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May 3, 2021
BioSpace
Precision BioSciences Announces Paper Presentation at the Association for Research in Vision and Ophthalmology 2021 Annual Meeting - read this article along with other careers information, tips and advice on BioSpace
Lucy Loram
April 28, 2021
www.abc.net.au
Car buyers in the market for a used vehicle are being warned to think twice before spending big as a lack of supply leads to soaring prices and opportunistic online scams.
Michael Le Page
April 28, 2021
New Scientist
In animal studies, 'smart' immune cells genetically engineered to attack tumours in new way eradicated brain, ovarian and asbestos-related tumours where normal immune cells failed
BioSpace
April 28, 2021
BioSpace
Nkarta, Inc. (Nasdaq: NKTX), a biopharmaceutical company developing engineered natural killer (NK) cell therapies to treat cancer, today announced that the U.S. Food & Drug Administration (FDA) has cleared an Investigational New Drug (IND) application to study NKX019 in patients with relapsed or refractory B cell malignancies.
Sean Szymkowski
April 26, 2021
Roadshow
With inventory so tight, car buyers are ready to pony up and pay sticker price.
BioSpace
April 15, 2021
BioSpace
Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology company developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS® genome editing platform, today announced that Alan List, M.D. has been appointed as the Company's Chief Medical Officer and a member of the senior leadership team at Precision BioSciences.
April 15, 2021
BioSpace
Precision BioSciences Reacquires Global Rights to its Allogeneic CAR T Programs - read this article along with other careers information, tips and advice on BioSpace
Research and Markets
April 15, 2021
www.prnewswire.com:443
/PRNewswire/ -- The "Leukapheresis Market by Product (Devices, Filters, Columns, Disposables), Leukopak (Mobilized, Non-Mobilized), Indication (ALL, NHL,...
April 15, 2021
BioSpace
CERo Therapeutics Expands Leadership Team with Experts in Cell Therapy Development - read this article along with other careers information, tips and advice on BioSpace
BioSpace
April 12, 2021
BioSpace
Precision BioSciences, Inc. (Nasdaq: DTIL), a clinical stage biotechnology company developing allogeneic CAR T and in vivo gene correction therapies with its ARCUS ® genome editing platform, today announced that Stanley R. Frankel, M.D. has been appointed as a Director on the Company's Board of Directors and a member of the Board's Science and Technology Committee
BioSpace
April 9, 2021
BioSpace
Award was presented to the St. Baldrick's Foundation-Stand Up 2 Cancer Pediatric Cancer Dream Team, co-led by CHOP, at the annual AACR conference
Children's Hospital of Philadelphia
April 9, 2021
www.prnewswire.com:443
/PRNewswire/ -- Twelve researchers in the Cancer Center at Children's Hospital of Philadelphia (CHOP) have won the 2021 Team Science Award from the American...
BioSpace
April 8, 2021
BioSpace
City of Hope, a world-renowned independent research and treatment center for cancer, diabetes and other life-threatening diseases, and CytoImmune Therapeutics Inc. ("CytoImmune"), a clinical-stage biopharmaceutical company focused on commercializing novel cancer immunotherapy products, announced that they have entered into worldwide exclusive license agreements.
BioSpace
April 8, 2021
BioSpace
ONK Therapeutics Ltd, an innovative natural killer (NK) cell therapy company, today announced that Philippe Moreau MD, Professor of Clinical Hematology and Head of the Translational Research Program in Hematology and Oncology, at the University Hospital of Nantes, France, has been appointed to its Scientific Advisory Board (SAB).
Weber, E. W., Parker, K. R., Sotillo, E., Lynn, R. C., Anbunathan, H., Lattin, J., Good, Z., Belk, J. A., Daniel, B., Klysz, D., Malipatlolla, M., Xu, P., Bashti, M., Heitzeneder, S., Labanieh, L., Vandris, P., Majzner, R. G., Qi, Y., Sandor, K., Chen, L.-C., Prabhu, S., Gentles, A. J., Wandless, T. J., Satpathy, A. T., Chang, H. Y., Mackall, C. L.
April 2, 2021
Science
Chimeric antigen receptor (CAR)-T cells, which are engineered to target specific tumor antigens, are increasingly used as an immunotherapy. CAR-T cells have shown promising results in patients, particularly in hematologic cancers, but their anticancer activity can be limited by the onset of exhaustion and the loss of effectiveness. Weber et al. characterized the phenotypic and epigenomic changes associated with CAR-T cell exhaustion caused by continuous activity and the beneficial effects of transient rest periods (see the Perspective by Mamonkin and Brenner). The authors tested different approaches for providing these rest periods, such as using the drug dasatinib to temporarily suppress T cell activity, which helped to prevent exhaustion and improved antitumor activity in mouse models. Science , this issue p. [eaba1786][1]; see also p. [34][2] ### INTRODUCTION More than 50% of patients treated with chimeric antigen receptor (CAR)-T cells for B cell malignancies develop progressive disease after CAR therapy, and these agents have not demonstrated consistent activity against solid tumors. CAR-T cell efficacy is often limited by T cell exhaustion, wherein global transcriptional and epigenetic alterations drive overexpression of immune inhibitory proteins and diminish function. Current therapeutic approaches for targeting T cell exhaustion, including immune checkpoint inhibitors, do not remodel the exhaustion-associated epigenome, which has led some to conclude that T cell exhaustion is an epigenetically fixed state with limited potential for reversal. ### RATIONALE We had previously demonstrated that human T cell exhaustion can be induced and maintained by tonic CAR signaling, and we therefore hypothesized that the inhibition of CAR signaling, or rest, could prevent and potentially reverse exhaustion in CAR-T cell populations. Rest was induced using a drug-regulatable degron system, whereby CAR expression and tonic CAR signaling were controlled by the presence (ON) or absence (OFF) of a small molecule. In an alternative approach, CAR-T cells were rested using dasatinib, a clinically available tyrosine kinase inhibitor which potently and reversibly inhibits essential proximal CAR signaling kinases. Rest was induced either just before the manifestation of the exhaustion or after cells had acquired full phenotypic, functional, transcriptomic, and epigenetic hallmarks of exhaustion. Multiomics analyses and functional studies in vitro and in xenograft models were conducted to examine the effects of rest on tonically signaling CAR-T cells and nontonically signaling CAR-T cells exposed to high tumor burdens. ### RESULTS Tonically signaling CAR-T cells expanded ex vivo in the ON state manifested phenotypic, transcriptional, and epigenetic hallmarks of exhaustion, whereas CAR-T cells expanded exclusively in the OFF state or in the presence of dasatinib exhibited diminished tonic CAR signaling, which resulted in a memory-like phenotype and superior antitumor activity both in vitro and following adoptive transfer into xenograft-bearing mice. The induction of rest in tonically signaling, pre-exhausted CAR-T cells redirected their cell fate away from exhaustion and toward a memory-like state. In CAR-T cells that had already acquired hallmark features of exhaustion, the induction of rest for as few as 4 days reversed the exhaustion phenotype and induced transcriptional reprogramming and global epigenetic remodeling to resemble healthy, nonexhausted controls. Further, exhausted CAR-T cells subjected to rest, including those previously exposed to 6 weeks of tonic CAR signaling, demonstrated restored antitumor functionality. The degree of functional reinvigoration was correlated with the duration of rest and was associated with decreased expression of the exhaustion-associated transcription factor TOX and increased expression of memory-associated transcription factors LEF1 and TCF1. These findings were not attributable to the outgrowth of a small subset of exhaustion-resistant cells because they were not associated with marked changes in proliferation, apoptosis, or clonal restriction of the T cell receptor (TCR) repertoire. Rather, functional reinvigoration was dependent on the activity of the histone methyltransferase EZH2, consistent with epigenetic remodeling in response to rest. Using dasatinib-insensitive liquid and solid-tumor xenograft models, CAR-T cells subjected to intermittent rest through the oscillation of CAR expression or pulsed dasatinib in vivo exhibited superior tumor control and enhanced survival compared with control mice. Single-cell analyses demonstrated that a single dasatinib pulse was sufficient to induce a memory-like phenotype and enhance functionality in exhausted tumor-infiltrating CAR-T cells ### CONCLUSION Inhibition of CAR signaling can enhance CAR-T cell fitness by preventing exhaustion, and it may have utility in clinical CAR-T cell manufacturing settings to enhance therapeutic efficacy. Moreover, in T cells that have acquired hallmark features of exhaustion, transient inhibition of CAR signaling, or rest, restores functionality and leads to global epigenetic remodeling, thereby challenging the notion that exhaustion is an epigenetically fixed state. These results predict that regulatable CAR-T cell regimens that are designed to incorporate periods of rest may exhibit superior efficacy compared with constitutive platforms, and they raise the prospect that targeting proximal CAR or TCR signaling kinases may represent an immunotherapeutic strategy for mitigating T cell exhaustion. ![Figure][3] Giving exhausted CAR-T cells a break. Exhaustion in CAR-T cells is promoted and maintained by excessive CAR signaling (left). Transient inhibition of CAR signaling, or rest, reverses phenotypic and transcriptional hallmarks of exhaustion, remodels the exhaustion-associated epigenome, and restores antitumor functionality (right). The duration of rest correlates with the degree to which functionality is restored. TFs, transcription factors. T cell exhaustion limits immune responses against cancer and is a major cause of resistance to chimeric antigen receptor (CAR)-T cell therapeutics. Using murine xenograft models and an in vitro model wherein tonic CAR signaling induces hallmark features of exhaustion, we tested the effect of transient cessation of receptor signaling, or rest, on the development and maintenance of exhaustion. Induction of rest through enforced down-regulation of the CAR protein using a drug-regulatable system or treatment with the multikinase inhibitor dasatinib resulted in the acquisition of a memory-like phenotype, global transcriptional and epigenetic reprogramming, and restored antitumor functionality in exhausted CAR-T cells. This work demonstrates that rest can enhance CAR-T cell efficacy by preventing or reversing exhaustion, and it challenges the notion that exhaustion is an epigenetically fixed state. [1]: /lookup/doi/10.1126/science.aba1786 [2]: /lookup/doi/10.1126/science.abh0583 [3]: pending:yes
Jasper Jolly
April 6, 2021
the Guardian
Plug-in vehicle sales account for almost 14% of all new car sales in March
Pavan Lall
April 2, 2021
@bsindia
The Mercedes-Benz E-Class LWB may not quite replace the S-Class but it is a classier, spacious upgrade from older avatars
Andrew J. Hawkins
March 26, 2021
The Verge
Volkswagen plans to introduce the ID Buzz electric microbus in Europe and the US starting in 2023. A commercial version will be VW's first autonomous vehicle.
Mark Sweney
March 21, 2021
the Guardian
Consumer price rises loom while dearth of semiconductors slow production from Samsung to Ford
Parker Institute for Cancer Immunotherapy
March 3, 2021
www.prnewswire.com:443
/PRNewswire/ -- From improving immunotherapy response in childhood cancer patients, to better understanding how cancer's spread to the liver affects the body's...
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