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"Porter, David"
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Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies
Potent CD19-directed immunotherapies, such as chimeric antigen receptor T cells (CART) and blinatumomab, have drastically changed the outcome of patients with relapsed/refractory B cell acute lymphoblastic leukemia (B-ALL). However, CD19-negative relapses have emerged as a major problem that is observed in approximately 30% of treated patients. Developing approaches to preventing and treating antigen-loss escapes would therefore represent a vertical advance in the field. Here, we found that in primary patient samples, the IL-3 receptor α chain CD123 was highly expressed on leukemia-initiating cells and CD19-negative blasts in bulk B-ALL at baseline and at relapse after CART19 administration. Using intravital imaging in an antigen-loss CD19-negative relapse xenograft model, we determined that CART123, but not CART19, recognized leukemic blasts, established protracted synapses, and eradicated CD19-negative leukemia, leading to prolonged survival. Furthermore, combining CART19 and CART123 prevented antigen-loss relapses in xenograft models. Finally, we devised a dual CAR-expressing construct that combined CD19- and CD123-mediated T cell activation and demonstrated that it provides superior in vivo activity against B-ALL compared with single-expressing CART or pooled combination CART. In conclusion, these findings indicate that targeting CD19 and CD123 on leukemic blasts represents an effective strategy for treating and preventing antigen-loss relapses occurring after CD19-directed therapies.
Journal Article
What Makes a Good Trader? On the Role of Intuition and Reflection on Trader Performance
Using laboratory experiments, we provide evidence on three factors influencing trader performance: fluid intelligence, cognitive reflection, and theory of mind (ToM). Fluid intelligence provides traders with computational skills necessary to draw a statistical inference. Cognitive reflection helps traders avoid behavioral biases and thereby extract signals from market orders and update their prior beliefs accordingly. ToM describes the degree to which traders correctly assess the informational content of orders. We show that cognitive reflection and ToM are complementary because traders benefit from understanding signals' quality only if they are capable of processing these signals.
Journal Article
Chimeric Antigen Receptor–Modified T Cells in Chronic Lymphoid Leukemia
A patient with refractory CLL had delayed development of the rapid tumor lysis syndrome and remission after an infusion of T cells engineered to express an antigen receptor capable of recognizing B cells (CD19) coupled to two signaling molecules.
With the use of gene-transfer techniques, T cells can be genetically modified to stably express antibodies on their surface, conferring new antigen specificity. Chimeric antigen receptors combine an antigen-recognition domain of a specific antibody with an intracellular domain of the CD3-zeta chain or FcγRI protein into a single chimeric protein.
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Although chimeric antigen receptors can trigger T-cell activation in a manner similar to that of endogenous T-cell receptors, a major impediment to the clinical application of this technique to date has been limited in vivo expansion of chimeric antigen receptor T cells and disappointing clinical activity.
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Chimeric antigen . . .
Journal Article
Decade-long leukaemia remissions with persistence of CD4+ CAR T cells
The adoptive transfer of T lymphocytes reprogrammed to target tumour cells has demonstrated potential for treatment of various cancers
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. 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 leukaemia
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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
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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
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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
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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.
Journal Article
Chimeric Antigen Receptor–Modified T Cells for Acute Lymphoid Leukemia
Chimeric antigen receptor–modified T cells have demonstrated efficacy in chronic lymphoid leukemia, an indolent disease. They have now been shown to have efficacy in two patients with rapidly progressive, treatment-refractory acute lymphoid leukemia.
Patients with relapsed and chemotherapy-refractory pre–B-cell ALL have a poor prognosis despite the use of aggressive therapies such as allogeneic hematopoietic stem-cell transplantation
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and bispecific CD19 antibody fragments.
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Chimeric antigen receptor–modified T cells that target the lineage-specific antigens CD19 and CD20 have been reported to be effective in adults with CLL and B-cell lymphomas.
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However, the effects of chimeric antigen receptor T cells on ALL blasts, a more immature leukemia that progresses more rapidly, have not been fully investigated. In particular, there has been uncertainty about whether chimeric antigen receptor T cells would expand in vivo in patients . . .
Journal Article