Optimizing Dosing Strategies in Cell Therapy With Machine Learning and Exposure-Response Integration.

<div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/Riviere square.png" data-image="1"></div><div class="author-det"><h3 class="author-name" style="color:#5D538A;">Isabelle Riviére</h3><h5 class="author-title" style="color:#5D538A;">Director, Cell Therapy and Cell Engineering Facility, Memorial Sloan Kettering Cancer Center</h5> Dr Rivière joined the faculty of the Memorial Sloan-Kettering Cancer Center (MSKCC) in 1999. She is currently the Director of the Cell Therapy and Cell Engineering Facility where she investigates novel strategies for cell therapies and immunotherapies to increase or retarget the immune response against tumors and treat hematological disorders. Her laboratory has developed multiple processes for clinical-grade gamma-retroviral and lentiviral vector production as well as hematopoietic and T-cell manufacturing. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/Kurtoglu photo copy.jpg" data-image="1"></div><div class="author-det"><h3 class="author-name" style="color:#00A795;">Metin Kurtoglu</h3><h5 class="author-title" style="color:#00A795;">Chief GMP Manufacturing and Chief Medical Officer, Cartesian Therapeutics</h5> Metin Kurtoglu, MD, PhD, is a medical oncologist board certified in internal medicine. Dr Kurtoglu’s clinical and basic science research career spans over 20 years and has focused on developing novel targets for drug-resistant cancer cells and cancer stem cells, including multiple myeloma. He has also been an investigator in various cancer immunotherapy trials. Cartesian Therapeutics is pioneering RNA cell therapies in and beyond oncology, with three assets in clinical trials for autoimmune, oncologic and respiratory disorders. The investigational therapies are manufactured at Cartesian’s cGMP manufacturing facility. </div></div></div><div class="authors authors-lg"><div class="author"><div class="author-img"><img src="https://cdn.insights.bio/uploads/Tariq Haq.JPG" data-image="1"></div><div class="author-det"><h3 class="author-name">Tariq Haq</h3><h5 class="author-title" style="color:#007589;">Head of Cell and Gene Therapy Segment Marketing at Lonza Bioscience Solutions</h5><p data-focus-visible-added="" class="focus-visible">Tariq Haq is the Head of Head of Cell and Gene Therapy Segment Marketing at Lonza Bioscience Solutions. He brings with him extensive bioprocess experience including strategy development, new product launch and commercialization. Previously he has held positions in marketing and product management while working in companies such as Pall, GE Healthcare, Thermo Fisher Scientific and Millipore. He has authored publications in peer-reviewed journals such as Science and Vaccine. Tariq holds degrees in Physics and Biotechnology from Aligarh Muslim University in India and in Biochemistry from Texas A&amp;M University in the US. </div></div></div>

CD133 Identifies a Human Bone Marrow Stem/Progenitor Cell Sub-population With a Repertoire of Secreted Factors That Protect Against Stroke

Driving the Chimeric Antigen Receptor: The Road Ahead for Cell Therapy

Gene Transfer Using HACs: A Key Step Closer to Ex Vivo Gene Therapy Using Autologous Gene–Corrected Cells to Treat Muscular Dystrophy

Adoptive cell therapy (ACT) has shown great success in the clinic for treating hematologic malignancies. However, solid tumor treatment with ACT monotherapy is still challenging, owing to insufficient expansion and rapid exhaustion of adoptive cells, tumor antigen downregulation/loss, and dense tumor extracellular matrix. Delivery strategies for combination cell therapy have great potential to overcome these hurdles. The delivery of vaccines, immune checkpoint inhibitors, cytokines, chemotherapeutics, and photothermal reagents in combination with adoptive cells, have been shown to improve the expansion/activation, decrease exhaustion, and promote the penetration of adoptive cells in solid tumors. Moreover, the delivery of nucleic acids to engineer immune cells directly in vivo holds promise to overcome many of the hurdles associated with the complex ex vivo cell engineering strategies. Here, these research advance, as well as the opportunities and challenges for integrating delivery technologies into cell therapy s are discussed, and the outlook for these emerging areas are criticlly analyzed.

Cardiac tissue reconstruction following myocardial infarction represents a major challenge in cardiovascular therapy, as current clinical approaches are limited in their ability to regenerate or replace damaged myocardium. Thus, different novel treatments have been introduced aimed at myocardial salvage and repair. Here, we present a review of recent advancements in cardiac cell, gene-based and tissue engineering therapies. Selected strategies in cell therapy and new tools for myocardial gene transfer are summarized. Finally, we consider novel approaches to myocardial tissue engineering as a platform for the integration of various modalities in an attempt to rejuvenate infarcted tissue in vivo.

Stem cell (SC) therapies displayed encouraging efficacy and clinical outcome in various disorders. Despite this huge hype, clinical translation of SC therapy has been disheartening due to contradictory results from clinical trials. The ability to monitor migration and engraftment of cells in vivo represents an ideal strategy in cell therapy. Therefore, suitable imaging approach to track MSCs would allow understanding of migratory and homing efficiency, optimal route of delivery and engraftment of cells at targeted location. Hence, longitudinal tracking of SCs is crucial for the optimization of treatment parameters, leading to improved clinical outcome and translation. Magnetic resonance imaging (MRI) represents a suitable imaging modality to observe cells non-invasively and repeatedly. Tracking is achieved when cells are incubated prior to implantation with appropriate contrast agents (CA) or tracers which can then be detected in an MRI scan. This review explores and emphasizes the importance of monitoring the distribution and fate of SCs post-implantation using current contrast agents, such as positive CAs including paramagnetic metals (gadolinium), negative contrast agents such as superparamagnetic iron oxides and 19 F containing tracers, specifically for the in vivo tracking of MSCs using MRI. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Emerging Technologies.

As evidenced by the seven U.S. Food and Drug Administration (FDA)-approved products, chimeric antigen receptor (CAR)-T cell therapy has gained unprecedented success in cancer treatment, particularly in blood cancers. Nonetheless, despite these impressive results, CAR-T cell therapy is a complex and challenging procedure with several hurdles that reduce its affordability and accessibility. These issues include time-consuming and labor-intensive ex vivo manufacturing, safety concerns regarding the viral-based gene delivery, and limited in vivo persistence and function. In recent years, nanoparticles (NPs) have been introduced as versatile tools with the potential to overcome these limitations and improve the efficacy and safety profile of CAR-T cells. Given the lack of a comprehensive analysis of the transformative potential of the use of NPs in CAR-T cell therapy and the roadblocks to their clinical translation in current literature, this review aims to provide a comprehensive and critical overview of NP-based strategies in CAR-T cell therapy, focusing on three key applications: production of CAR-T cells using a fully non-viral approach, enhancing the in vivo persistence and function of CAR-T cells, and in vivo generation and genome editing of CAR-T cells to circumvent the laborious ex vivo cell engineering and expansion stages. We explore the comparative advantages of different types of NPs (e.g., lipid-based and polymeric NPs) and discuss various approaches for optimizing NP design to address manufacturing and regulatory barriers. Finally, to provide a holistic view of the current state and future opportunities in these emerging fields, various roadblocks to their clinical translation (such as safety, scalability, and regulatory hurdles) and potential solutions are discussed. By exploring preclinical innovations and their clinical applicability, this review can guide future research toward scalable, efficient, and safe NP-assisted CAR-T cell therapy.

Patients' Peripheral Blood as a Possible Source of Donor-Derived NK Cells for Ex Vivo Expansion and Genetic Modification for Post-Transplant Cellular Immunotherapy In Cord Blood Recipients

YTB323 (Rapcabtagene Autoleucel) Demonstrates Durable Efficacy and a Manageable Safety Profile in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma: Phase I Study Update

The last 5 years have witnessed an explosion in the use of genes and cells as biomedicines. While primarily aimed at cancer, gene engineering and cell therapy strategies have additionally been used for Mendelian, neurodegenerative and metabolic disorders. The main focus of gene and cell therapy strategies in metabolism has been diabetes mellitus. This disease is a disorder of glucose homeostasis, either due to the immune-mediated eradication of pancreatic beta cells in the islets of Langerhans (type 1 diabetes) or resulting from insulin resistance and obesity syndromes where the insulin-producing capability of the beta cell is ultimately exhausted in the face of insensitivity to the effects of insulin in the peripheral glucose-utilising tissues (type 2 diabetes). A significant number of animal studies have demonstrated the potential in restoring normoglycaemia by islet transplantation in the context of immunoregulation achieved by gene transfer of immunoregulatory genes to allo- and xenogeneic islets ex vivo. Additionally, gene and cell therapy has also been used to induce tolerance to auto- and alloantigens and to generate the tolerant state in autoimmune rodent animal models of type 1 diabetes or rodent recipients of allogeneic/xenogeneic islet transplants. The achievements of gene and cell therapy in type 2 diabetes are less evident, but seminal studies promise that this modality can be relevant to treat and perhaps prevent the underlying causes of the disease. Here we present an overview of the current status of gene and cell therapy for type 1 and 2 diabetes and we propose potential therapeutic options that could be clinically useful. For type 1 diabetes, transplantation of islets engineered to evade or suppress the recipient immune response is the most readily-available technology today. A number of gene delivery vectors encoding proteins that impair a variety of immune cells have already been examined and proven versatile. More challenging but, nonetheless, just over the horizon are attempts to promote tolerance to islet allografts. Type 2 diabetes will likely require a better understanding of the processes that determine insulin sensitivity in the periphery. Targeting tissues such as muscle and fat with vectors encoding genes whose products promote insulin sensitivity and glucose uptake is an approach that does not carry with it the side-effects often associated with pharmacologic agents currently in use. In the end, progress in vector design, elucidation of antigen-specific immunity and insulin sensitivity will provide the framework for gene drug use in the treatment of type 1 and type 2 diabetes.

Predicting in vitro human mesenchymal stromal cell expansion based on individual donor characteristics using machine learning

Background: Human mesenchymal stem cells (hMSCs) are utilized preclinically and clinically as a candidate cell therapy for a wide range of inflammatory and degenerative diseases. Despite promising results in early clinical trials, consistent outcomes with hMSC-based therapies have proven elusive in many of these applications. In this work, we attempt to address this limitation through the design of a stem cell therapy to enrich hMSCs for desired electrical and ionic properties with enhanced stemness and immunomodulatory/regenerative capacity. Materials and Methods: In this study, we sought to develop initial protocols to achieve electrically enriched hMSCs (EE-hMSCs) with distinct electrical states and assess the potential relationship with respect to hMSC state and function. We sorted hMSCs based on fluorescence intensity of tetramethylrhodamine ethyl ester (TMRE) and investigated phenotypic differences between the sorted populations. Results: Subpopulations of EE-hMSCs exhibit differential expression of genes associated with senescence, stemness, immunomodulation, and autophagy. EE-hMSCs with low levels of TMRE, indicative of depolarized membrane potential, have reduced mRNA expression of senescence-associated markers, and increased mRNA expression of autophagy and immunomodulatory markers relative to EE-hMSCs with high levels of TMRE (hyperpolarized). Conclusions : This work suggests that the utilization of EE-hMSCs may provide a novel strategy for cell therapies, enabling live cell enrichment for distinct phenotypes that can be exploited for different therapeutic outcomes.

Development and Evaluation of an Optimal Human Single-Chain Variable Fragment-Derived BCMA-Targeted CAR T Cell Vector.

Adoptive cell therapies involve infusing engineered immune cells into cancer patients to recognize and eliminate tumor cells. Adoptive cell therapy, as a form of living drug, has undergone explosive growth over the past decade. The recognition of tumor antigens by the T-cell receptor (TCR) is one of the natural mechanisms that the immune system used to eliminate tumor cells. TCR-T cell therapy, which involves introducing exogenous TCRs into patients’ T cells, is a novel cell therapy strategy. TCR-T cell therapy can target the entire proteome of cancer cells. Engineering T cells with exogenous TCRs to help patients combat cancer has achieved success in clinical trials, particularly in treating solid tumors. In this review, we examine the progress of TCR-T cell therapy over the past five years. This includes the discovery of new tumor antigens, protein engineering techniques for TCR, reprogramming strategies for TCR-T cell therapy, clinical studies on TCR-T cell therapy, and the advancement of TCR-T cell therapy in China. We also propose several potential directions for the future development of TCR-T cell therapy.