Table 1.

Toxicity, positive comments, and caveats pertaining to immunomodulating mAbs

AgentToxicityPositive commentsCaveats
Ipilimumab (anti–CTLA-4; refs. 12, 13)Rash, colitis, diarrhea, hepatotoxicity, endocrinopathies, neuropathiesTwo randomized phase III trials showed improvement in OS in patients with melanoma as first- and second-line therapy. First therapy ever to show a survival improvement in metastatic melanoma.More efficacious schedule and dosage to be defined. Increase in tumor lesion size due to lymphocyte infiltrates might be confused with disease progression and makes decision making difficult. Lack of predictive biomarkers.
Tremelimumab (anti–CTLA-4; ref. 18)Colitis, diarrhea, rash, pruritus, endocrinopathiesTreatment schedule with administrations every 90 days (too long interval) with the same safety profile as ipilimumab. Confirmed clinical activity in some patients.Negative results in the melanoma phase III study, compared with standard chemotherapy.
Nivolumab (anti–PD-1; refs. 42–44)Relevant toxicity is uncommon. Some patients develop fatigue, rash, diarrhea, pruritus, pneumonitis; rare decreases in appetite and hemoglobin, pyrexia.Dramatic and sustained clinical responses in 20%–30% of patients with melanoma, renal cell cancer, and non–small cell lung cancer.Effective at low doses (1 mg/kg). Better safety profile as compared with ipilimumab and tremelimumab.Not yet studied in phase III trials. Lack of confirmed biomarkers (PD-L1 expression under study, pending confirmation).
MK-3475 (anti–PD-1; ref. 46)Fatigue, pruritus, dyspnea, nausea, anorexiaPromising efficacy and safety profile (no grade 3–4 adverse events in the phase I trial)Early phase of development.
BMS936559 (anti–PD-L1; ref. 108)Fatigue, infusion-related reaction, diarrhea, arthralgia, rash, nausea, pruritusTheoretically a better inhibition PD-1/PD-L1 because directly inside the malignant tissue (where there is the higher PD-L1 expression from the tumor and PD-1 expression on TILs). Good safety profile.Early phase of development.
Anti-CD40 (58)Dacetuzumab (67)Cytokine release syndrome, thromboembolic syndromes, transient cytopenias, depletion of T cells in multidose trialCP-870,893 has shown clinical efficacy in a number of settings of patients with advanced cancer.Dacetuzumab has shown single-agent activity in DLBCL. No tumor regression was observed in multiple myeloma.It is necessary to improve our understanding of the mechanism of action of different CD40 mAb and understand which of the many mechanisms is the most appropriate for the clinical use.
Possible combination with a checkpoint blockade mAbs (i.e., anti–CTLA-4, anti–PD-1), as well as rituximab, and chemotherapuetic agents.
Urelumab (anti-CD137; ref. 31)Fatigue, rash, fever, rare cytopenias, and hepatotoxicity.Possible combination with anti-immune checkpoint blockade mAbs (ipilimumab, nivolumab).Severe hepatic toxicity (seems dose related, not observed at lower doses). Early phase of development.
Anti-OX40Fatigue, transient lymphopeniaExcellent for combination with other molecules.Early phase of development.
Anti-TGF-β (GC1008) Fresolimumab (109)Rash, gingival bleeding, SCC, keratoacanthomasPromising result in phase I trial.Early phase of development.