Synonym(s)
DefinitionThis section has been translated automatically.
PD-1 = Acronym for Programmed Cell Death 1 Protein. Anti-PD-1 antibodies block the interaction between programmed cell death and its ligand PDL1. Programmed cell death (PD-1) is an important receptor protein that is expressed by activated T cells. PD-1 functions primarily in tissue where T cells encounter the immunosuppressive ligand of PD-1. These PD-1 ligands (PD-L1 and PD-L2) are produced by tumour cells themselves as well as by cells of the tumour stroma. If the interactions between PD-1 and its ligands are inhibited, the effectiveness of the ligands is reduced. Their immunosuppressive effect is weakened. The T-cell response (e.g. against the tumour tissue) is strengthened, an immunosuppressive response is suppressed.
Pharmacodynamics (Effect)This section has been translated automatically.
Analogous to the effect of ipilimumab, anti-PD1/PDL1 antibodies thus enable the patient's immune system to attack the tumor itself.
In a study published in July 2014 in the New England Journal of Medicine, 38 percent of 135 patients with advanced melanoma responded to therapy with the anti-PD1 antibody. It was irrelevant whether the patients had previously received ipilimumab(CTLA-4-Ak).
Prior studies in patients with advanced melanoma (n = 104), non-small cell lung cancer (n = 122), renal cell carcinoma (n = 34), and prostate carcinoma (n = 17) and colon carcinoma (n = 19) were included. The anti-PD-1 antibody was applied every 2 weeks. Patients received a maximum of 12 treatment cycles until disease progression or complete remission. Patients with squamous cell carcinoma had the best response rate (33%). 26 of 94 evaluable melanoma patients (28%) showed an objectifiable response.
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Undesirable effectsThis section has been translated automatically.
General: The most common ADRs were fatigue, lack of appetite, nausea, diarrhea (indicative of colitis), cough, dyspnea, constipation, vomiting, exanthema, fever and headache. Around 15% of patients had grade 3 and 4 ADR events. Around 5% of patients discontinued treatment due to ADRs.
Endocrinopathies: Common endocrine side effects include thyroid dysfunction (destructive thyroiditis, less common than classic immunohyperthyroidism) and hypophysitis, which occurred mainly with combination therapy of nivolumab/ipilimumab (28%/7%) and anti-PD-1-AK (15%/1%). Adrenalitis (1-4%), diabetes mellitus and diabetes insipidus (<1%) are rarer.
Skin and subcutis: Furthermore, maculopapular, psoriasiform and lichenoid and, in rarer cases, autoimmune bullous exanthema (see below lichen ruber pemphigoides) as well as mucositis and vitiligo have been reported (Mueller KA et al. 2021). In rare cases, the occurrence oflipodystrophy and erythema multiforme and TEN has been reported (Kähler K et al. 2020).
Eye and orbit (<1% of patients): Uveitis with photophobia, scleritis, keratitis, ocular dryness. Endocrine orbitopathies are rarer.
Kidney: renal toxicity, granulomatous and lupus nephritis
Lung (<10%): Immune-mediated pneumonitis (dry cough and dyspnea)
Neurological side effects: headache, dizziness, ataxia, tremor, paralysis, speech disorders, seizures, fatique
Hematologic ADR: hemolytic anemia, pancytopenia, agranulocytosis, hemophilia, hemophagocytic lymphohistiocytosis.
Around 1% deaths in connection with PD-1-AK therapy were observed (cause mostly pneumonitis).
PreparationsThis section has been translated automatically.
Approved preparations are:
- Pembrolizumab (approved as monotherapy for the treatment of patients with recurrent or metastatic cSCC that cannot be cured by surgery or radiotherapy. This approval has since been extended: patients with locally advanced cSCC can now also be treated with pembrolizumab as monotherapy in the USA).
- Nivolumab (monoclonal PD-1 antibody used to treat non-resectable or metastatic malignant melanoma and locally advanced or metastatic non-small cell lung cancer (NSCLC).
- Cemiplimab (approved by the EMA for cSCC since 2019)
Note(s)This section has been translated automatically.
Conclusion: Anti-PD-L1 antibody induces objective response in patients with non-small cell lung cancer, melanoma or renal car cinoma.
LiteratureThis section has been translated automatically.
- Blank C et al. (2004) PD-L1 / B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8 + T cells. Cancer Res 64: 1140-1145
- Kähler KC et al. (2020) Side effect management of immune checkpoint blockade by CTLA-4 and PD-1 antibodies in metastatic melanoma - an update. J Dtsch Dermatol Ges 18: 582-609.
- Mohr P (2014) Immuno-oncological therapy with ipilimumab-innovative approach ushers in a new era in cancer therapy. Thieme Case Report 4:1-24
- Ribas A et al. (2004) J Clin Oncol 32: Abstr. LBA9000
- Topalian SL et al. (2012) Safety, activity, and immune correlates of anti-PD-1 antibody in cancer. N Engl J Med 366: 2443-2454