Chimeric antigen receptor (CAR)–T cells have been clinically effective in killing certain hematological malignancies, but achieving long-term patient responses for solid tumors remains a challenge. Reinhard et al. describe a two-part “CARVac” strategy to overcome poor CAR-T cell stimulation and responses in vivo. They introduce the tight junction protein claudin 6 (CLDN6) as a new CAR-T cell target and designed a nanoparticulate RNA vaccine encoding a chimeric receptor directed toward CLDN6. This lipoplex RNA vaccine promotes CLDN6 expression on the surface of dendritic cells, which in turn stimulates and enhances the efficacy of CLDN6-CAR-T cells for improved tumor therapy.
Anemocyte, an innovative Italian company working in the field of cell and gene therapies, with special focus on plasmid production and non-viral gene modification approaches, attends Phacilitate Leaders World (Miami, 21-24 January 2020), a leading event for companies, professionals and investors working in the Advanced Therapy sector. Anemocyte is a key player and the first ever Biotech Manufacturing Organization (BMO) operating in the Life Science sector: company helps CGT developers to articulate initial ideas, perform clinical trials and engage in commercial production. The BMO also develops technological platform strategies for innovative R&D, HQ and GMP processes.
The planarian flatworm is a simple animal with a mighty ability: it can regenerate itself from nearly every imaginable injury, including decapitation. Scientists have studied these worms for decades to better understand fundamental principles of natural regeneration and repair. Specifically, Petersen and Schad discovered that a gene called mob4 suppresses tissue growth in the animals. The gene, they found, works in a rather surprising way: by preventing the descendants of stem cells from producing a growth factor called Wnt, a protein released from cells to communicate across distances. The Wnt signaling pathway is known to play a role in cancer cell regeneration.
According to a study published in the Blood journal, drug profiling and the CRISPR-Cas9 gene editing method have opened new avenues in the development of CAR T-cell therapy, used to treat leukaemia and lymphoma. The study, carried out collaboratively by the University of Helsinki and the Finnish Red Cross Blood Service, surveyed the effect of more than 500 cancer drugs on the function of CAR T cells. The drug profiling highlighted a class of drugs known as SMAC mimetics, which in laboratory tests sensitised cancer cells to CAR T cells. At the same time, drugs that inhibit the function of CAR T cells were found, which have potential in the treatment of adverse effects. By employing the CRISPR gene editing method, the researchers investigated which mechanisms impact the sensitivity of cancer cells to CAR T cells.
Chemical nerve agents are some of the most horrifying tools of war today. For years, researchers have been searching for antidotes or treatments that could save those afflicted by these deadly chemicals. In a paper out today in Science Translational Medicine, a team from the U.S. Army Medical Research Institute of Chemical Defense has announced a potential solution: a gene therapy that grants immunity to the effects of nerve agents like sarin.
A novel anti-CD19 CAR T-cell therapy attained a high response rate with minimal neurotoxicity in patients with advanced B-cell lymphoma, according to a preliminary clinical trial.
The results showed that 11 of 20 patients attained complete remissions (CRs) with the Hu19-CD828Z CAR T-cell construct, identical to the CR rate in a previous trial of the FMC63-28Z construct. However, only one of the 20 patients developed severe neurologic toxicity, as compared with half of the patients in the trial of FMC63-28Z, the construct used in axicabtagene ciloleucel (Yescarta).
New research by Dorothy P. Schafer, PhD, at the University of Massachusetts Medical School, reveals the molecular process in which synaptic connections in the brain are damaged in multiple sclerosis and how this contributes to neurodegenerative symptoms. The paper, published in Immunity, also shows how gene therapy may be used to preserve neural circuits and protect against vision loss in the disease.
In the new study, led by scientists at Cardiff University in the UK, researchers used CRISPR–Cas9 screening to discover a new kind of TCR in T-cells: a receptor molecule called MR1.
MR1 functions similarly to HLA in terms of scanning and recognising cancer cells, but one big difference is that, unlike HLA, it doesn't vary in the human population – which means it could potentially form the basis of a T-cell therapy that works for a much broader range of people (in theory, at least).
For the first time in Italy, two children with hereditary retinal dystrophy, of 8- and 9-years of age, have been treated with gene therapy at the Eye Clinic of the University of Campania "Luigi Vanvitelli"of Naples in collaboration with Novartis. The innovative therapy for hereditary retinal dystrophy, devised in Naples 12 years ago in collaboration with the Telethon Foundation and the Children's Hospital of Philadelphia, is approved at European level and is now awaiting AIFA approval. This gene therapy, which consists in correcting the genetic defect underlying the disease, is administered through surgery by injecting the drug directly into the retina, and has allowed the two treated children, that had severely impaired vision from birth due to the pathology, to regain their vision.
Patients with relapsed or refractory mantle cell lymphoma from prior therapies may benefit greatly from treatment with anti-CD19 KTE-X19 CAR T cells. The results of an interim analysis of the phase 2 ZUMA-2 study, presented in Orlando at the 61st Congress of the American Society of Hematology (ASH) demonstrated that after a single infusion of these CAR Ts, 93% of patients responded to treatment and 67% received a complete response.
Janssen, a Johnson & Johnson pharmaceutical company, presented the Phase 1b/II Cartitude-1 study, conducted in 29 patients with relapsed or refractory multiple myeloma to evaluate the efficacy of a Car-T therapy targeting B-cell maturation antigen (BCMA). The 'enhanced' immunotherapy that exploits the reworked T cells to better target the tumor allows a therapeutic response to be achieved in 100% of cases, with a very good or better response in 86% of patients and partial in 14%. The anti-Bcma Car-T therapy allowed 27 of 29 patients to be free from disease progression at the 6-month follow-up.
An Italian algorithm, presented at the 61st Congress of the American Society of Hematology (Ash) in Orlando, Florida, will help guide the choice of which beta-thalassemic transfusion-dependent patients could mostly benefit from gene therapy - a cure that corrects inside the DNA the defect underlying the blood disorder. The algorithm has been developed by an Italian group of super-experts with the support of Site (Italian society thalassemia and hemoglobinopathies). Gene therapy will not be a therapy for everyone, in fact, of the 5-6 thousand Italian beta-thalassemic patients, the forecast is about 800 candidates; the algorithm will help to divide the possible candidates into three categories, indicating: " Patient with high priority; patient, to be assessed, but with ongoing therapy readjustment and patient excluded ".
Four initial phase studies were presented at the 61st Congress of the American Society of Hematology (Ash) in Orlando, Florida as the forerunners of a second-generation anti-cancer cellular immunotherapy, which strives to overcome the limitations of products already available. The innovations include double-target Car-T, capable of hitting cancer cells by attacking them in two points instead of one and Car-Nk, obtained starting from induced pluripotent stem cells. These innovations bring substantial advantages: improving the efficacy of Car T cells therapy, designing products capable of attacking multiple targets; extending cellular immunotherapy to other blood cancers such as multiple myeloma and the possibility of thinking of a 'Car' cellular immunotherapy not produced each time tailored to each patient, but 'prêt-à-porter', standardized and ready to use, reducing production time and costs.
The first gene therapy treatment in Italy to treat a patient with severe hemophilia A has just ended at the Milan Polyclinic. Haemophilia A is a rare genetic disease that affects 5,000 people in Italy, and it is due to a deficit of one of the proteins involved in coagulation, leading to bleeding that can also be fatal. The administration of this gene therapy will allow the haemophiliac patient to avoid the frequent infusions (administered regularly: even 3 times a week for life) for several years, and to have a blood coagulation equal to that of anyone else, with a huge impact on its quality of life.
Biomedical engineers at Duke University have developed a method to address failures in a promising anti-cancer drug, bringing together tools from genome engineering, protein engineering and biomaterials science to improve the efficacy, accuracy and longevity of certain cancer therapies; using a combination of CRISPR-based targeting, a protein depot that allows for sustained release of the drug and a highly potent binding system, the team showed that this new strategy could overcome three critical problems that limit the efficacy of many cancer drugs, that is the limited potency, their quick elimination from the body, and the ability of cancer cells to develop resistance to the drug. The research was published on Science Advances
Researchers at the University of Missouri School of Medicine have shown in a mouse study that the powerful gene editing technique known as CRISPR may provide the means for lifelong correction of the genetic mutation, that causes a deficiency of dystrophin, responsible for the disorder. With more study, the researchers hope this cell-targeted CRISPR approach may one day lead to longlasting therapies for children with DMD
In experiments with mice, researchers have developed a way to successfully transplant certain protective brain cells without the need for lifelong anti-rejection drugs; the idea behind the experiments, developed by Johns Hopkins Medicine, was to exploit the natural tendencies of costimulatory signals to train the immune system to accept transplanted cells as self-permanently. To do that, they used two antibodies, CTLA4-Ig and anti-CD154, which keep T cells from beginning an attack when encountering foreign particles by binding to the T-cell surface. The study was published in the journal Brain
A new study, presented at the American Society of Radiation Oncology Annual Meeting, shows that patients who received radiation therapy before chimeric antigen receptor T-cell therapy for relapsed or refractory non-Hodgkin lymphoma were less likely to have severe treatment-related toxicities; none of the patients who received induction radiation therapy less than 30 days before CAR T-cell infusion experienced high-grade cytokine release syndrome or neurotoxicity, two of the common treatment-related toxicities associated with CAR T-cell therapy
Benitec Biopharma, a gene therapy-focused biotechnology company developing novel genetic medicines derived from the proprietary DNA-directed RNA interference platform, announced their plans to complete three non-clinical studies that will facilitate the filing of an Investigational New Drug application and the formal initiation of a Phase I clinical trial in patients suffering from Oculopharyngeal Muscular Dystrophy. BB-301 is an internally optimized, AAV-based gene therapy agent that can both silence the expression of mutated, disease-causing genes and replace the mutant genes with normal, "wild type" genes. This approach to disease management is called "silence and replace" and this biological mechanism offers the potential to restore the underlying physiology of the treated tissues and, in the process, improve treatment outcomes for patients suffering from the chronic and, potentially, fatal effects of the disease
CytoSorbents Corporation, a critical care immunotherapy leader commercializing its CytoSorb blood purification technology to treat deadly inflammation, announced that Hannover Medical School in Germany will begin the first clinical study called CYTORELEASE, evaluating the use of CytoSorb in treating CRS and inflammation of the brain called CAR-related Encephalopathy Syndrome, following CAR-T cell immunotherapy. The trial is a randomized, controlled pilot study in 34 cancer patients who have received CAR-T cell immunotherapy and who have developed either severe CRS or CRES for a duration less than 6 hours
Atara Biotherapeutics, a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, has announced the presentation of initial efficacy data as well as updated safety results from its ongoing Phase 1 study of ATA188 for the treatment of progressive forms of multiple sclerosis. The data are featured in a late-breaking poster presentation at the 35th Congress of the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS), held in Stockholm, September 11-13, 2019. At approximately 6 months from initial dose, 4 of 6 patients in cohort 1 demonstrated clinical decline which was maintained at 12 months; safety results showed that across the 4 planned dose cohorts, ATA188 was well tolerated in patients with progressive forms of MS with no evidence of cytokine release syndrome, graft versus host disease or dose-limiting toxicities
Biotherapeutics company Momotaro-Gene has announced the beginning of a Phase 2 clinical trial on their innovative treatment for malignant mesothelioma. The study will analyze the efficacy of the company’s novel gene therapy called MTG201 combined with the PD-1 inhibitor Opdivo on patients whose cancer has returned. MTG201 works in two ways: it first delivers the REIC/Dkk-3 gene into cancer cells via the company’s proprietary adenoidal vector technology platform, raising the gene expression in cells in which it has been reduced and triggering cell death, while at the same time increasing the gene’s expression in healthy cells within the tumor. This activates natural killer cells within the body’s immune system. The two actions together work particularly well when combined with the checkpoint inhibitor nivolumab
Data from the first two patients treated with FLT180a, Freeline’s single-infusion gene therapy for patients with hemophilia B, showed a rise in levels of clotting factor IX to 40%, with levels remaining stable for over a year. The experimental therapy uses a harmless adeno-associated virus capsid, or protein shell, to deliver a functional version of human clotting factor IX, whose low levels are the cause of hemophilia B
Freeline, a biotech company focused on innovative gene therapies, has announced the dosing of the first patient in its MARVEL1 study, a multi-centre Phase I/II clinical trial of its AAV gene therapy for Fabry Disease; this disease is a type of lysosomal storage disorder due to deficiency of α-galactosidase A enzyme resulting in an accumulation of lipids throughout the body. The study aimed to deliver a replacement copy of the missing gene to the liver, which will then produce continuous high levels of αGLA, offering the potential for therapy with a single treatment. It is estimated that Fabry Disease affects one in every 40,000 people
Adverum Biotechnologies, a gene therapy company targeting unmet medical needs in ocular and rare diseases, has announced positive 24-week clinical data from the first cohort of patients treated with a one-time intravitreal dose of ADVM-022 in the OPTIC phase 1 clinical trial in wet age-related macular degeneration; patients treated in this cohort achieved vision maintenance and improvements in retinal anatomy, with zero anti-VEGF rescue injections required, after a one-time intravitreal dose of ADVM-022, through week 24. These patients previously required frequent anti-VEGF injections to control their wet AMD and to maintain functional vision. ADVM-022 was safe and well tolerated
Gracell Biotechnologies, a immune cell therapy company, has announced a positive continued clinical readout of a multi-center pilot study designed to evaluate the safety and efficacy of Gracell's first-in-class FasT CAR-19 (GC007F) investigational cell gene therapy; the results were announced during the CAR-TCR Summit held from 10-13 September in Boston. At present, anti-CD19 CAR-T bioprocessing takes on average two weeks to manufacture and seven days to pass quality testings. However, with Gracell's FasT CAR solution, customized treatments which genetically modifies patient's T-cells to express CD19-specific CAR, preparation time can be cut to one day, with a manufacturing success rate of 100% without patient loss. The treatment efficacy was assessed in 24 treated patients over 28 days of follow-up, of which 23 achieved complete remission and 21 achieved undetectable minimal residual disease
new gene therapy turns glial cells, abundant support cells in the brain, into neurons, repairing damage that results from stroke and significantly improving motor function in mice. A paper describing the new therapy, which uses the NeuroD1 gene, appears online in the journal Molecular Therapy. Once further developed, this NeuroD1-based gene therapy could potentially be used to treat stroke, which is a leading cause of disability in the USA, with 800.000 new stroke patients every year
In a new study published in Nature, Penn Medicine's Abramson Cancer Center’s researchers have explored the potential of cell therapy for removing activated fibroblasts that contribute to the development of heart disease. Cardiac fibrosis is a contributing factor to the many different types of heart disease, caused by a proliferation of cardiac fibroblasts; when these cells are over-activated, often after cardiac injury, they deposit excess extracellular matrix in the cardiac muscle, causing thickening of the muscle and a loss of flexibility. The researchers built on cell immunotherapy work targeting cancer cells to try and target pathologic cardiac fibroblasts utilizing a mouse model; they endeavoured to identify a protein that was specifically expressed by activated fibroblasts, like fibroblast activation protein (FAP), with the promising initial results
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