The Risks and Benefits of Immune Checkpoint Blockade in Anti-AChR Antibody-Seropositive Non-Small Cell Lung Cancer Patients

Background: Anti-programmed cell death 1 (PD-1) monoclonal antibodies (Abs) unleash an immune response to cancer. However, a disruption of the immune checkpoint function by blocking PD-1/PD-ligand 1(PD-L1) signaling may trigger myasthenia gravis (MG) as a life-threatening immune-related adverse event. MG is a neuromuscular disease and is closely associated with being positive for anti-acetylcholine receptor (anti-AChR) Abs, which are high specific and diagnostic Abs for MG. Methods: A 72-year-old man was diagnosed with chemotherapy-refractory lung squamous cell carcinoma and nivolumab was selected as the third-line regimen. We describe the first report of an anti-AChR Ab-seropositive lung cancer patient achieving a durable complete response (CR) to an anti-PD-1 antibody therapy. To further explore this case, we performed multiplex immunofluorescence analysis on a pretreatment tumor. Results: The patient achieved a durable CR without developing MG. However, the levels of anti-AChR Abs were elevated during two years of anti-PD-1 antibody therapy. The tumor of the subclinical MG patient had high PD-L1 expression and an infiltrated⁻inflamed tumor immune microenvironment. Conclusions: This study suggests that immune checkpoint inhibitors can be safely used and provide the benefits for advanced cancer patients with immunologically ‘hot’ tumor even if anti-AChR Abs are positive. Although careful monitoring clinical manifestation in consultation with neurologist is needed, immune checkpoint inhibitors should be considered as a treatment option for asymptomatic anti-AChR Ab-seropositive cancer patients

Clinical effects of direct hemoperfusion using a polymyxin B-immobilized fiber column in clinically amyopathic dermatomyositis-associated rapidly progressive interstitial pneumonias

Abstract Background Rapidly progressive interstitial pneumonias (RPIPs) associated with clinically amyopathic dermatomyositis (CADM) are highly resistant to therapy and have a poor prognosis. Multimodal therapies, including direct hemoperfusion using a polymyxin B-immobilized fiber column (PMX-DHP), have a protective effect on RPIPs. We evaluated the effects of PMX-DHP on CADM-associated RPIPs. Methods We retrospectively enrolled 14 patients with CADM-associated RPIPs and acute respiratory failure treated with PMX-DHP, corticosteroids, and immunosuppressive agents. Clinical manifestations were compared between survivors and non-survivors at 90 days after PMX-DHP. Results The survival rate at 90 days after PMX-DHP was 35.7% (5/14). Before PMX-DHP, the survivor group exhibited a significantly higher PaO2/FiO2 (P/F) ratio and serum surfactant protein-D (SP-D) levels and significantly lower lactate dehydrogenase (LDH) and ferritin levels than the non-survivor group. Platelet counts were significantly decreased after PMX-DHP therapy in both groups, but remained higher in the survivor group than the non-survivor group over the course of treatment. Anti-melanoma differentiation-associated gene 5 (MDA-5) antibody positive patients demonstrated a poor 90-day survival rate, lower platelet counts and P/F ratio, and higher LDH levels than anti-MDA-5 antibody negative patients. Conclusions CADM-associated RPIPs with anti-MDA-5 antibody is associated with a very poor prognosis. A higher P/F ratio and SP-D level, lower LDH and ferritin levels, higher platelet counts, and anti-MDA-5 antibody negativity are important prognostic markers in patients with CADM-associated RPIPs treated with PMX-DHP

Efficacy of direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP) in rapidly progressive interstitial pneumonias: results of a historical control study and a review of previous studies

Background: Direct hemoperfusion using polymyxin B-immobilized fiber column (PMX-DHP) therapy has been approved for sepsis-associated acute respiratory distress syndrome, but its efficacy for other rapidly progressive interstitial pneumonias (RPIPs) is unclear. The purpose of this study was to examine the efficacy of PMX-DHP therapy for acute respiratory failure in patients with RPIPs, when compared with a historical control receiving conventional treatment without PMX-DHP. Methods: This study comprised 77 patients with RPIPs in our institute between January 2002 and December 2015. The initial 36 patients between January 2002 and March 2007 were treated without PMX-DHP (historical control group), and the following 41 patients between April 2007 and December 2015 were treated with PMX-DHP (PMX-DHP group) once daily for two successive days concurrently with corticosteroids and/or immunosuppressive agents. The 90-day mortality and clinical factors were compared between the groups. Cox proportional hazards models were constructed to analyze 90-day mortality and identify predictors. Results: The 90-day mortality rate was significantly lower in the PMX-DHP group than in the controls (41.5% versus 66.7%, p = 0.019). PMX-DHP therapy was significantly associated with mortality (hazard ratio 0.505; 95% confidence interval, 0.270–0.904; p = 0.032). There were significant differences in the serial changes in the PaO 2 /FiO 2 ratio, SOFA score, and blood neutrophil counts from days 0–5 after PMX-DHP between the survivor and non-survivor groups ( p = 0.015, p < 0.001, p = 0.035, respectively). The improved PaO 2 /FiO 2 ratio on day 3 significantly correlated with the change in blood neutrophil counts (r s = −0.431, p = 0.006). Conclusions: PMX-DHP therapy may be effective in RPIPs patients accompanied by acute respiratory failure and is expected to reduce mortality rates

Clinical Implications and Molecular Characterization of Drebrin-Positive, Tumor-Infiltrating Exhausted T Cells in Lung Cancer

T cells express an actin-binding protein, drebrin, which is recruited to the contact site between the T cells and antigen-presenting cells during the formation of immunological synapses. However, little is known about the clinical implications of drebrin-expressing, tumor-infiltrating lymphocytes (TILs). To address this issue, we evaluated 34 surgical specimens of pathological stage I&ndash;IIIA squamous cell lung cancer. The immune context of primary tumors was investigated using fluorescent multiplex immunohistochemistry. The high-speed scanning of whole-slide images was performed, and the tissue localization of TILs in the tumor cell nest and surrounding stroma was automatically profiled and quantified. Drebrin-expressing T cells were characterized using drebrin+ T cells induced in vitro and publicly available single-cell RNA sequence (scRNA-seq) database. Survival analysis using the propensity scores revealed that a high infiltration of drebrin+ TILs within the tumor cell nest was independently associated with short relapse-free survival and overall survival. Drebrin+ T cells induced in vitro co-expressed multiple exhaustion-associated molecules. The scRNA-seq analyses confirmed that the exhausted tumor-infiltrating CD8+ T cells specifically expressed drebrin. Our study suggests that drebrin-expressing T cells present an exhausted phenotype and that tumor-infiltrating drebrin+ T cells affect clinical outcomes in patients with resectable squamous cell lung cancer

Disorder of Coagulation-Fibrinolysis System: An Emerging Toxicity of Anti-PD-1/PD-L1 Monoclonal Antibodies

A disruption of immune checkpoints leads to imbalances in immune homeostasis, resulting in immune-related adverse events. Recent case studies have suggested the association between immune checkpoint inhibitors (ICIs) and the disorders of the coagulation-fibrinolysis system, implying that systemic immune activation may impact a balance between clotting and bleeding. However, little is known about the association of coagulation-fibrinolysis system disorder with the efficacy of ICIs. We retrospectively evaluated 83 lung cancer patients who received ICI at Kumamoto University Hospital. The association between clinical outcome and diseases associated with disorders of the coagulation-fibrinolysis system was assessed along with tumor PD-L1 expression. Among 83 NSCLC patients, total 10 patients (12%) developed diseases associated with the disorder of coagulation-fibrinolysis system. We found that disorders of the coagulation-fibrinolysis system occurred in patients with high PD-L1 expression and in the early period of ICI initiation. In addition, high tumor responses (72%) were observed, including two complete responses among these patients. Furthermore, we demonstrate T-cell activation strongly induces production of a primary initiator of coagulation, tissue factor in peripheral PD-L1high monocytes, in vitro. This study suggests a previously unrecognized pivotal role for immune activation in triggering disorders of the coagulation-fibrinolysis system in cancer patients during treatment with ICI