Case Report: Neuromyelitis Optica After Treatment of Uveal Melanoma With Nivolumab and Ipilimumab.

The development of immune checkpoint inhibitors (ICIs) has greatly improved survival of patients with advanced malignancies. ICIs can cause immune-related adverse effects (irAEs) involving any organ. Neurological irAEs are infrequent and have mostly been reported in patients with melanoma. We describe the case of a 57-year-old male with right eye uveal melanoma, gene expression profile (class 2), and PRAME (preferentially expressed antigen in melanoma) positivity, who received plaque brachytherapy with Iodine-125 for 4 days with subsequent adjuvant ICIs (immune checkpoint inhibitors), nivolumab and ipilimumab. 18 weeks after discontinuation of immunotherapy, the patient presented with acute onset of left-sided headaches, pain with eye movements, and vision loss. The patient was tested positive for serum anti-aquaporin-4 antibody (AQP4-Ab) and was diagnosed with neuromyelitis optica spectrum disorder (NMOSD). Subsequently, he was treated with 5 days of intravenous methylprednisolone followed by an oral prednisone taper over 10 weeks, with improvement in symptoms. We report a unique case of neuromyelitis optica spectrum disorder (NMOSD) following treatment with ICIs. To our best knowledge, this is the third reported case in English literature of NMOSD following ICI therapy and the first reported case of NMOSD caused by ICI treatment in uveal melanoma.

Dose-escalation study of vemurafenib with sorafenib or crizotinib in patients with BRAF-mutated advanced cancers.

BACKGROUND: BRAF inhibitors are effective in melanoma and other cancers with BRAF mutations; however, patients ultimately develop therapeutic resistance through the activation of alternative signaling pathways such as RAF/RAS or MET. The authors hypothesized that combining the BRAF inhibitor vemurafenib with either the multikinase inhibitor sorafenib or the MET inhibitor crizotinib could overcome therapeutic resistance. METHODS: Patients with advanced cancers and BRAF mutations were enrolled in a dose-escalation study (3 + 3 design) to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities (DLTs) of vemurafenib with sorafenib (VS) or vemurafenib with crizotinib (VC). RESULTS: In total, 38 patients (VS, n = 24; VC, n = 14) were enrolled, and melanoma was the most represented tumor type (VS, 38%; VC, 64%). In the VS arm, vemurafenib 720 mg twice daily and sorafenib 400 mg am/200 mg pm were identified as the MTDs, DLTs included grade 3 rash (n = 2) and grade 3 hypertension, and partial responses were reported in 5 patients (21%), including 2 with ovarian cancer who had received previous treatment with BRAF, MEK, or ERK inhibitors. In the VC arm, vemurafenib 720 mg twice daily and crizotinib 250 mg daily were identified as the MTDs, DLTs included grade 3 rash (n = 2), and partial responses were reported in 4 patients (29%; melanoma, n = 3; lung adenocarcinoma, n = 1) who had received previous treatment with BRAF, MEK, and/or ERK inhibitors. Optional longitudinal collection of plasma to assess dynamic changes in circulating tumor DNA demonstrated the elimination of BRAF-mutant DNA from plasma during therapy (P = .005). CONCLUSIONS: Vemurafenib combined with sorafenib or crizotinib was well tolerated with encouraging activity, including among patients who previously received treatment with BRAF, MEK, or ERK inhibitors.

Calcium-sensing receptor autoantibody-mediated hypoparathyroidism associated with immune checkpoint inhibitor therapy: diagnosis and long-term follow-up.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have produced significant survival benefit across many tumor types. However, immune-related adverse events are common including autoimmune responses against different endocrine organs. Here, a case of ICI-mediated hypoparathyroidism focusing on long-term follow-up and insights into its etiology is presented. CASE AND METHODS: A 73-year-old man developed severe symptomatic hypocalcemia after the initiation of ipilimumab and nivolumab for the treatment of metastatic melanoma. Hypoparathyroidism was diagnosed with undetectable intact parathyroid hormone (PTH). Immunoprecipitation assays, ELISAs, and cell-based functional assays were used to test the patient for antibodies against the calcium-sensing receptor (CaSR). NACHT leucine-rich repeat protein 5 (NALP5) and cytokine antibodies were measured in radioligand binding assays and ELISAs, respectively. RESULTS: The patient's symptoms improved with aggressive calcium and vitamin D supplementation. At 3 years and 3 months since the diagnosis of hypoparathyroidism, PTH was still inappropriately low at 7.6 pg/mL, and attempted discontinuation of calcium and calcitriol resulted in recurrent symptomatic hypocalcemia. Analysis for an autoimmune etiology of the patient's hypoparathyroidism indicated that CaSR antibodies were negative before treatment and detected at multiple time points afterwards, and corresponded to the patient's clinical course of hypoparathyroidism. CaSR antibodies purified from the patient's serum activated the human CaSR. The patient was seronegative for NALP5 and cytokine antibodies, indicating that their hypoparathyroidism was not a manifestation of autoimmune polyendocrine syndrome type 1. CONCLUSION: The etiology of hypocalcemia is likely autoimmune hypoparathyroidism caused by the development of CaSR-activating antibodies that might prevent PTH release from the parathyroid.

Induction of cellular and molecular Immunomodulatory pathways by vitamin E and vitamin C.

INTRODUCTION: Vitamins E and C are well known small molecules that have been used to maintain health for decades. Recent studies of the cellular and molecular pathways leading to immunomodulation by these molecules have been of interest, as have their anti-oxidant properties and signal transduction pathways for curing or improving infectious diseases and cancer. Areas covered: Herein, the authors provide a definition and the structural classification of vitamins E and C and how these molecules influence cellular function. The studies include in vitro, ex vivo and in vivo studies in animal models as well as clinical trials. The authors give particular focus to the scientifically factual and putative roles of these molecules in innate and adaptive immunomodulation and prevention or cure of diseases. Expert opinion: The antioxidant properties of vitamins E and C are well studied. However, whether there is a link between their antioxidant and immunomodulation properties is unclear. In addition, there is a strong, albeit putative, prevailing notion that vitamin C can prevent or cure infectious diseases or cancer. Presently, while there is proven evidence that vitamin E possesses immunomodulatory properties that may play a positive role in disease outcomes, this evidence is less available for vitamin C.

Comparative Safety and Efficacy Profile of a Novel Oil in Water Vaccine Adjuvant Comprising Vitamins A and E and a Catechin in Protective Anti-Influenza Immunity.

Non-replicating vaccines, such as those based on recombinant proteins, require adjuvants and delivery systems, which have thus far depended on mimicking pathogen danger signals and strong pro-inflammatory responses. In search of a safer and more efficacious alternative, we tested whether vaccinations with influenza recombinant hemagglutinin (HA) mixed with a novel vegetable oil in water emulsion adjuvant (Natural Immune-enhancing Delivery System, NIDS), based on the immune-enhancing synergy of vitamins A and E and a catechin, could protect against intra-nasal challenge with live influenza virus. Vaccinations of inbred Brag Albino strain c (BALB/c) mice, with HA mixed with NIDS compared to other adjuvants, i.e., a squalene oil in water emulsion (Sq. oil), and the Toll Like Receptor 3 (TLR3) agonist Poly (I:C), induced significantly lower select innate pro-inflammatory responses in serum, but induced significantly higher adaptive antibody and splenic T Helper 1 (TH1) or TH2, but not TH17, responses. Vaccinations with NIDS protected against infection, as measured by clinical scores, lung viral loads, and serum hemagglutination inhibition titers. The NIDS exhibited a strong dose sparing effect and the adjuvant action of NIDS was intact in the outbred CD1 mice. Importantly, vaccinations with the Sq. oil, but not NIDS, induced a significantly higher Serum Amyloid P component, an acute phase reactant secreted by hepatocytes, and total serum IgE. Thus, the NIDS may be used as a clinically safer and more efficacious vaccine adjuvant against influenza, and potentially other infectious diseases.

Vitamin A or E and a catechin synergize as vaccine adjuvant to enhance immune responses in mice by induction of early interleukin-15 but not interleukin-1ß responses.

Vitamins A and E and select flavonoids in the family of catechins are well-defined small molecules that, if proven to possess immunomodulatory properties, hold promise as vaccine adjuvants and various therapies. In an effort to determine the in vivo immunomodulatory properties of these molecules, we found that although mucosal and systemic vaccinations with a recombinant HIV-1BaL gp120 with either a catechin, epigallo catechin gallate (EGCG) or pro-vitamin A (retinyl palmitate) alone in a vegetable-oil-in-water emulsion (OWE) suppressed antigen-specific responses, the combination of EGCG and vitamin A or E in OWE (Nutritive Immune-enhancing Delivery System, NIDS) synergistically enhanced adaptive B-cell, and CD4(+) and CD8(+) T-cell responses, following induction of relatively low local and systemic innate tumour necrosis factor-α (TNF-α), interleukin-6 (IL-6) and IL-17, but relatively high levels of early systemic IL-15 responses. For induction of adaptive interferon-γ and TNF-α responses by CD4(+) and CD8(+) T cells, the adjuvant effect of NIDS was dependent on both IL-15 and its receptor. In addition, the anti-oxidant activity of NIDS correlated positively with higher expression of the superoxide dismutase 1, an enzyme involved in reactive oxygen species elimination but negatively with secretion of IL-1ß. This suggests that the mechanism of action of NIDS is dependent on anti-oxidant activity and IL-15, but independent of IL-1ß and inflammasome formation. These data show that this approach in nutritive vaccine adjuvant design holds promise for the development of potentially safer effective vaccines.

Pomegranate Supplementation Protects against Memory Dysfunction after Heart Surgery: A Pilot Study.

Memory dysfunction is a common complaint following heart surgery and may be related to a diffuse ischemic state induced by microemboli dislodged during the procedure. Ischemia can induce damage by a number of mechanisms, including oxidative stress. Because pomegranates contain a variety of polyphenols with antioxidant and other potentially beneficial effects, we tested whether supplementation with a pomegranate extract before and after heart surgery could protect against postoperative cognitive dysfunction. Patients undergoing elective coronary artery bypass graft and/or valve surgery were given either 2 g of pomegranate extract (in 2 POMx pills) or placebo (pills containing no pomegranate ingredients) per day from one week before surgery to 6 weeks after surgery. The patients were also administered a battery of neuropsychological tests to assess memory function at 1 week before surgery (baseline), 2 weeks after surgery, and 6 weeks after surgery. The placebo group had significant deficits in postsurgery memory retention, and the pomegranate treatment not only protected against this effect, but also actually improved memory retention performance for up to 6 weeks after surgery as compared to presurgery baseline performance.

Selumetinib (AZD6244; ARRY-142886) in the treatment of metastatic melanoma.

INTRODUCTION: Melanoma is the fifth most common cancer in men and seventh most common in women in the USA, and prognosis for patients with advanced melanoma is poor. The mitogen-activated protein (MAP) kinase signaling pathway is essential for proliferation and survival of melanoma cells. Effective inhibition of MAP kinase kinase (MEK) protein has been shown to downregulate the MAP kinase pathway, resulting in melanoma cell growth arrest and apoptosis. Selumetinib is an orally available, selective non-ATP-competitive MEK1 and MEK2 inhibitor. AREAS COVERED: In this review, the authors discuss the rationale for MEK inhibition therapy in melanoma and summarize data from the preclinical and clinical studies of selumetinib for advanced melanoma. EXPERT OPINION: As a majority of advanced melanomas have an activated MAP kinase signal transduction pathway, there is a strong preclinical rationale for investigating selumetinib in patients with metastatic melanoma. The results of early clinical studies of selumetinib suggest that selumetinib may have a role in melanoma therapy, especially in certain subsets of patients, such as those whose tumor harbors a BRAF mutation. Current studies of selumetinib are addressing the efficacy of selumetinib in these patients.