Checkpoint Inhibitors

Abstract

Background: Treatment with checkpoint inhibitors such as anti-programmed death-1 (anti-PD-1), anti-PD-ligand 1 (anti-PD-L1), and anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) antibodies can prolong the survival of cancer patients, but it also induces autoimmune side effects in 86-96% of patients by activating the immune system. In 17-59% of patients, these are severe or even life-threatening.

Methods: This review is based on pertinent articles retrieved by a search in PubMed and on an evaluation of a side-effect registry.

Results: Checkpoint-inhibitor-induced autoimmune side effects manifest themselves in all organ systems, most commonly as skin lesions (46-62%), autoimmune colitis (22-48%), autoimmune hepatitis (7-33%), and endocrinopathies (thyroiditis, hypophysitis, adrenalitis, diabetes mellitus; 12-34%). Rarer side effects include pneumonitis (3-8%), nephritis (1-7%), cardiac side effects including cardiomyositis (5%), and neurological side effects (1-5%). Severe (sometimes lethal) side effects arise in 17-21%, 20-28%, and 59% of patients undergoing anti-PD-1 and anti- CTLA-4 antibody treatment and the approved combination therapy, respectively. With proper monitoring, however, these side effects can be recognized early and, usually, treated with success. Endocrine side effects generally require long-term hormone substitution. Patients who have stopped taking checkpoint inhibitors because of side effects do not show a poorer response of their melanoma or shorter survival in comparison to patients who continue to take checkpoint inhibitors.

Conclusion: The complex management of checkpoint-inhibitor-induced side effects should be coordinated in experienced centers. The creation of an interdisciplinary "tox team" with designated experts for organ-specific side effects has proven useful. Prospective registry studies based on structured documentation of side effects in routine clinical practice are currently lacking and urgently needed.

Figure:

Pneumonitis (a), leukotrichia (b) a) Typical ground-glass opacity in the chest x-ray of a patient with pneumonitis. Cough, fever, and exhaustion arose after one infusion of pembrolizumab. b) Leukotrichia of the eyebrows and lashes in a 62-year-old man after combined treatment with ipilimumab and the anti-PD-1 antibody nivolumab.

Figure:

Pneumonitis (a), leukotrichia (b) a) Typical ground-glass opacity in the chest x-ray of a patient with pneumonitis. Cough, fever, and exhaustion arose after one infusion of pembrolizumab. b) Leukotrichia of the eyebrows and lashes in a 62-year-old man after combined treatment with ipilimumab and the anti-PD-1 antibody nivolumab.

eFigure a)

Colitis: Erythema and granular change of the rectosigmoid mucosa with contact vulnerability and contact hemorrhage. Endoscopic images (colon) in weeks 11 and 15 of treatment additionally show white punctate erosions and spots suggesting concomitant infection. (Reprinted from [34] with the kind permission of Taylor & Francis.)

eFigure b)

An enlarged pituitary gland is seen in a woman with hypophysitis under treatment with ipilimumab. These MRI changes in the pituitary gland are not seen in all patients with hypophysitis.