Neoadjuvant atezolizumab for resectable non-small cell lung cancer: an open-label, single-arm phase II trial.

In an ongoing, open-label, single-arm phase II study ( NCT02927301 ), 181 patients with untreated, resectable, stage IB-IIIB non-small cell lung cancer received two doses of neoadjuvant atezolizumab monotherapy. The primary end point was major pathological response (MPR; ≤10% viable malignant cells) in resected tumors without EGFR or ALK alterations. Of the 143 patients in the primary end point analysis, the MPR was 20% (95% confidence interval, 14-28%). With a minimum duration of follow-up of 3 years, the 3-year survival rate of 80% was encouraging. The most common adverse events during the neoadjuvant phase were fatigue (39%, 71 of 181) and procedural pain (29%, 53 of 181), along with expected immune-related toxicities; there were no unexpected safety signals. In exploratory analyses, MPR was predicted using the pre-treatment peripheral blood immunophenotype based on 14 immune cell subsets. Immune cell subsets predictive of MPR in the peripheral blood were also identified in the tumor microenvironment and were associated with MPR. This study of neoadjuvant atezolizumab in a large cohort of patients with resectable non-small cell lung cancer was safe and met its primary end point of MPR ≥ 15%. Data from this single-arm, non-randomized trial suggest that profiles of innate immune cells in pre-treatment peripheral blood may predict pathological response after neoadjuvant atezolizumab, but additional studies are needed to determine whether these profiles can inform patient selection and new therapeutic approaches.

EGFR High Copy Number Together With High EGFR Protein Expression Predicts Improved Outcome for Cetuximab-based Therapy in Squamous Cell Lung Cancer: Analysis From SWOG S0819, a Phase III Trial of Chemotherapy With or Without Cetuximab in Advanced NSCLC.

BACKGROUND: The phase III S0819 trial investigated addition of cetuximab to first-line chemotherapy (CT) in NSCLC. Subgroup analyses suggested an OS benefit among patients with EGFR copy number gain in squamous cell carcinomas (SCC), (HR = 0.58 [0.39-0.86], P = .0071). A more detailed model based on EGFR FISH, EGFR IHC and KRAS mutation status was evaluated to yield a more precise predictive paradigm of cetuximab-based therapy in advanced NSCLC. METHODS: FISH was performed using the Colorado Scoring Criteria; H-Score was used to quantify EGFR IHC expression (cut-off ≥ 200). A Cox model was used to assess treatment effects for OS and PFS within biomarker and clinical subgroups. KRAS mutation was analyzed using Therascreen. The false discovery rate controlled for multiple comparisons. S0819 ClinicalTrials.gov Identifier: NCT00946712. RESULTS: Of 1,313 eligible patients, assay results were obtained for FISH on 976 patients (41% positive), for IHC on 945 patients (31% positive), and KRAS mutation status on 627 patients (26% positive). In SCC patients, OS was significantly improved with addition of cetuximab when both EGFR FISH and EGFR IHC were positive (N = 58), (OS HR: 0.32 [95% CI 0.18-0.59]; P = .0002, q = 0.08), median 12.6 versus 4.6 months. The results were independent of KRAS mutation status. In Non-SCC, no predictive value of EGFR IHC, EGFR FISH status and/or KRAS status was seen. CONCLUSIONS: In NSCLC SCC, a combination index of EGFR FISH plus EGFR IHC results was associated with improved OS when cetuximab was added to CT, representing a potential predictive molecular paradigm for patients suitable for EGFR-antibody therapy.

Testing Cancer Immunotherapy in a Human Immune System Mouse Model: Correlating Treatment Responses to Human Chimerism, Therapeutic Variables and Immune Cell Phenotypes.

Over the past decade, immunotherapies have revolutionized the treatment of cancer. Although the success of immunotherapy is remarkable, it is still limited to a subset of patients. More than 1500 clinical trials are currently ongoing with a goal of improving the efficacy of immunotherapy through co-administration of other agents. Preclinical, small-animal models are strongly desired to increase the pace of scientific discovery, while reducing the cost of combination drug testing in humans. Human immune system (HIS) mice are highly immune-deficient mouse recipients rtpeconstituted with human hematopoietic stem cells. These HIS-mice are capable of growing human tumor cell lines and patient-derived tumor xenografts. This model allows rapid testing of multiple, immune-related therapeutics for tumors originating from unique clinical samples. Using a cord blood-derived HIS-BALB/c-Rag2nullIl2rγnullSIRPαNOD (BRGS) mouse model, we summarize our experiments testing immune checkpoint blockade combinations in these mice bearing a variety of human tumors, including breast, colorectal, pancreatic, lung, adrenocortical, melanoma and hematological malignancies. We present in-depth characterization of the kinetics and subsets of the HIS in lymph and non-lymph organs and relate these to protocol development and immune-related treatment responses. Furthermore, we compare the phenotype of the HIS in lymph tissues and tumors. We show that the immunotype and amount of tumor infiltrating leukocytes are widely-variable and that this phenotype is tumor-dependent in the HIS-BRGS model. We further present flow cytometric analyses of immune cell subsets, activation state, cytokine production and inhibitory receptor expression in peripheral lymph organs and tumors. We show that responding tumors bear human infiltrating T cells with a more inflammatory signature compared to non-responding tumors, similar to reports of "responding" patients in human immunotherapy clinical trials. Collectively these data support the use of HIS mice as a preclinical model to test combination immunotherapies for human cancers, if careful attention is taken to both protocol details and data analysis.

c-MET as a biomarker in patients with surgically resected non-small cell lung cancer.

BACKGROUND: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet. PATIENTS AND METHODS: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored. RESULTS: c-MET H-score ≥20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64-0.97). The prognostic effect of c-MET H-score ≥20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40-0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43-0.83). CONCLUSION: c-MET H-score ≥20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score ≥20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC.

Hepatic Metastases is Associated with Poor Efficacy of Erlotinib as 2nd/3rd Line Therapy in Patients with Lung Adenocarcinoma.

BACKGROUND: Hepatocyte growth factor (HGF)-mediated mesenchymal-to-epithelial transition factor (MET) gene amplification is a common mechanism for acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs). MET gene amplification has also been associated with hepatic metastases in patients with lung cancer. The aim of this study was to investigate whether hepatic metastases are associated with decreased efficacy of erlotinib in patients with adenocarcinoma. MATERIAL/METHODS: A cohort of 329 patients with stage IV lung adenocarcinoma, known EGFR mutation status, and who received treatment with erlotinib in the 2nd or 3rd line setting were enrolled into this study over a period of 4 years between January 2011 and January 2015. The cohort was stratified based on the presence or absence of hepatic metastases and the efficacy of erlotinib was defined based on disease control rate (DCR) and progression-free survival (PFS). RESULTS: Hepatic metastases were present in 220 of the 329 enrolled lung adenocarcinoma patients. EGFR-activating mutations (exon 19 deletion or an exon 21 L858R mutation) were identified in 113 (34.3%) patients. The DCR was significantly lower in the hepatic metastases group than in patients without hepatic metastases (39.5% vs. 51.4% P=0.045). In patients with hepatic metastases, median PFS was 2.3 months in the EGFR mutation-positive group versus 1.4 months in the EGFR mutation-negative group (95% CI 1.3-3.3 vs. 1.3-1.5; P=0.055). Of note, erlotinib therapy in patients with hepatic metastases was complicated by elevated alanine transaminase (ALT) levels. CONCLUSIONS: Hepatic metastasis in patients with lung adenocarcinoma predicts poor response to erlotinib as a 2nd/3rd line therapy. Combination therapy, for example with MET-TKI, may be a good choice for patients with liver metastases with poor prognosis.

Uric acid in metabolic syndrome: From an innocent bystander to a central player.

Uric acid, once viewed as an inert metabolic end-product of purine metabolism, has been recently incriminated in a number of chronic disease states, including hypertension, metabolic syndrome, diabetes, non-alcoholic fatty liver disease, and chronic kidney disease. Several experimental and clinical studies support a role for uric acid as a contributory causal factor in these conditions. Here we discuss some of the major mechanisms linking uric acid to metabolic and cardiovascular diseases. At this time the key to understanding the importance of uric acid in these diseases will be the conduct of large clinical trials in which the effect of lowering uric acid on hard clinical outcomes is assessed. Elevated uric acid may turn out to be one of the more important remediable risk factors for metabolic and cardiovascular diseases.

Fructokinase, Fructans, Intestinal Permeability, and Metabolic Syndrome: An Equine Connection?

Fructose is a simple sugar present in honey and fruit, but can also exist as a polymer (fructans) in pasture grasses. Mammals are unable to metabolize fructans, but certain gram positive bacteria contain fructanases and can convert fructans to fructose in the gut. Recent studies suggest that fructose generated from bacteria, or directly obtained from the diet, can induce both increased intestinal permeability and features of metabolic syndrome, especially the development of insulin resistance. The development of insulin resistance is driven in part by the metabolism of fructose by fructokinase C in the liver, which results in oxidative stress in the hepatocyte. Similarly, the metabolism of fructose in the small bowel by intestinal fructokinase may lead to increased intestinal permeability and endotoxemia. While speculative, these observations raise the possibility that the mechanism by which fructans induce laminitis could involve intestinal and hepatic fructokinase. Further studies are indicated to determine the role of fructanases, fructose and fructokinase in equine metabolic syndrome and laminitis.

Minimal change disease in graft versus host disease: a podocyte response to the graft?

Nephrotic syndrome is a rare complication of hematopoietic cell transplantation. It has been suggested that nephrotic syndrome may represent a limited form of graft-versus-host disease although the pathological link between these two entities remains unclear. In this paper, we report a case of a 61-year-old female who underwent nonmyeloablative allogenic stem cell transplantation for T-cell prolymphocytic leukemia and subsequently developed biopsy proven minimal change disease shortly after cessation of her immunosuppression therapy. Urinary CD80 was markedly elevated during active disease and disappeared following corticosteroid-induced remission. We hypothesize that alloreactive donor T cells target the kidney and induce podocyte expression of CD80 that results in proteinuria from limited 'graft versus host' disease.

Macrophages mediate lung inflammation in a mouse model of ischemic acute kidney injury.

Serum IL-6 is increased in acute kidney injury (AKI) and inhibition of IL-6 reduces AKI-mediated lung inflammation. We hypothesized that circulating monocytes produce IL-6 and that alveolar macrophages mediate lung inflammation after AKI via chemokine (CXCL1) production. To investigate systemic and alveolar macrophages in lung injury after AKI, sham operation or 22 min of renal pedicle clamping (AKI) was performed in three experimental settings: 1) systemic macrophage depletion via diphtheria toxin (DT) injection to CD11b-DTR transgenic mice, 2) DT injection to wild-type mice, and 3) alveolar macrophage depletion via intratracheal (IT) liposome-encapsulated clodronate (LEC) administration to wild-type mice. In mice with AKI and systemic macrophage depletion (CD11b-DTR transgenic administered DT) vs. vehicle-treated AKI, blood monocytes and lung interstitial macrophages were reduced, renal function was similar, serum IL-6 was increased, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In wild-type mice with AKI administered DT vs. vehicle, serum IL-6 was increased. In mice with AKI and alveolar macrophage depletion (IT-LEC) vs. AKI with normal alveolar macrophage content, blood monocytes and lung interstitial macrophages were similar, alveolar macrophages were reduced, renal function was similar, lung inflammation was improved, lung CXCL1 was reduced, and lung capillary leak was increased. In conclusion, administration of DT in AKI is proinflammatory, limiting the use of the DTR-transgenic model to study systemic effects of AKI. Mice with AKI and either systemic mononuclear phagocyte depletion or alveolar macrophage depletion had reduced lung inflammation and lung CXCL1, but increased lung capillary leak; thus, mononuclear phagocytes mediate lung inflammation, but they protect against lung capillary leak after ischemic AKI. Since macrophage activation and chemokine production are key events in the development of acute lung injury (ALI), these data provide further evidence that AKI may cause ALI.

Minimal change disease: a "two-hit" podocyte immune disorder?

Minimal change disease (MCD) is the most common nephrotic syndrome in children and is commonly thought to be a T-cell disorder mediated by a circulating factor that alters podocyte function resulting in massive proteinuria. We suggest that MCD is a "two-hit" disorder. As originally hypothesized by Reiser et al. in 2004, we propose that the initial hit is the induction of CD80 (also known as B7.1) on the podocyte, and that this results in an alteration in shape with actin rearrangement that alters glomerular permeability and causes proteinuria. We propose that CD80 expression may result from either direct binding of the podocyte by cytokines from activated T cells or by activation of podocyte toll-like receptors (TLR) by viral products or allergens. We further hypothesize that under normal circumstances, CD80 expression is only transiently expressed and proteinuria is minimal due to rapid autoregulatory response by circulating T regulatory cells or by the podocyte itself, probably due to the expression of factors [cytotoxic T-lymphocyte-associated (CTLA)-4, interleukin (IL)-10, and possibly transforming growth factor (TGF)-ß] that downregulate the podocyte CD80 response. In MCD, however, there is a defect in CD80 podocyte autoregulation. This results in persistent CD80 expression and persistent proteinuria. If correct, this hypothesis may lead to both new diagnostic tests and potential therapeutics for this important renal disease.