Phase I study of BMS-663513, a fully human anti-CD137 agonist monoclonal antibody, in patients (pts) with advanced cancer (CA)

Sznol, Mario; Hodi, F. Stephen; Margolin, Kim; McDermott, David F.; Ernstoff, Marc S.; Kirkwood, John M.; Wojtaszek, C.; Feltquate, David; Logan, Theodore F.

doi:10.1200/jco.2008.26.15_suppl.3007

Cited by 177 publications

(124 citation statements)

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“…These findings were observed with similar severity in the anti-4-1BB-alone treatment arms and have been described previously with another mouse-reactive anti-4-1BB (44). The human relevance of the mouse findings is apparent in a previous report listing neutropenia and transaminitis as two of the most common adverse events in a phase I trial of a 4-1BB agonist antibody in patients with cancer (45). The most notable combination effect in the mouse study was the synergistic decrease in peripheral lymphocytes observed at the 1-mg/kg dose of anti-4-1BB in combination with anti-PD-1.…”

Section: Discussionsupporting

confidence: 83%

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

231

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: Discussionsupporting

confidence: 83%

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

231

167

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“…For example, BMS-666513, a fully humanized mAb against 4-1BB, has completed phase I and II trials for its anticancer properties in patients with melanoma, renal cell carcinoma, and ovarian cancer (74). The results thus far suggest that the Ab therapy is well tolerated across various dose ranges (0.3-15 mg/kg body weight given every 3 weeks).…”

Section: Activation Of the 4-1bb Pathway In Human Immunotherapy Trialsmentioning

confidence: 99%

“…The results thus far suggest that the Ab therapy is well tolerated across various dose ranges (0.3-15 mg/kg body weight given every 3 weeks). Biomarker analysis revealed elevated expression of IFN-inducible genes in peripheral blood and in posttreatment biopsies of patients receiving BMS-666513 (74). However, 6% to 15% of the patients developed grade 3 or higher neutropenia and liver enzymes, mild fatigue, rash, pruritus, diarrhea, and fever (74).…”

Section: Activation Of the 4-1bb Pathway In Human Immunotherapy Trialsmentioning

confidence: 99%

“…Biomarker analysis revealed elevated expression of IFN-inducible genes in peripheral blood and in posttreatment biopsies of patients receiving BMS-666513 (74). However, 6% to 15% of the patients developed grade 3 or higher neutropenia and liver enzymes, mild fatigue, rash, pruritus, diarrhea, and fever (74). In future trials, it will be important to determine the dose ranges of anti-4-1BB that are safe and effective.…”

Section: Activation Of the 4-1bb Pathway In Human Immunotherapy Trialsmentioning

confidence: 99%

See 1 more Smart Citation

Immunotherapy of Cancer with 4-1BB

Vinay

Kwon²

2012

Molecular Cancer Therapeutics

161

130

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4-1BB (CD137), a member of the TNF receptor superfamily, is an activation-induced T-cell costimulatory molecule. Signaling via 4-1BB upregulates survival genes, enhances cell division, induces cytokine production, and prevents activation-induced cell death in T cells. The importance of the 4-1BB pathway has been underscored in a number of diseases, including cancer. Growing evidence indicates that anti-4-1BB monoclonal antibodies possess strong antitumor properties, which in turn are the result of their powerful CD8þ T-cell activating, IFN-g producing, and cytolytic marker-inducing capabilities. In addition, combination therapy of anti-4-1BB with other anticancer agents, such as radiation, has robust tumor-regressing abilities against nonimmunogenic or poorly immunogenic tumors. Furthermore, the adoptive transfer of ex vivo anti-4-1BB-activated CD8þ T cells from previously tumor-treated animals efficiently inhibits progression of tumors in recipient mice that have been inoculated with fresh tumors. In addition, targeting of tumors with variants of 4-1BBL directed against 4-1BB also have potent antitumor effects. Currently, a humanized anti-4-1BB is in clinical trials in patients with solid tumors, including melanoma, renal carcinoma, and ovarian cancer, and so far seems to have a favorable toxicity profile. In this review, we discuss the basis of the therapeutic potential of targeting the 4-1BB-4-1BBL pathway in cancer treatment.

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“…Binding of the ligand or anti-CD137 antibody with 4-1BB receptor on the surface of T lymphocytes provides a co-stimulating signal enhancing the cell's activation and triggering its proliferation. The phase I trial enrolling 54 patients with solid tumors has shown acceptable toxicity level and a certain clinical activity of BMS-663513 (Sznol et al, 2008). We look forward to the results of large randomised phase II study which has just been completed (US National Institutes of Health [NIH], 2008a).…”

Section: Active Non-specific Immunotherapymentioning

confidence: 99%