Maria I. Schmidgen

Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death receptor-1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma as well as for other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects affect skin, gastrointestinal tract, liver, endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centers were treated with pembrolizumab or nivolumab; 242 side-effects were described in 138 patients. In 116 of the 138 patients, side-effects affected the skin, gastrointestinal tract, liver, endocrine, and renal system. Rare side-effects included diabetes mellitus, lichen planus, and pancreas insufficiency due to pancreatitis. CONCLUSION Anti-PD1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Neurological, respiratory, musculoskeletal, cardiac and ocular side-effects of anti-PD-1 therapy

BACKGROUND Anti-programmed cell death 1 (PD-1) antibodies represent an effective treatment option for metastatic melanoma and other cancer entities. They act via blockade of the PD-1 receptor, an inhibitor of the T-cell effector mechanisms that limit immune responses against tumours. As reported for ipilimumab, the anti-PD-1 antibodies pembrolizumab and nivolumab can induce immune-related adverse events (irAEs). These side-effects can involve skin, gastrointestinal tract, liver, the endocrine system and other organ systems. Since life-threatening and fatal irAEs have been reported, adequate diagnosis and management are essential. METHODS AND FINDINGS In total, 496 patients with metastatic melanoma from 15 skin cancer centres were treated with pembrolizumab or nivolumab. Two hundred forty two side-effects in 138 patients have been analysed. In 77 of the 138 patients side-effects affected the nervous system, respiratory tract, musculoskeletal system, heart, blood and eyes. Not yet reported side-effects such as meningo-(radiculitis), polyradiculitis, cardiac arrhythmia, asystolia, and paresis have been observed. Rare and difficult to manage side-effects such as myasthenia gravis are described in detail. CONCLUSION Anti-PD-1 antibodies can induce a plethora of irAEs. The knowledge of them will allow prompt diagnosis and improve the management resulting in decreased morbidity.

Angiotensin II–Induced Vascular Dysfunction Depends on Interferon-γ–Driven Immune Cell Recruitment and Mutual Activation of Monocytes and NK-Cells

Objective—Immune cells contribute to angiotensin II (ATII)–induced vascular dysfunction and inflammation. Interferon-&ggr; (IFN-&ggr;), an inflammatory cytokine exclusively produced by immune cells, seems to be involved in ATII-driven cardiovascular injury, but the actions and cellular source of IFN-&ggr; remain incompletely understood. Approach and Results—IFN-&ggr;−/− and Tbx21−/− mice were partially protected from ATII-induced (1 mg/kg per day of ATII, infused subcutaneously by miniosmotic pumps) vascular endothelial and smooth muscle dysfunction, whereas mice overexpressing IFN-&ggr; showed constitutive vascular dysfunction. Absence of T-box expressed in T cells (T-bet), the IFN-&ggr; transcription factor encoded by Tbx21, reduced vascular superoxide and peroxynitrite formation and attenuated expression of nicotinamide adenosine dinucleotide phosphate oxidase subunits as well as inducible NO synthase, monocyte chemoattractant protein 1, and interleukin-12 in aortas of ATII-infused mice. Compared with controls, IFN-&ggr;−/− and Tbx21−/− mice were characterized by reduced ATII-mediated vascular recruitment of both natural killer (NK)1.1+ NK-cells as the major producers of IFN-&ggr; and CD11b+Gr-1low interleukin-12 secreting monocytes. Selective depletion and adoptive transfer experiments identified NK-cells as essential contributors to vascular dysfunction and showed that T-bet+lysozyme M+ myelomonocytic cells were required for NK-cell recruitment into vascular tissue and local IFN-&ggr; production. Conclusions—We provide first evidence that NK-cells play an essential role in ATII-induced vascular dysfunction. In addition, we disclose the T-bet-IFN-&ggr; pathway and mutual monocyte–NK-cell activation as potential therapeutic targets in cardiovascular disease.

Pembrolizumab-induced lichen planus pemphigoides in a patient with metastatic melanoma

Immune checkpoint inhibitors targeting PD-1 (programmed cell death receptor 1) are indicated in the treatment of advanced melanoma. Cutaneous complications represent the most common immune-related adverse events (irAEs) [ 1 ] . We present the case of an advanced melanoma patient with complete response to treatment with the anti-PD-1 antibody pembrolizumab who developed lichen planus pemphigoides (LPP). A 64-year-old Caucasian man with metastatic melanoma was enrolled in the MK-3475-002 phase II trial comparing pembrolizumab 2 mg/kg or 10 mg/kg (randomized and blinded for the dose received) with standard chemotherapy. Tumor staging showed a partial response after nine cycles of pembrolizumab (given at three-week intervals). However, a CTCAE (Common Terminology Criteria for Adverse Events) grade 2 bullous pemphigoid (BP)-like drug reaction with vesicular lesions of the oral mucosa (Figure 1 a) and scattered papules with central vesicles on the skin prompted the patients exclusion from the trial. Subsequent treatment with topical clobetasol, prednisolone (1 mg/kg PO, followed by a slow taper over the course of four months), and rituximab (375 mg/m2 IV every four weeks; discontinuation after three doses due to CTCAE grade 3 thrombocytopenia) only led to minor improvement of the skin lesions. Six months later, the patient presented with a complete tumor response but also with CTCAE grade 3 white reticular lesions of the oral mucosa ( Wickham striae , Figure 1 b) and pruritic erythematous papules and plaques with central vesicles on the trunk and extremities (Figure 1 c). Histology (biopsy taken from the back) was consistent with lichen planus (LP), showing orthohyperkeratosis, hypergranulosis, cytoid bodies, and lichenoid interface dermatitis with a band-like lymphocytic infi ltrate obscuring the dermoepidermal junction (Figure 1 d, e). Repeated treatment with topical clobetasol and prolonged therapeutic attempts with systemic prednisolone (1 mg/kg PO, followed by a gradual taper over the course of eight months), PUVA therapy (methoxsalen 60 mg PO and UVA 1,2 J/cm2 four times weekly for three weeks), acitretin (50 mg PO once a day for one week), and sirolimus (2 mg PO once a day, discontinuation after eight weeks due to CTCAE grade 3 heart failure) were unsatisfactory.