Elsevier

Seminars in Oncology

Volume 42, Issue 3, June 2015, Pages 423-428
Seminars in Oncology

Toxicity Patterns With Immunomodulating Antibodies and Their Combinations,☆☆

https://doi.org/10.1053/j.seminoncol.2015.02.011Get rights and content

Immune checkpoint molecules cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed death-1 (PD-1), but also LAG-3 and TIM-3, are involved in regulation of peripheral tolerance in order to prevent autoimmunity. Blocking of these cell surface proteins by antibodies has resulted in remarkable anti-tumor immunity; however this immunity is accompanied by immune-related adverse reactions (irAEs), resembling autoimmune diseases. Hence, treatment with immunosuppressive drugs is highly effective and resolves the symptoms caused by these adverse events rapidly. In this review, toxicity patterns observed with immune checkpoint blockade are described for single-agent and combination treatments.

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

References (33)

  • C.A. Sabatos et al.

    Interaction of Tim-3 and Tim-3 ligand regulates T helper type 1 responses and induction of peripheral tolerance

    Nat Immunol

    (2003)
  • A. Sánchez-Fueyo et al.

    Tim-3 inhibits T helper type 1–mediated auto- and alloimmune responses and promotes immunological tolerance

    Nat Immunol

    (2003)
  • Characterization of the major histocompatibility complex class II binding site on LAG-3 protein....
  • PD-1 and LAG-3 inhibitory co-receptors act synergistically to prevent autoimmunity in mice....
  • S.R. Woo et al.

    Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape

    Cancer Res

    (2012)
  • Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity....
  • Cited by (0)

    Conflicts of interest: J.H.—Advisory board: BMS, GSK, Roche, MSD; Honoraria: MSD, BMS; Research grants: GSK, BMS, MSD. H.T.—No disclosures.

    ☆☆

    C.B.—Advisory board: BMS, GSK, Roche, MSD, Novartis; Honoraria: MSD, BMS, GSK; Research grant: Novartis.

    View full text