Quill Science LLC’s Post

The administration of genetically modified T cells with the capacity to deplete B cells and/or plasma cells has tremendous therapeutic potential in autoimmune diseases. In the past few years, CD19-based and B cell maturation antigen (BCMA)-based CAR T cell therapies have been applied to various B cell-mediated autoimmune diseases including systemic lupus erythematosus, idiopathic inflammatory myopathy, systemic sclerosis, neuromyelitis optica spectrum disorder, myasthenia gravis and multiple sclerosis. The scientific rationale behind this approach is that deep depletion of B cells, including autoreactive B cell clones, could restore normal immune function, referred to as an immune reset. https://lnkd.in/gUtdBbQY

🧬 CAR T Cells Beyond Cancer 🧬 Extending the potential of CAR T cells beyond oncology marks a creative leap in medical science. Diseases like lupus, diabetes, and even challenges in organ transplantation are now on the radar for this groundbreaking therapy. By harnessing this technology, we're stepping into a realm where the quality of life for patients with autoimmune diseases could be dramatically improved. https://lnkd.in/dkxxge4b #cartcelltherapy #autoimmunediseases #immunology

Potential and pitfalls of repurposing the CAR-T cell regimen for the treatment of autoimmune disease - Early trials using CAR-T cells in diseases such as SLE have demonstrated their potential to eliminate pathogenic B cells and improve disease outcomes. However, more data are needed in order to optimise CAR-T cell technology for treatment of autoimmunity and to address potential risks and logistical roadblocks. - In order to ensure the full potential of repurposing CAR-T cells for autoimmune disease immunotherapy, it is important to realise that this therapy may not benefit all patients equally. - This is particularly the case for heterogeneous, systemic diseases, such as lupus, in which patients with different molecular features can be identified that are associated with different responses to therapeutic modalities. - For example: In some individuals, targeting CD19 alone may eliminate normal B cells and miss critical disease-relevant B cell populations, as IgG-secreting plasma cells lacking CD19 have been found to be increased in patients with active lupus. - Immunodepletion using cyclophosphamide (approved for treatment of many cancers, including B cell malignancies) and fludarabine (approved for treatment of B cell chronic lymphocytic leukaemia) is commonly employed as a preconditioning regimen. - However, there is a surprising lack of studies evaluating the necessity for lymphodepletion for the success of CAR-T cell therapy and it is unknown whether this co-therapy is necessary in the context of SLE (that is often associated with lymphopenia and decreased Treg function). - If efficacy and safety can be established, CAR-T cell regimens have the potential to transform the landscape of therapeutic options for previously difficult-to-treat autoimmune diseases. https://lnkd.in/de42_7ur #autoimmunity #celltherapy #CART #lupus

Allogeneic CAR-T therapy drives autoimmune diseases into remission: Early reports suggest that chimeric antigen receptor (CAR)-T therapy has remarkable potential for treating autoimmune disease. Current approaches rely on autologous CAR-T cells, creating a bottleneck to the broad deployment of this therapy.  A recent publication in Cell reports the first use of allogeneic CAR-T cells in three patients with systemic autoimmune disease. This off-the-shelf cell product (TyU19) was manufactured by isolating T cells from a healthy donor’s peripheral blood mononuclear cells, transducing the T cells with a second-generation CD19 CAR, and then using CRISPR-Cas9 to target TRAC, HLA-A, HLA-B, CIITA, and PD-1 to reduce the risk of immune rejection and graft-versus-host disease (GvHD). These cells were then banked and infused into one patient with immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis. In all three patients, CAR-T cells engrafted and expanded, coinciding with a complete depletion of circulating B cells for at least 2 months. Impressively, all three patients showed significant clinical improvement via respective clinical indexes, molecular markers, and radiographic measures. Remarkably, fibrosis in the lungs and hearts of some patients showed improvement. Although follow-up has only been extended to 6 months, these patients have remained in remission. This scientific discovery holds great potential for future treatment of autoimmune diseases. Original publication: https://lnkd.in/ejPsikBa Further reading: https://lnkd.in/e9DssDqa https://lnkd.in/e2zB33zN https://lnkd.in/eH2aY-XG https://lnkd.in/egSa6gCH https://lnkd.in/eKKdWAWg https://lnkd.in/eFA4mcpN

We are delighted to announce further success in our collaboration with AstraZeneca. Using BenevolentAI’s AI-drug discovery platform, a novel target for systemic lupus erythematosus (SLE) has been identified. 🎯 The target has been experimentally validated by AstraZeneca and added to its discovery portfolio. Following the heart failure milestone, it’s the second target to be selected this year from our extended collaboration. 📣 Prof Maria Belvisi, SVP and Head of Research and Early Development Respiratory and Immunology at AstraZeneca said: “By combining our immunology disease area expertise and BenevolentAI’s AI-driven discovery platform, we are increasing our ability to identify new targets based on patient insights, complementing our portfolio of potential treatments for this debilitating disease.” SLE, or lupus, can cause inflammation, pain and damage – often affecting the organs and joints in severe cases. Extreme fatigue and cognitive issues are also common, along with comorbidities including cardiovascular disease. Read more here: https://lnkd.in/e2mq8haw

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Metabolic dysfunction may increase the risk of liver-related events and hepatocellular carcinoma (HCC) in patients with chronic hep C virus (HCV) who achieved sustained virologic response (SVR) with direct-acting antiviral (DAA) therapy. https://lnkd.in/eS4xQNbq

🔈 Research by Lida Iliopoulou in George KOLLIAS #lab delineates IL-12 and IL-23 implications in #Crohn’s Disease. The recent study, published in Mucosal Immunology, identified interleukin 23 (IL-23) as a dominant #cytokine driving the progression of #Crohn’s disease (CD), a severe form of inflammatory bowel disease (IBD) affecting the #ileum. While Ustekinumab, a widely used monoclonal antibody, targets both interleukin 12 (IL-12) and IL-23, which of the two cytokines is mainly involved in CD progression, remained poorly understood. The research study revealed that IL-23 plays a far more critical role in perpetuating inflammation, with IL-12 only contributing when IL-23 is absent. Read more 👉 https://lnkd.in/gXmXws4Q

Interesting in Cell: Allogeneic CD19-targeted CAR-T therapy in patients with severe myositis and systemic sclerosis https://lnkd.in/dDq-Txyx Allogeneic chimeric antigen receptor (CAR)-T cells hold great promise for expanding the accessibility of CAR-T therapy, whereas the risks of allograft rejection have hampered its application. Here, we genetically engineered healthy-donor-derived, CD19-targeting CAR-T cells using CRISPR-Cas9 to address the issue of immune rejection and treated one patient with refractory immune-mediated necrotizing myopathy and two patients with diffuse cutaneous systemic sclerosis with these cells. This study was registered at ClinicalTrials.gov(NCT05859997). The infused cells persisted for over 3 months, achieving complete B cell depletion within 2 weeks of treatment. During the 6-month follow-up, we observed deep remission without cytokine release syndrome or other serious adverse events in all three patients, primarily shown by the significant improvement in the clinical response index scores for the two diseases, respectively, and supported by the observations of reversal of inflammation and fibrosis. Our results demonstrate the high safety and promising immune modulatory effect of the off-the-shelf CAR-T cells in treating severe refractory autoimmune diseases.