BackgroundWe assessed the efficacy and safety of programmed cell death 1 (PD-1) inhibition with pembrolizumab in patients with advanced non–small-cell lung cancer enrolled in a phase 1 study. We also sought to define and validate an expression level of the PD-1 ligand 1 (PD-L1) that is associated with the likelihood of clinical benefit. MethodsWe assigned 495 patients receiving pembrolizumab (at a dose of either 2 mg or 10 mg per kilogram of body weight every 3 weeks or 10 mg per kilogram every 2 weeks) to either a training group (182 patients) or a validation group (313 patients). We assessed PD-L1 expression in tumor samples using immunohistochemical analysis, with results reported as the percentage of neoplastic cells with staining for membranous PD-L1 (proportion score). Response was assessed every 9 weeks by central review. ResultsCommon side effects that were attributed to pembrolizumab were fatigue, pruritus, and decreased appetite, with no clear difference according to dose or schedule. Among all ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1501824

Pembrolizumab for the treatment of non-small cell lung cancer

The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor–1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair–deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair–deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers’ tissue of origin.

/pdf/mismatch-repair-deficiency-predicts-response-of-solid-tumors-2mgnsq9rdf.pdf

Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade

Colorectal cancer (CRC) is a frequently lethal disease with heterogeneous outcomes and drug responses. To resolve inconsistencies among the reported gene expression-based CRC classifications and facilitate clinical translation, we formed an international consortium dedicated to large-scale data sharing and analytics across expert groups. We show marked interconnectivity between six independent classification systems coalescing into four consensus molecular subtypes (CMSs) with distinguishing features: CMS1 (microsatellite instability immune, 14%), hypermutated, microsatellite unstable and strong immune activation; CMS2 (canonical, 37%), epithelial, marked WNT and MYC signaling activation; CMS3 (metabolic, 13%), epithelial and evident metabolic dysregulation; and CMS4 (mesenchymal, 23%), prominent transforming growth factor-β activation, stromal invasion and angiogenesis. Samples with mixed features (13%) possibly represent a transition phenotype or intratumoral heterogeneity. We consider the CMS groups the most robust classification system currently available for CRC-with clear biological interpretability-and the basis for future clinical stratification and subtype-based targeted interventions.

https://serval.unil.ch/resource/serval:BIB_6206DC2BFE0E.P001/REF.pdf

The consensus molecular subtypes of colorectal cancer

Immunotherapy is proving to be an effective therapeutic approach in a variety of cancers. But despite the clinical success of antibodies against the immune regulators CTLA4 and PD-L1/PD-1, only a subset of people exhibit durable responses, suggesting that a broader view of cancer immunity is required. Immunity is influenced by a complex set of tumour, host and environmental factors that govern the strength and timing of the anticancer response. Clinical studies are beginning to define these factors as immune profiles that can predict responses to immunotherapy. In the context of the cancer-immunity cycle, such factors combine to represent the inherent immunological status - or 'cancer-immune set point' - of an individual.

Elements of cancer immunity and the cancer–immune set point

https://thelancet.com/pdfs/journals/lancet/PIIS0140-6736(16)00561-4.pdf

Atezolizumab in patients with locally advanced and metastatic urothelial carcinoma who have progressed following treatment with platinum-based chemotherapy: A single-arm, multicentre, phase 2 trial

BackgroundSomatic mutations have the potential to encode “non-self” immunogenic antigens. We hypothesized that tumors with a large number of somatic mutations due to mismatch-repair defects may be susceptible to immune checkpoint blockade. MethodsWe conducted a phase 2 study to evaluate the clinical activity of pembrolizumab, an anti–programmed death 1 immune checkpoint inhibitor, in 41 patients with progressive metastatic carcinoma with or without mismatch-repair deficiency. Pembrolizumab was administered intravenously at a dose of 10 mg per kilogram of body weight every 14 days in patients with mismatch repair–deficient colorectal cancers, patients with mismatch repair–proficient colorectal cancers, and patients with mismatch repair–deficient cancers that were not colorectal. The coprimary end points were the immune-related objective response rate and the 20-week immune-related progression-free survival rate. ResultsThe immune-related objective response rate and immune-related progression-free survival ...

/pdf/pd-1-blockade-in-tumors-with-mismatch-repair-deficiency-1eb0ztv7j7.pdf

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

There are few morphologic studies on idiopathic dilated cardiomyopathy (CM) treated with transplant. We prospectively correlated gross, histologic, and clinical findings pertaining to hearts explanted in a 5-year period from patients with a clinical diagnosis of nonischemic CM and also correlated left ventricular diameter with preoperative echocardiographic reports. Of 64 patients with a clinical diagnosis of dilated cardiomyopathy (DC), 42 were men (age, 51 ± 13 y) and 22 were women (age, 42 ± 18 y). The pathologic diagnosis was idiopathic (dilated) cardiomyopathy (DC) in 55 patients (86%) and features of specific CM in 9 patients (14%). Specific diagnoses were fibrofatty change consistent with arrhythmogenic right ventricular cardiomyopathy (n=6), amyloidosis (n=2), and sarcoidosis (n=1), none of which were suspected clinically. The 55 hearts with idiopathic DC had a mean heart weight of 508 (range, 220 to 980) g. Pathologic subsets of the DC group included 4 hearts without enlargement, cavity dilatation, or significant histologic findings (minimal DC); 3 hearts with histologic evidence of healed myocarditis; and 5 hearts with mildly noncompacted left ventricle with hypertrabeculation. Five patients had prior mitral or tricuspid valve replacement/repairs to manage heart failure. There were 7 postpartum DC cases, 1 with a histologic pattern of healed myocarditis and 1 alcoholism-associated DC. Familial DC comprised 16% (9 of 55) of patients. In patients without prior assist device placement, pathologic left ventricular cavity diameter correlated with echocardiographic end-diastolic volume (r , 0.8, P<0.0001). Morphologically, DC is a heterogeneous group. Areas of fibrofatty change and features of noncompaction are not uncommon. Left ventricular measurement at explant correlates well with echocardiographic findings, with a relatively consistent underestimation of the diameter.

Allograft pathology in patients transplanted for idiopathic dilated cardiomyopathy.

Tactile corpuscle-like bodies (TCLB) are microscopic Schwannian structures that simulate the superficial mechanoreceptors of the peripheral nervous system (Wagner-Meissner corpuscles). They have been described nearly exclusively in peripheral nerve sheath tumors, namely diffuse neurofibromas, and schwannomas but also in cellular nevi. There are rare reports of these structures in the gastrointestinal tract (predominantly the lower tract), with the presumption that they are incidental reactive neural proliferations. We compiled 9 cases showing this rare phenomenon in gastrointestinal-type mucosa in nonsyndromic patients to further characterize its features. There were 6 men and 3 women (age range, 39 to 79 y, mean 56 y) with lesions involving esophagus/gastro-esophageal junction (n=7), sigmoid colon (n=1), and gastric heterotopia of the cricopharynx (n=1). Endoscopic examination was abnormal in 6 of the 7 cases (including changes consistent with Barrett esophagus and polypoid/nodular mucosa) and normal in 1 of 7 cases for which this information was available. The histologic features were similar in all cases, with unencapsulated clusters of lamellated and concentrically arranged spindle cells in the lamina propria. The foci of TCLB ranged in size from <0.1 to 1.5 mm in the greatest dimension. Abnormal histopathologic findings were identified in the background mucosa in 6 of 9 cases (including Barrett esophagus, active and inactive chronic gastritis, enterochromaffin-like cell hyperplasia, and gastric intestinal metaplasia). None of the patients showed signs of neurofibromatosis type 1, multiple endocrine neoplasia type 2B, Cowden syndrome, or other inherited syndrome. No morbidity related to TCLB was reported for the patients with available follow-up.

Thomas Huebner

Papers

PD-1 Blockade in Tumors with Mismatch-Repair Deficiency

Allograft pathology in patients transplanted for idiopathic dilated cardiomyopathy.

Tactile Corpuscle-like Bodies in Gastrointestinal-type Mucosa: A Case Series.