showed no additional safety signals, and only minimally increased severity of the known toxicity relative to 4-1BB agonist alone. Therefore, in the absence of any cancer vaccine, anti-4-1BB/anti-PD-1 combination therapy is sufficient to elicit a robust antitumor effector/memory T-cell response in an aggressive tumor model and is therefore a candidate for combination trials in patients.

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Section: Discussionmentioning

confidence: 95%

Section: Introductionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

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Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Chen

Lee

Fisher

et al. 2015

Cancer Immunology Research

236

167

View full text Add to dashboard Cite

show abstract

“…Preclinical data suggest that combined targeting of costimulatory and inhibitory immune checkpoint pathways may enhance antitumor immune responses and prolong survival and could reduce the incidence of immune-mediated AEs, including liver inflammation (16,(24)(25)(26). In summary, urelumab at 0.1 mg/kg every 3 weeks is well tolerated with evidence of immunologic activity.…”

Section: Discussionmentioning

confidence: 99%

Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody

Segal

Logan

Hodi

et al. 2017

Clinical Cancer Research

323

275

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Purpose: Urelumab is an agonist antibody to CD137 with potential application as an immuno-oncology therapeutic. Data were analyzed to assess safety, tolerability, and pharmacodynamic activity of urelumab, including the dose selected for ongoing development in patients with advanced solid tumors and lymphoma.Experimental Design: A total of 346 patients with advanced cancers who had progressed after standard treatment received at least one dose of urelumab in one of three dose-escalation, monotherapy studies. Urelumab was administered at doses ranging from 0.1 to 15 mg/kg. Safety analyses included treatmentrelated and serious adverse events (AEs), as well as treatmentrelated AEs leading to discontinuation and death, with a focus on liver function test abnormalities and hepatic AEs.Results: Urelumab doses between 1 and 15 mg/kg given every 3 weeks resulted in a higher frequency of treatment-related AEs than 0.1 or 0.3 mg/kg every 3 weeks. Dose was the single most important factor contributing to transaminitis development, which was more frequent and severe at doses 1 mg/kg. At the MTD of 0.1 mg/kg every 3 weeks, urelumab was relatively well tolerated, with fatigue (16%) and nausea (13%) being the most common treatment-related AEs, and was associated with immunologic and pharmacodynamic activity demonstrated by the induction of IFN-inducible genes and cytokines.Conclusions: Integrated evaluation of urelumab safety data showed significant transaminitis was strongly associated with doses of 1 mg/kg. However, urelumab 0.1 mg/kg every 3 weeks was demonstrated to be safe, with pharmacodynamic activity supporting continued clinical evaluation of this dose as monotherapy and in combination with other immuno-oncology agents.

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“…Previous studies have found that B cell depletion results in an increased tumor growth, 50 although it has also been shown, as in our case, to enhance survival in combination with checkpoint inhibitors. 51 …”

Section: Discusionmentioning

confidence: 99%

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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Long-lasting Complete Regression of Established Mouse Tumors by Counteracting Th2 Inflammation

Cited by 41 publications

References 47 publications

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Combination of 4-1BB Agonist and PD-1 Antagonist Promotes Antitumor Effector/Memory CD8 T Cells in a Poorly Immunogenic Tumor Model

Results from an Integrated Safety Analysis of Urelumab, an Agonist Anti-CD137 Monoclonal Antibody

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

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