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Scooped by
BigField GEG Tech
May 30, 2023 5:28 AM
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Vα24-invariant natural killer T cells (NKTs) have anti-tumor properties that can be enhanced by chimeric antigen receptors (CARs). Here we report updated interim results from the first-in-human phase 1 evaluation of autologous NKTs co-expressing a GD2-specific CAR with interleukin 15 (IL15) (GD2-CAR.15) in 12 children with neuroblastoma (NB). The primary objectives were safety and determination of maximum tolerated dose (MTD). The anti-tumor activity of GD2-CAR.15 NKTs was assessed as a secondary objective. Immune response evaluation was an additional objective. No dose-limiting toxicities occurred; one patient experienced grade 2 cytokine release syndrome that was resolved by tocilizumab. The MTD was not reached. The objective response rate was 25% (3/12), including two partial responses and one complete response. The frequency of CD62L+NKTs in products correlated with CAR-NKT expansion in patients and was higher in responders (n = 5; objective response or stable disease with reduction in tumor burden) than non-responders (n = 7). BTG1 (BTG anti-proliferation factor 1) expression was upregulated in peripheral GD2-CAR.15 NKTs and is a key driver of hyporesponsiveness in exhausted NKT and T cells. GD2-CAR.15 NKTs with BTG1 knockdown eliminated metastatic NB in a mouse model. We conclude that GD2-CAR.15 NKTs are safe and can mediate objective responses in patients with NB. Additionally, their anti-tumor activity may be enhanced by targeting BTG1. ClinicalTrials.gov registration: NCT03294954 . In updated results from a phase 1 trial of GD2-specific CAR-NKT cells in patients with neuroblastoma, no dose-limiting toxicities were observed across multiple dose levels; the maximum tolerated dose was not reached; and there was evidence of anti-tumor activity.
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BigField GEG Tech
May 24, 2023 7:02 AM
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Antibiotic treatments have detrimental effects on the microbiome and lead to antibiotic resistance. To develop a phage therapy against a diverse range of clinically relevant Escherichia coli, we screened a library of 162 wild-type (WT) phages, identifying eight phages with broad coverage of E. coli, complementary binding to bacterial surface receptors, and the capability to stably carry inserted cargo. Selected phages were engineered with tail fibers and CRISPR–Cas machinery to specifically target E. coli. We show that engineered phages target bacteria in biofilms, reduce the emergence of phage-tolerant E. coli and out-compete their ancestral WT phages in coculture experiments. A combination of the four most complementary bacteriophages, called SNIPR001, is well tolerated in both mouse models and minipigs and reduces E. coli load in the mouse gut better than its constituent components separately. SNIPR001 is in clinical development to selectively kill E. coli, which may cause fatal infections in hematological cancer patients. Phage engineered with tail fibers and CRISPR–Cas reduce Escherichia coli load in animals.
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BigField GEG Tech
May 15, 2023 5:41 AM
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CRISPR-Cas9 is widely used to edit the genome by studying genes of interest and modifying disease-associated genes.
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Scooped by
BigField GEG Tech
May 10, 2023 1:31 PM
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Decades of oncologic clinical use have demonstrated that cancer immunotherapy provides
unprecedented therapeutic benefits. Tragically, only a minority of patients respond
to existing immunotherapies. RNA lipid nanoparticles have recently emerged as modular
tools for immune stimulation. Here, we discuss advancements in RNA-based cancer immunotherapies
and opportunities for improvement.
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Scooped by
BigField GEG Tech
April 18, 2023 7:01 AM
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Chimeric antigen receptor T-cell (CAR-T) therapy has transformed cancer treatment, yet relatively few studies have investigated the impact of the therapy on longitudinal patient quality of life – an aspect of care that often suffers from receiving traditional intensive cancer medications, such as chemotherapy.
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Scooped by
BigField GEG Tech
April 13, 2023 7:32 AM
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Scooped by
BigField GEG Tech
March 29, 2023 6:41 AM
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A new approach that delivers a "one-two punch" to help T cells attack solid tumors is the focus of a preclinical study by researchers from the Perelman School of Medicine at the University of Pennsylvania.
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Scooped by
BigField GEG Tech
March 23, 2023 8:12 AM
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Range of DNA repair in response to double-strand breaks induced in human preimplantation embryos remains uncertain due to the complexity of analyzing single- or few-cell samples. Sequencing of such minute DNA input requires a whole genome amplification that can introduce artifacts, including coverage nonuniformity, amplification biases, and allelic dropouts at the target site. We show here that, on average, 26.6% of preexisting heterozygous loci in control single blastomere samples appear as homozygous after whole genome amplification indicative of allelic dropouts. To overcome these limitations, we validate on-target modifications seen in gene edited human embryos in embryonic stem cells. We show that, in addition to frequent indel mutations, biallelic double-strand breaks can also produce large deletions at the target site. Moreover, some embryonic stem cells show copy-neutral loss of heterozygosity at the cleavage site which is likely caused by interallelic gene conversion. However, the frequency of loss of heterozygosity in embryonic stem cells is lower than in blastomeres, suggesting that allelic dropouts is a common whole genome amplification outcome limiting genotyping accuracy in human preimplantation embryos. DNA repair in response to DSBs in the preimplantation embryo is hard to analyze. Here the authors show that over 25% of pre-existing heterozygous loci in control single blastomere samples appeared as homozygous after whole genome amplification, therefore, they validated gene editing seen in human embryos in ESCs.
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Scooped by
BigField GEG Tech
March 20, 2023 10:41 AM
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The lack of registered drugs for nonalcoholic fatty liver disease (NAFLD) is partly due to the paucity of human-relevant models for target discovery and compound screening. Here we use human fetal hepatocyte organoids to model the first stage of NAFLD, steatosis, representing three different triggers: free fatty acid loading, interindividual genetic variability (PNPLA3 I148M) and monogenic lipid disorders (APOB and MTTP mutations). Screening of drug candidates revealed compounds effective at resolving steatosis. Mechanistic evaluation of effective drugs uncovered repression of de novo lipogenesis as the convergent molecular pathway. We present FatTracer, a CRISPR screening platform to identify steatosis modulators and putative targets using APOB−/− and MTTP−/− organoids. From a screen targeting 35 genes implicated in lipid metabolism and/or NAFLD risk, FADS2 (fatty acid desaturase 2) emerged as an important determinant of hepatic steatosis. Enhancement of FADS2 expression increases polyunsaturated fatty acid abundancy which, in turn, reduces de novo lipogenesis. These organoid models facilitate study of steatosis etiology and drug targets. Organoid models of early liver disease aid target discovery and drug screening.
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Scooped by
BigField GEG Tech
February 23, 2023 6:18 AM
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Understanding moral acceptability and willingness to use is crucial for informing policy
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Scooped by
BigField GEG Tech
February 13, 2023 9:16 AM
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Dual-action cell therapy engineered to eliminate established tumors and train the immune system to eradicate primary tumor and prevent cancer’s recurrence.
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Scooped by
BigField GEG Tech
January 27, 2023 10:58 AM
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With a slew of tools to trick out immune cells, researchers are expanding the repertoire of CAR-T therapies.
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Scooped by
BigField GEG Tech
January 24, 2023 10:37 AM
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Scooped by
BigField GEG Tech
May 25, 2023 4:56 AM
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Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are engineered cell-surface receptors that sense a target antigen and respond by activating T cell receptor signaling or a customized gene program, respectively. Here, to expand the targeting capabilities of these receptors, we develop “universal” receptor systems for which receptor specificity can be directed post-translationally via covalent attachment of a co-administered antibody bearing a benzylguanine (BG) motif. A SNAPtag self-labeling enzyme is genetically fused to the receptor and reacts with BG-conjugated antibodies for covalent assembly, programming antigen recognition. We demonstrate that activation of SNAP-CAR and SNAP-synNotch receptors can be successfully targeted by clinically relevant BG-conjugated antibodies, including anti-tumor activity of SNAP-CAR T cells in vivo in a human tumor xenograft mouse model. Finally, we develop a mathematical model to better define the parameters affecting universal receptor signaling. SNAP receptors provide a powerful strategy to post-translationally reprogram the targeting specificity of engineered cells. Chimeric antigen receptors (CARs) and synthetic Notch (synNotch) receptors are promising platforms for cell-based immunotherapies. Here, the authors develop highly programmable versions of these receptors that can be universally targeted to antigens of interest through covalent enzyme chemistry.
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Scooped by
BigField GEG Tech
May 15, 2023 1:52 PM
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Scooped by
BigField GEG Tech
May 12, 2023 7:09 AM
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Adoptive transfer of genetically engineered chimeric antigen receptor (CAR) T cells is becoming a promising treatment option for hematological malignancies. However, T cell immunotherapies have mostly failed in individuals with solid tumors. Here, with a CRISPR–Cas9 pooled library, we performed an in vivo targeted loss-of-function screen and identified ST3 β-galactoside α-2,3-sialyltransferase 1 (ST3GAL1) as a negative regulator of the cancer-specific migration of CAR T cells. Analysis of glycosylated proteins revealed that CD18 is a major effector of ST3GAL1 in activated CD8+ T cells. ST3GAL1-mediated glycosylation induces the spontaneous nonspecific tissue sequestration of T cells by altering lymphocyte function-associated antigen-1 (LFA-1) endocytic recycling. Engineered CAR T cells with enhanced expression of βII-spectrin, a central LFA-1-associated cytoskeleton molecule, reversed ST3GAL1-mediated nonspecific T cell migration and reduced tumor growth in mice by improving tumor-specific homing of CAR T cells. These findings identify the ST3GAL1–βII-spectrin axis as a major cell-intrinsic program for cancer-targeting CAR T cell migration and as a promising strategy for effective T cell immunotherapy. CAR T cell success requires targeting tumors, but these cells can get trapped in other tissues, such as in the lungs, where they can cause pathology. Here, the authors use a loss-of-function CRISPR screen to identify regulators of CAR T cell tumor trafficking and engineer CAR T cells accordingly to overcome this limitation.
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Scooped by
BigField GEG Tech
April 19, 2023 7:18 AM
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The expanding applications of nonviral genomic medicines in the lung remain restricted by delivery challenges. Here, leveraging a high-throughput platform, we synthesize and screen a combinatorial library of biodegradable ionizable lipids to build inhalable delivery vehicles for messenger RNA and CRISPR–Cas9 gene editors. Lead lipid nanoparticles are amenable for repeated intratracheal dosing and could achieve efficient gene editing in lung epithelium, providing avenues for gene therapy of congenital lung diseases. A high-throughput screen improves lipid nanoparticle delivery of gene editors in the lung.
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Scooped by
BigField GEG Tech
April 17, 2023 7:22 AM
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Researchers from Utah State University and Germany’s Helmholtz Institute for RNA-based Infection Research demonstrate that upon recognition of an RNA target, Cas12a2 cleaves all the other nucleic acids present, destroying the bacterial cell and preventing bacteriophage from replicating.
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Scooped by
BigField GEG Tech
April 6, 2023 7:15 AM
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The genetic mutation underlying a severe immune system deficiency can be corrected
by adenine base editing of human patient stem cells, restoring the ability of these
cells to develop into functional T cells in model systems, and paving the path for
future treatment of CD3δ SCID in patients.
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Scooped by
BigField GEG Tech
March 24, 2023 6:26 AM
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Indiana University School of Medicine researchers have identified a new therapeutic target that could lead to more effective treatment of glaucoma.
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Scooped by
BigField GEG Tech
March 22, 2023 12:26 PM
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Pancreatic cancer is an incurable form of cancer, and gene therapies are currently in clinical testing to treat this deadly disease. A comprehensive review of the gene and cell biotherapies in development to combat pancreatic cancer is published in the peer-reviewed journal Human Gene Therapy.
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Scooped by
BigField GEG Tech
March 8, 2023 12:08 PM
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A new tool to predict the chances of successfully inserting a gene-edited sequence of DNA into the genome of a cell, using a technique known as prime editing, has been developed by researchers at the Wellcome Sanger Institute.
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Scooped by
BigField GEG Tech
February 17, 2023 7:16 AM
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Adding a molecular anchor to the key protein used to recognize cancer in cellular immunotherapies can make the treatments significantly more effective.
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Scooped by
BigField GEG Tech
January 30, 2023 4:50 AM
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CRISPR-Cas9 gene editing is emerging as a prospective therapy for genomic mutations. However, current editing approaches are directed primarily toward relatively small cohorts of patients wit
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Scooped by
BigField GEG Tech
January 26, 2023 7:03 AM
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The recent years have seen a wave of adoptive cell therapies (ACTs), a type of immunotherapy in which T cells (T cell transfer therapy) and other immune cells are obtained from patients, activated and multiplied outside the body, and infused in larger numbers back into the blood circulation to help fight cancers.
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Researchers report, in Nature Medicine, the interim results of a first-in-man phase 1 clinical trial evaluating the safety, antitumor activity and immunological characteristics of a genetically engineered natural killer (NKT) cell immunotherapy for neuroblastoma, a childhood tumor that most commonly arises in the adrenal gland. NKT cells were engineered to express a GD2-specific CAR, which enables immune cells to target a molecule found on the surface of neuroblastoma cells, and interleukin-15 a natural protein that supports NKT cell survival. Based on results obtained in 12 patients with recurrent stage 4 neuroblastoma resistant to other therapies, the researchers found that the treatment was safe for all 12 patients on four doses. No dose-limiting toxicities were reported. A further discovery revealed a regulatory gene in NKT cells that could have an impact on treatment efficacy. Leveraging the multiomics platform of key collaborator Immunai, Inc. the researchers discovered that up-regulation of the anti-proliferation factor 1 gene BTG in CAR NKT-infused cells indicates cell exhaustion and limits the functional activity of CAR NKT cells. Conversely, artificially reducing BTG1 expression in CAR NKT cells enhanced their therapeutic activity against neuroblastoma in a mouse model