Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer.

BackgroundT cells engineered to express chimeric antigen receptors (CARs) have established efficacy in the treatment of B-cell malignancies, but their relevance in solid tumors remains undefined. Here we report results of the first human trials of CAR-T cells in the treatment of solid tumors performed in the 1990s.MethodsPatients with metastatic colorectal cancer (CRC) were treated in two phase 1 trials with first-generation retroviral transduced CAR-T cells targeting tumor-associated glycoprotein (TAG)-72 and including a CD3-zeta intracellular signaling domain (CART72 cells). In trial C-9701 and C-9702, CART72 cells were administered in escalating doses up to 1010 total cells; in trial C-9701 CART72 cells were administered by intravenous infusion. In trial C-9702, CART72 cells were administered via direct hepatic artery infusion in patients with colorectal liver metastases. In both trials, a brief course of interferon-alpha (IFN-α) was given with each CART72 infusion to upregulate expression of TAG-72.ResultsFourteen patients were enrolled in C-9701 and nine in C-9702. CART72 manufacturing success rate was 100% with an average transduction efficiency of 38%. Ten patients were treated in CC-9701 and 6 in CC-9702. Symptoms consistent with low-grade, cytokine release syndrome were observed in both trials without clear evidence of on target/off tumor toxicity. Detectable, but mostly short-term (≤14 weeks), persistence of CART72 cells was observed in blood; one patient had CART72 cells detectable at 48 weeks. Trafficking to tumor tissues was confirmed in a tumor biopsy from one of three patients. A subset of patients had 111Indium-labeled CART72 cells injected, and trafficking could be detected to liver, but T cells appeared largely excluded from large metastatic deposits. Tumor biomarkers carcinoembryonic antigen (CEA) and TAG-72 were measured in serum; there was a precipitous decline of TAG-72, but not CEA, in some patients due to induction of an interfering antibody to the TAG-72 binding domain of humanized CC49, reflecting an anti-CAR immune response. No radiologic tumor responses were observed.ConclusionThese findings demonstrate the relative safety of CART72 cells. The limited persistence supports the incorporation of co-stimulatory domains in the CAR design and the use of fully human CAR constructs to mitigate immunogenicity

Statin-Associated Muscular and Renal Adverse Events: Data Mining of the Public Version of the FDA Adverse Event Reporting System

OBJECTIVE: Adverse event reports (AERs) submitted to the US Food and Drug Administration (FDA) were reviewed to assess the muscular and renal adverse events induced by the administration of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) and to attempt to determine the rank-order of the association. METHODS: After a revision of arbitrary drug names and the deletion of duplicated submissions, AERs involving pravastatin, simvastatin, atorvastatin, or rosuvastatin were analyzed. Authorized pharmacovigilance tools were used for quantitative detection of signals, i.e., drug-associated adverse events, including the proportional reporting ratio, the reporting odds ratio, the information component given by a Bayesian confidence propagation neural network, and the empirical Bayes geometric mean. Myalgia, rhabdomyolysis and an increase in creatine phosphokinase level were focused on as the muscular adverse events, and acute renal failure, non-acute renal failure, and an increase in blood creatinine level as the renal adverse events. RESULTS: Based on 1,644,220 AERs from 2004 to 2009, signals were detected for 4 statins with respect to myalgia, rhabdomyolysis, and an increase in creatine phosphokinase level, but these signals were stronger for rosuvastatin than pravastatin and atorvastatin. Signals were also detected for acute renal failure, though in the case of atorvastatin, the association was marginal, and furthermore, a signal was not detected for non-acute renal failure or for an increase in blood creatinine level. CONCLUSIONS: Data mining of the FDA's adverse event reporting system, AERS, is useful for examining statin-associated muscular and renal adverse events. The data strongly suggest the necessity of well-organized clinical studies with respect to statin-associated adverse events

Cellular Therapy with Engineered T Cells, Efficacy and Side Effects

The cellular basis of cancer immune surveillance, already hypothesized in ancient times, was only demonstrated with the advent of HSCT. Indeed, the discovery of the nature of GVHD and its antileukemic effects (Weiden et al

Systematic evaluation of immune regulation and modulation

Cancer immunotherapies are showing promising clinical results in a variety of malignancies. Monitoring the immune as well as the tumor response following these therapies has led to significant advancements in the field. Moreover, the identification and assessment of both predictive and prognostic biomarkers has become a key component to advancing these therapies. Thus, it is critical to develop systematic approaches to monitor the immune response and to interpret the data obtained from these assays. In order to address these issues and make recommendations to the field, the Society for Immunotherapy of Cancer reconvened the Immune Biomarkers Task Force. As a part of this Task Force, Working Group 3 (WG3) consisting of multidisciplinary experts from industry, academia, and government focused on the systematic assessment of immune regulation and modulation. In this review, the tumor microenvironment, microbiome, bone marrow, and adoptively transferred T cells will be used as examples to discuss the type and timing of sample collection. In addition, potential types of measurements, assays, and analyses will be discussed for each sample. Specifically, these recommendations will focus on the unique collection and assay requirements for the analysis of various samples as well as the high-throughput assays to evaluate potential biomarkers

Association between physical activity and academic performance in Korean adolescent students

<p>Abstract</p> <p>Background</p> <p>Recently, physical activity (PA) was found to improve cognitive and memory functions in the brain; however, no epidemiological studies have specifically investigated this phenomenon in the Korean adolescent student population. The purpose of this study was to investigate the effects of various types of PA undertaken at various frequencies, on the academic performance of Korean adolescent students.</p> <p>Methods</p> <p>A total of 75,066 adolescent students (39,612 males and 35,454 females) from the 7^th to the 12^th grades took part in the 5^th Korea Youth Risk Behavior Web-based Survey (KYRBWS-V) project, conducted in 2009. Using data acquired by that survey, potential relations between PA and academic performance were explored in this current study through multivariate logistic regression analysis incorporating adjustment for covariate variables including age, body mass index, the parents’ education level, and the income status of the family.</p> <p>Results</p> <p>Compared with boys who did not regularly participate in any vigorous PA, those who did so 2, 3, or 4 times a week had greater odds of reporting an average or above-average academic performance. Compared with boys who did not participate in any moderate PA, those who did so 1, 2, 3, 4, or ≥5 times a week also had greater odds of reporting an average or above-average academic performance. Interestingly, when compared with boys who did not participate in any strengthening exercises, those undertaking strengthening exercises ≥5 times a week had lesser odds of reporting a below-average academic performance. Compared with girls who did not regularly participate in any vigorous PA, those who did so ≥5 times a week had greater odds of reporting an average or above-average academic performance. Compared with girls who did not participate in any moderate PA, those that did so 2 or 3 times a week had greater odds of reporting an average or above-average academic performance. Interestingly, when compared with girls who did not regularly participate in any strengthening exercises, those undertaking strengthening exercises ≥5 times a week had lesser odds of reporting a below-average academic performance.</p> <p>Conclusions</p> <p>Our analyses of the relevant data from the KYRBWS-V suggested that vigorous PA was positively correlated with academic performance in the case of boys, and moderate PA was positively correlated with academic performance in both boys and girls. However, strengthening exercises were not positively correlated with academic performance in boys or girls. Furthermore, when undertaken 5 or more times a week, vigorous PA in boys and strengthening exercises in both boys and girls were negatively correlated with academic performance. The results from this study are potentially relevant to the development of future education policies in Korean schools, particularly with regard to early intervention strategies designed to identify and counteract potential factors contributing to academic underachievement.</p