Toxicity Patterns With Immunomodulating Antibodies and Their Combinations☆,☆☆
Section snippets
Toxicity of CTLA-4–Blocking Antibodies
Two human anti–CTLA-4 monoclonal antibodies have been developed, tremelimumab and ipilimumab. Both antibodies have undergone extensive clinical testing, including randomized controlled phase III trials.17, 18, 19
Tremelimumab is a fully human IgG2 monoclonal antibody with high affinity for CTLA-4. Early clinical studies demonstrated an objective response rate of around 6%–7% in patients with metastatic melanoma.20 Side effects were mostly immune-related and consisted of colitis, dermatitis, and
Toxicity of PD-1–Blocking Antibodies
Pembrolizumab and nivolumab are both anti–PD-1 monoclonal antibodies.
Pembolizumab (previously called lambrolizumab and MK-3475) is a humanized IgG4 monoclonal antibody that was recently tested both in an ipilimumab-refractory and ipilimumab-naïve metastatic melanoma patient population. Three different doses/schedules were tested: 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, and 10 mg/kg every 2 weeks.23 In total, 411 patients were enrolled in different cohorts and the results were presented
Toxicity of PD-L1–Blocking Antibodies
Brahmer et al published the results from a large multi-cohort phase I study with anti–PD-L1 antibody BMS-936559.28 This is a fully human IgG4 monoclonal antibody with high affinity for PD-L1–blocking its interaction with both PD1 and CD80. BMS-936559 was studied in patients suffering from metastatic melanoma, non-small cell lung cancer, renal cell cancer, ovarian cancer, stomach cancer, colorectal cancer, pancreatic cancer, and breast cancer. Several dose levels were tested: 0.3, 1.0, 3.0, and
Toxicity With Combination of Ipilimumab and Nivolumab
In June 2013, the first results were published from a phase I study in which the combination of CTLA4 and PD-1 blockade was tested in metastatic melanoma patients.16 The study was designed as either sequential or concurrent treatment. In the latter treatment arm, dose escalation of both drugs was tested. Four infusions of ipilimumab and nivolumab were given every 3 weeks, followed by four 3-weekly infusions of nivolumab alone. Thereafter, the combination was administered every 3 months for
Toxicity Patterns With Immune Checkpoint Blockade
Based on preclinical studies and clinical studies, interference with normal ligation of immune checkpoint molecules CTLA-4 and PD-1 or PD-L1 not only allows for activation of an anti-tumor immune response but also induction of autoimmune phenomena. Based on the frequency of these irAEs or adverse events of specific interest, interruption of normal interaction between PD-1 and PD-L1 or PD-L2 by anti–PD-1 monoclonal antibodies, appears to have the best safety profile, with the fewest grade 3–4
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Cited by (52)
Chloroquine treatment influences immunological memory through the PD-1/PD-L1 pathway during the initiation of Plasmodium chabaudi infection
2022, International ImmunopharmacologyCitation Excerpt :On immune cells, checkpoint molecules act as negative regulators [7]. The immune checkpoints (ICs) are the molecules that modulate immunity, maintain immune homeostasis, and prevent autoimmunity [8]; thus, ICs influence immune tolerance and immune balance [9]. PD-1 is an important IC molecule [10], which is involved in immune suppression and tolerability.
British Society of Gastroenterology endorsed guidance for the management of immune checkpoint inhibitor-induced enterocolitis
2020, The Lancet Gastroenterology and HepatologyCitation Excerpt :This risk is affected by the type of immunotherapy regimen, with diarrhoea occurring most frequently in patients treated with anti-CTLA-4 antibodies, and is more common in anti-CTLA-4 and anti-PD-1 combination therapy than with anti-PD-1 monotherapy (figure 1). Colonic perforation occurs in 1–3% of patients, of whom most are on anti-CTLA-4-containing regimens.16,20–23 There is some evidence that risk of immune checkpoint inhibitor-induced enterocolitis might be linked to tumour type, with higher incidence reported in patients with melanoma.24
A Case of Anti–PD-L1-associated Remitting Seronegative Symmetric Synovitis With Pitting Edema
2019, Clinical Genitourinary CancerCitation Excerpt :Ongoing correlative studies are investigating potential mechanisms of action of the combination. In addition to facilitating immune-mediated tumor destruction, checkpoint inhibitors can impair peripheral immune tolerance,28 resulting in inflammatory immune-related adverse events (irAEs) largely attributed to T cell-mediated damage to normal tissue.2 The American Society of Clinical Oncology recently published guidelines for management of these toxicities.29
Idiosyncratic Adverse Drug Reactions
2018, Comprehensive Toxicology: Third Edition
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Conflicts of interest: J.H.—Advisory board: BMS, GSK, Roche, MSD; Honoraria: MSD, BMS; Research grants: GSK, BMS, MSD. H.T.—No disclosures.
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C.B.—Advisory board: BMS, GSK, Roche, MSD, Novartis; Honoraria: MSD, BMS, GSK; Research grant: Novartis.