Search

BACKGROUND. CAR T cells are a promising therapy for hematologic malignancies. B cell maturation antigen (BCMA) is a rational target in multiple myeloma (MM). METHODS. We conducted a phase I study of autologous T cells lentivirally transduced with a fully human, BCMA-specific CAR containing CD3[zeta] and 4-1BB signaling domains (CART-BCMA), in subjects with relapsed/refractory MM. Twenty-five subjects were treated in 3 cohorts as follows: cohort 1, 1 x [10.sup.8] to 5 x [10.sup.8] CART-BCMA cells alone; cohort 2, cyclophosphamide (Cy) 1.5 g/ [m.sup.2] plus 1 x [10.sup.7] to 5 x [10.sup.7] CART-BCMA cells; cohort 3, Cy 1.5 g/[m.sup.2] plus 1 x [10.sup.8] to 5 x [10.sup.8] CART-BCMA cells. No prespecified BCMA expression level was required. RESULTS. CART-BCMA cells were manufactured and expanded in all subjects. Toxicities included cytokine release syndrome and neurotoxicity, which were grade 3-4 in 8 (32%) and 3 (12%) subjects, respectively, and reversible. One subject died at day 24 from candidemia and progressive myeloma, following treatment for severe cytokine release syndrome and encephalopathy. Responses (based on treated subjects) were seen in 4 of 9 (44%) in cohort 1, 1 of 5 (20%) in cohort 2, and 7 of 11 (64%) in cohort 3, including 5 partial, 5 very good partial, and 2 complete responses, 3 of which were ongoing at 11, 14, and 32 months. Decreased BCMA expression on residual MM cells was noted in responders; expression increased at progression in most. Responses and CART-BCMA expansion were associated with CD4/CD8 T cell ratio and frequency of [CD45RO.sup.-] [CD27.sup.+][CD8.sup.+] T cells in the premanufacturing leukapheresis product. CONCLUSION. CART-BCMA infusions with or without lymphodepleting chemotherapy are clinically active in heavily pretreated patients with MM. TRIAL REGISTRATION. NCT02546167. FUNDING. University of Pennsylvania-Novartis Alliance and NIH., Introduction Despite advances in multiple myeloma (MM) therapy, the disease remains incurable in most patients, and novel approaches are needed. B cell maturation antigen (BCMA) is a cell surface receptor [...]

An infinite hidden Markov model (iHMM) is used for unusual-event detection in a video sequence. The iHMM maintains a full posterior density function on all model parameters.

There is an error in S3 Table. Some data in the columns are duplicated. Please view the correct S3 Table below.Supporting informationS3 Table(XLSX)By Adam A. Friedman; Arnaud Amzallag; Iulian Pruteanu-Malinici; Subash Baniya; Zachary A. Cooper; Adriano Piris; Leeza Hargreaves; Vivien Igras; Dennie T. Frederick; Donald P. Lawrence; Daniel A. Haber; Keith T. Flaherty; Jennifer A. Wargo; Sridhar Ramaswamy; Cyril H. Benes and David E. FisherReported by Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author; Author [Extracted from the article]

The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers1–7. However, little is known about the long-term potential and clonal stability of the infused cells. Here we studied long-lasting CD19-redirected chimeric antigen receptor (CAR) T cells in two patients with chronic lymphocytic leukaemia1–4 who achieved a complete remission in 2010. CAR T cells remained detectable more than ten years after infusion, with sustained remission in both patients. Notably, a highly activated CD4+ population emerged in both patients, dominating the CAR T cell population at the later time points. This transition was reflected in the stabilization of the clonal make-up of CAR T cells with a repertoire dominated by a small number of clones. Single-cell profiling demonstrated that these long-persisting CD4+ CAR T cells exhibited cytotoxic characteristics along with ongoing functional activation and proliferation. In addition, longitudinal profiling revealed a population of gamma delta CAR T cells that prominently expanded in one patient concomitant with CD8+ CAR T cells during the initial response phase. Our identification and characterization of these unexpected CAR T cell populations provide novel insight into the CAR T cell characteristics associated with anti-cancer response and long-term remission in leukaemia.Infusion of CD19-directed chimeric antigen receptor T cells into two patients with chronic lymphocytic leukaemia resulted in complete tumour remission and persistence of the infused cells more than ten years later. [ABSTRACT FROM AUTHOR]

We consider the problem of inferring and modeling topics in a sequence of documents with known publication dates. The documents at a given time are each characterized by a topic and the topics are drawn from a mixture model. The proposed model infers the change in the topic mixture weights as a function of time. The details of this general framework may take different forms, depending on the specifics of the model. For the examples considered here, we examine base measures based on independent multinomial-Dirichlet measures for representation of topic-dependent word counts. The form of the hierarchical model allows efficient variational Bayesian inference, of interest for large-scale problems. We demonstrate results and make comparisons to the model when the dynamic character is removed, and also compare to latent Dirichlet allocation (LDA) and Topics over Time (TOT). We consider a database of Neural Information Processing Systems papers as well as the US Presidential State of the Union addresses from 1790 to 2008. [ABSTRACT FROM AUTHOR]

High levels of IL1β can result in chronic inflammation, which in turn can promote tumor growth and metastasis. Inhibition of IL1β could therefore be a promising therapeutic option in the treatment of cancer. Here, the effects of IL1β blockade induced by the mAbs canakinumab and gevokizumab were evaluated alone or in combination with docetaxel, anti-programmed cell death protein 1 (anti-PD-1), anti-VEGFα, and anti-TGFβ treatment in syngeneic and humanized mouse models of cancers of different origin. Canakinumab and gevokizumab did not show notable efficacy as single-agent therapies; however, IL1β blockade enhanced the effectiveness of docetaxel and anti-PD-1. Accompanying these effects, blockade of IL1β alone or in combination induced significant remodeling of the tumor microenvironment (TME), with decreased numbers of immune suppressive cells and increased tumor infiltration by dendritic cells (DC) and effector T cells. Further investigation revealed that cancer-associated fibroblasts (CAF) were the cell type most affected by treatment with canakinumab or gevokizumab in terms of change in gene expression. IL1β inhibition drove phenotypic changes in CAF populations, particularly those with the ability to influence immune cell recruitment. These results suggest that the observed remodeling of the TME following IL1β blockade may stem from changes in CAF populations. Overall, the results presented here support the potential use of IL1β inhibition in cancer treatment. Further exploration in ongoing clinical studies will help identify the best combination partners for different cancer types, cancer stages, and lines of treatment., (©2023 American Association for Cancer Research.)