BACKGROUND In a phase 1 trial, axicabtagene ciloleucel (axi-cel), an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, showed efficacy in patients with refractory large B-cell lymphoma after the failure of conventional therapy. METHODS In this multicenter, phase 2 trial, we enrolled 111 patients with diffuse large B-cell lymphoma, primary mediastinal B-cell lymphoma, or transformed follicular lymphoma who had refractory disease despite undergoing recommended prior therapy. Patients received a target dose of 2×106 anti-CD19 CAR T cells per kilogram of body weight after receiving a conditioning regimen of low-dose cyclophosphamide and fludarabine. The primary end point was the rate of objective response (calculated as the combined rates of complete response and partial response). Secondary end points included overall survival, safety, and biomarker assessments. RESULTS Among the 111 patients who were enrolled, axi-cel was successfully manufactured for 110 (99%) and administered to 101 (91%). The objective response rate was 82%, and the complete response rate was 54%.With a median follow-up of 15.4 months, 42% of the patients continued to have a response, with 40% continuing to have a complete response. The overall rate of survival at 18 months was 52%. The most common adverse events of grade 3 or higher during treatment were neutropenia (in 78% of the patients), anemia (in 43%), and thrombocytopenia (in 38%). Grade 3 or higher cytokine release syndrome and neurologic events occurred in 13% and 28% of the patients, respectively. Three of the patients died during treatment. Higher CAR T-cell levels in blood were associated with response. CONCLUSIONS In this multicenter study, patients with refractory large B-cell lymphoma who received CAR T-cell therapy with axi-cel had high levels of durable response, with a safety profile that included myelosuppression, the cytokine release syndrome, and neurologic events. (Funded by Kite Pharma and the Leukemia and Lymphoma Society Therapy Acceleration Program; ZUMA-1 ClinicalTrials.gov number, NCT02348216.)

A B S T R A C T PurposePanitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and MethodsKRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. ResultsKRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P Ͻ .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. ConclusionPanitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

The binding of cytokines to their cell surface receptors activates, by tyrosine phosphorylation, a family of latent cytoplasmic transcription factors termed STATs (signal transducer and activator of transcription). After cytokine receptor activation, STATs dimerize and translocate into the nucleus to activate genes. Seven members of the STAT family, activated by a variety of cytokines, have been cloned (1-5). Genetic knockout studies indicate that STATs have highly specific functions. Stat1, the founding member of the STAT family, is essential for innate response to either viral or bacterial infection (6, 7). Stat1 is phosphorylated on a single residue, Tyr-701, in response to stimulation by a number of ligands including interferons (IFNs), interleukin 6 (IL-6), and epidermal growth factor (8-11). The phosphorylation on the Tyr-701 residue of Stat1 is required for its nuclear translocation, dimerization, DNA binding, and gene activation (8,12).Although great progress has been made toward the understanding of STAT activation, little is known about how STAT signals are down-regulated. Several mechanisms to downregulate STAT signaling have been proposed. (i) Because the activities of STATs depend on tyrosine phosphorylation, the precise recognition and dephosphorylation of STATs by their protein tyrosine phosphatases (PTPases) is expected to be crucial for gene regulation (13-16). However, it is not known what and how PTPases can dephosphorylate STATs. (ii) Inhibitors of proteosome activity are shown to prolong the activation of Stat1, implying the involvement of ubiquitination in the degradation of Stat1 (17). However, because these inhibitors also affect the half-life of IFN receptor, the importance of the degradation of Stat1 through ubiquitination pathway remains unclear (4, 16). (iii) Recently, a family of cytokine-inducible inhibitors of signaling have been isolated (18)(19)(20). This family of proteins, named SOCS͞JAB͞SSI, are relatively small protein molecules that contain mainly SH2 domains. SOCS͞JAB͞SSI proteins can directly bind to JAKs and can inhibit the tyrosine kinase activity of JAKs.We have identified recently a protein named PIAS3 (protein inhibitor of activated Stat3) that functions as a specific inhibitor of Stat3 signaling (21). We report here the identification of four additional members of the PIAS family. We found that PIAS1 was associated with Stat1, but not with Stat2 or Stat3 in vivo in cells treated with IFN or IL-6. The PIAS1-Stat1 interaction requires the phosphorylation of Stat1 on Tyr-701. Furthermore, PIAS1 but not other PIAS proteins blocked the DNA binding activity of Stat1 and inhibited Stat1-mediated gene activation. Our results suggest that PIAS1 is a specific inhibitor of Stat1-mediated gene activation. The mode of the PIAS-mediated inhibition on STAT activity is distinct from other known inhibitory mechanisms involved in STAT signaling. MATERIALS AND METHODSCells. U3A and U3A-derived cell lines were maintained in DMEM containing 10% fetal bovine serum at 10% CO 2 . Human Daud...

BackgroundMetabolomics is the rapidly evolving field of the comprehensive measurement of ideally all endogenous metabolites in a biological fluid. However, no single analytic technique covers the entire spectrum of the human metabolome. Here we present results from a multiplatform study, in which we investigate what kind of results can presently be obtained in the field of diabetes research when combining metabolomics data collected on a complementary set of analytical platforms in the framework of an epidemiological study.Methodology/Principal Findings40 individuals with self-reported diabetes and 60 controls (male, over 54 years) were randomly selected from the participants of the population-based KORA (Cooperative Health Research in the Region of Augsburg) study, representing an extensively phenotyped sample of the general German population. Concentrations of over 420 unique small molecules were determined in overnight-fasting blood using three different techniques, covering nuclear magnetic resonance and tandem mass spectrometry. Known biomarkers of diabetes could be replicated by this multiple metabolomic platform approach, including sugar metabolites (1,5-anhydroglucoitol), ketone bodies (3-hydroxybutyrate), and branched chain amino acids. In some cases, diabetes-related medication can be detected (pioglitazone, salicylic acid).Conclusions/SignificanceOur study depicts the promising potential of metabolomics in diabetes research by identification of a series of known and also novel, deregulated metabolites that associate with diabetes. Key observations include perturbations of metabolic pathways linked to kidney dysfunction (3-indoxyl sulfate), lipid metabolism (glycerophospholipids, free fatty acids), and interaction with the gut microflora (bile acids). Our study suggests that metabolic markers hold the potential to detect diabetes-related complications already under sub-clinical conditions in the general population.