Pneumonitis is an uncommon but potentially fatal toxicity of anti-programmed death-1 (PD-1)/ programmed death ligand 1 (PD-L1) monoclonal antibodies (mAbs). Clinical, radiologic, and pathologic features are poorly described. MethodsPatients who received anti-PD-1/PD-L1 monotherapy or in combination with anti-cytotoxic T-cell lymphocyte-4 mAb were identified at two institutions (Memorial Sloan Kettering Seventy-two percent (31 of 43) of cases were grade 1 to 2, and 86% (37 of 43) improved/resolved with drug holding/immunosuppression. Five patients worsened clinically and died during the course of pneumonitis treatment; proximal cause of death was pneumonitis (n = 1), infection related to immunosuppression (n = 3), or progressive cancer (n = 1). Radiologic and pathologic features of pneumonitis were diverse. ConclusionPneumonitis associated with anti-PD-1/PD-L1 mAbs is a toxicity of variable onset and clinical, radiologic, and pathologic appearances. It is more common when anti-PD-1/PD-L1 mAbs are combined with anti-cytotoxic T-cell lymphocyte-4 mAb. Most events are low grade and improve/ resolve with drug holding/immunosuppression. Rarely, pneumonitis worsens despite immunosuppression, and may result in infection and/or death.

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Type II diabetes is a major health problem worldwide. Some populations, such as aboriginal peoples, are particularly at risk for this disease. In the Cree Nation of Quebec, Canada, prevalence in adults is approaching 20%, and the consequences are compounded by low compliance with modern medicine. In 2003, we conducted an ethnobotanical study of Cree medicinal plants used for the treatment of symptoms of diabetes. This served as the basis for a project designed to identify efficacious complementary treatment options more readily accepted by this population. The present study assesses the in vitro anti-diabetic potential of extracts from the 8 most promising plants to emerge from the ethnobotanical study. Cell-based bioassays were employed to screen for (i) potentiation of glucose uptake by skeletal muscle cells (C2C12) and adipocytes (3T3-L1); (ii) potentiation of glucose-stimulated insulin secretion (GSIS) and insulin production by pancreatic beta cells (INS 832/13); (iii) potentiation of triglyceride accumulation in differentiating 3T3-L1 cells; (iv) protection against glucose toxicity and glucose deprivation in pre-sympathetic neurons (PC12-AC). Additionally, anti-oxidant activity was measured biochemically by the diphenylpicrylhydrazyl (DPPH) reduction assay. All plant extracts potentiated basal or insulin-stimulated glucose uptake to some degree in muscle cells or adipocytes. Adipocyte differentiation was accelerated by 4 extracts. Five extracts conferred protection in PC12 cells. Three extracts displayed free radical scavenging activity similar to known anti-oxidants. None of the plant extracts enhanced GSIS or insulin content in INS 832/13 beta cells. It is concluded that the Cree pharmacopoeia contains several plants with significant anti-diabetic potential.

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The seeds of Nigella sativa L. (NS), a plant of the Runanculaceae family, are used in traditional medicine in North Africa and the Middle East for the treatment of diabetes. Despite widespread use and a number of scientific studies, the target tissues and cellular mechanisms of action of this plant product are not well understood. This study evaluated the effects of NS seed crude ethanol extract on insulin secretion in INS832/13 and βTC-tet lines of pancreatic β-cells and on glucose disposal by C2C12 skeletal muscle cells and 3T3-L1 adipocytes. An 18-h treatment with NS amplified glucose-stimulated insulin secretion by more than 35% without affecting sensitivity to glucose. NS treatment also accelerated β-cell proliferation. An 18-h treatment with NS increased basal glucose uptake by 55% (equivalent to approximately two-fold the effect of 100 nM insulin) in muscle cells and approximately by 400% (equal to the effect of 100 nM insulin) in adipocytes; this effect was perfectly additive to that of insulin in adipocytes. Finally, NS treatment of pre-adipocytes undergoing differentiation accelerated triglyceride accumulation comparably with treatment with 10 µM rosiglitazone. It is concluded that the well-documented in vivo antihyperglycemic effects of NS seed extract are attributable to a combination of therapeutically relevant insulinotropic and insulin-like properties.

Resistance to anti-PD1-based immune checkpoint blockade (ICB) remains a problem for the treatment of metastatic melanoma. Tumor cells as well as host myeloid cells can express the immune checkpoint ligand CD155 to regulate immune cell function. However, the effect of tumor CD155 on the immune context of human melanoma has not been well described. This observational study characterizes tumor CD155 ligand expression by metastatic melanoma tumors and correlates results with differences in immune cell features and response to ICB.Experimental Design: Pretreatment tumor specimens, from 155 patients with metastatic melanoma treated with ICB and from 50 patients treated with BRAF/MEK-directed targeted therapy, were assessed for CD155 expression by IHC. Intratumor T-cell features were analyzed using multiplex-immunohistofluorescence for CD8, PD1, and SOX10. Correlations were made between CD155 tumor level and bulk tumor RNA sequencing results, as well as clinical RECIST response and progression-free survival.Results: High pretreatment CD155 tumor levels correlated with high parenchymal PD1 þ CD8 þ /CD8 þ T-cell ratios (PD1 tR ) and poor response to anti-PD1 therapy. In PDL1 negative tumors, high CD155 tumor expression was associated with patients who had poor response to combination anti-PD1/ CTLA4 therapy.Conclusions: Our findings are the first to suggest that tumor CD155 supports an increase in the fraction of PD1 þ CD8 þ T cells in anti-PD1 refractory melanoma tumors and, further, that targeting the CD155 pathway might improve response to anti-PD1 therapy for patients with metastatic melanoma.

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