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Mechanism of action of CAR T-cell therapy. Patient's T cells are collected by leukapheresis and are then transduced with a vector encoding the CAR. The CAR T cells are expanded ex vivo while the patient undergoes bridging and/or lymphodepleting chemotherapy. The CAR T cells are then infused into the patient to fight the malignant cells.
Source publication
Chimeric antigen receptor (CAR) T-cell therapy is an investigational immunocellular therapy that reprograms a patient's cytotoxic T cells to engage and eliminate malignant cells. CAR T-cell therapies targeting the CD19 antigen have demonstrated high efficacy in clinical trials for patients with B-cell malignancies and may potentially be available o...
Context in source publication
Citations
... CAR-T cell therapy is a new immunotherapy approach that has started to been used in recent years and is developing rapidly (1). While immunotherapies boost the immune system, some immunotherapies directly target cancer cells (2). CAR-T cells used as immunotherapy destroy the tumor cell both directly and through an increased release of cytokines (3). ...
... Facilities must be strategically designed to make optimal use of available space. The use of isolators and closed systems can limit the need for larger cleanrooms [5,6]. Careful planning allows the creation of multi-product facilities that segregate therapies like viral vectors or gene-modified cells. ...
... Finding personnel with experience in clinical cell bioprocessing is not always simple. Staff availability can limit capacity, so manufacturing strategies maximizing operator productivity can enable hospitals to meet clinical demand within personnel constraints [5]. Extensive planning and financial investment are critical for establishing the necessary infrastructure, staff, training, and multi-departmental coordination for hospital ATMP facilities, to effectively transition new therapies from research to clinical application. ...
Cell and gene therapies represent promising new treatment options for many diseases, but also face challenges for clinical translation and delivery. Hospital-based GMP facilities enable rapid bench-to-bedside development and patient access but require significant adaptation to implement pharmaceutical manufacturing in healthcare infrastructures constrained by space, regulations, and resources. This article reviews key considerations, constraints, and solutions for establishing hospital facilities for advanced therapy medicinal products (ATMPs). Technologies like process analytical technology (PAT), continuous manufacturing, and artificial intelligence (AI) can aid these facilities through enhanced process monitoring, control, and automation. However, quality systems tailored for product quality rather than just compliance, and substantial investment in infrastructure, equipment, personnel, and multi-departmental coordination, remain crucial for successful hospital ATMP facilities and to drive new therapies from research to clinical impact.
... CAR-T cell therapy uses an adoptive cell therapy (ACT) approach in which cancer cells are killed using modified T-cells collected from the patient where the process is autologous or taken from a healthy donor where it becomes allogeneic [6]. The therapy begins with a specialized process known as Leukapheresis; a process whereby white blood cells are extracted from the peripheral blood [28]. Leukapheresis as highlighted in Figure 1, separates mononuclear CD3+ T cells derived from the bone marrow. ...
... The CAR-T cell therapy is then introduced to the patient's bloodstream via a central line. The patients are required to stay proximal to the treatment site for 21-28 days for monitoring against adverse reactions [28]. The modified cell in the body leads to cell death of the cancer cells by attachment to expressed antigens. ...
Targeting the molecule cluster of differentiation 19 (CD19), chimeric antigen receptor (CAR)-T- cell therapy is an artificial immune cell therapy now used in clinical practice for hematological malignancies. In addition to discussing cost and accessibility, this study seeks to present a broad overview of the clinical uses, safety, efficacy, and future prospects of CAR T-cell therapy. Studies on CAR-T-cell therapy have shown that it is highly effective, with high objective response rates (ORRs) and, in certain cases, promising progression-free survival (PFS). Notwithstanding, certain obstacles persist, such as the emergence of resistance mechanisms such the loss of CD19 antigen and immune suppression caused by the tumor microenvironment. Immune checkpoint inhibitors, allogeneic CAR-T cell treatment, and sequential CAR-T cell therapy are methods to deal with these issues. Furthermore, novel strategies for boosting CAR-T cell efficacy and dual-target CAR-T cells are being researched. Research on the use of CAR-T-cell therapy for T-cell malignancies and other disorders is still underway, despite the treatment's impressive results in treating B-cell malignancies. The therapy's high purchase cost and the lack of conclusive clinical proof make cost-effectiveness difficult to achieve. The scarcity of specialist facilities providing CAR-T therapy further impedes access, necessitating patients to surmount logistical and financial obstacles. To increase accessibility and affordability and to ascertain its long-term cost-effectiveness, more thorough investigations are required. CAR T-cell immunotherapy has a bright future ahead of it, but in order to be used more widely and fairly, several important issues must be resolved
... Once it has been verified that the collected product complies with the specifications, such as total nucleated cells (TNC) or percentage and number of T-cells, it is sent to the manufacturing laboratory. There, T cells are selected, activated, transduced and expanded and, after CAR-T cell generation is completed, the product is shipped to the center and administered to the patient 5,6 . Regarding the mononuclear cell (MNC) collection step, product could be shipped cryopreserved or not, with no great differences in product quality 7 . ...
Background:
Chimeric antigen receptor (CAR) T-cell therapy is increasingly used in patients affected by B-cell lymphoma and acute lymphoblastic leukemia. For logistical reasons, initial apheresis products may be cryopreserved for shipment to manufacturing centers. Due to the characteristics of these patients, cells are often collected in large volumes, meaning more bags must be cryopreserved. This requires increased storage, time and monetary costs. In this context, we aimed to evaluate a high cell concentration cryopreservation protocol by centrifugation to standardize the initial CAR-T manufacturing procedure.
Materials and methods:
Sixty-eight processes of leukapheresis of 57 patients affected by refractory/relapsed B cell lymphoma and 9 patients affected by acute lymphoblastic leukemia who were eligible for anti-CD19 CAR-T cell treatment performed between June 2019 and October 2022 were analyzed. Whole blood count, percentage and number of T cells were assessed on the apheresis final product. The apheresis product, which was alternatively stored overnight at 4°C, was centrifuged, adjusting the volume to approximately 40 mL. The product was immediately cryopreserved to achieve a final cell concentration of 50-200×106 cells/ml for cryopreservation.
Results:
Leukapheresis volume was reduced by almost fivefold (median: 185 to 40 mL), resulting in a higher product concentration in one bag. In addition, the number of non-target cells (monocytes, platelets and erythrocytes) was also reduced during the development of CAR T cell therapy, thereby maintaining T lymphocyte levels and providing a purer starting material.
Discussion:
The advantages of the protocol include reducing economic costs, saving storage space, simplifying the manufacturing process, and facilitating shipping logistics. In conclusion, we present a validated, simple, and cost-effective cell enrichment processing protocol that provides high-quality cryopreserved products as starting material for the CAR-T cell manufacturing process.
... Once T-cells have been collected, they are sent to a laboratory where they are genetically engineered to express the CAR gene. The CAR gene is transduced in T-cells using a viral (lentivirus or retrovirus) or non-viral (transposon or CRISP-cas9) gene transfer system [19][20][21]. Electroporation of in vitro transcribed RNA in T-cells have also gained interest in last few years [22]. ...
Chimeric antigen receptor (CAR)-T cell therapy is a promising new treatment for cancer that involves genetically modifying a patient’s T-cells to recognize and attack cancer cells. This review provides an overview of the latest discoveries and clinical trials related to CAR-T cell therapy, as well as the concept and applications of the therapy. The review also discusses the limitations and potential side effects of CAR-T cell therapy, including the high cost and the risk of cytokine release syndrome and neurotoxicity. While CAR-T cell therapy has shown promising results in the treatment of hematologic malignancies, ongoing research is needed to improve the efficacy and safety of the therapy and expand its use to solid tumors. With continued research and development, CAR-T cell therapy has the potential to revolutionize cancer treatment and improve outcomes for patients with cancer.
... Once T-cells have been collected, they are sent to a laboratory where they are genetically engineered to express the CAR gene. The CAR gene is transduced in T-cells using a viral (lentivirus or retrovirus) or non-viral (transposon or CRISP-cas9) gene transfer system [19][20][21]. Electroporation of in vitro transcribed RNA in T-cells have also gained interest in last few years [22]. ...
Multiple fixed-wing and multirotor uncrewed aircraft systems were deployed to measure the early morning katabatic flow along a valley as part of the lower atmosphere profiling studies at elevation a remotely-piloted aircraft team experiment (LAPSE-RATE) campaign. The valley’s topography was that of a narrow canyon emerging into a broader shallow-sloped valley, allowing for an assessment of the suitability of one-dimensional approximations for the broad, flat part of the valley. The one-dimensional integral model predicts growth in the katabatic layer with downslope distance, which was not observed in the broader portions of the valley. Instead, observations revealed thinning of the katabatic layer at the valley centreline, coinciding with oscillatory behavior with a period between 30 and 60 min. These features were attributed to strong asymmetry and three-dimensional features initiating in the narrow part of the valley. These features produced initial conditions upstream of the broad slope flow that were not captured by the one-dimensional model.
... Although high-dose corticosteroids can alleviate CRS, to some extent, they may also reduce the clinical effect of CAR-T cell therapy and even cause cancer recurrence by blocking T cell activation, function and proliferation [99]. However, according to clinical experience, corticosteroids should be used when patients do not respond effectively to tocilizumab or the severity of CRS is over grade 3 [102]. Etanercept, an inhibitor of TNFα, also shows good clinical efficacy in controlling CRS. ...
Background
Coronavirus disease 2019 (COVID-19) is currently rampant all over the world, resulting in unpredictable harm to humans. High blood levels of cytokines and chemokines have been marked in patients with COVID-19 infection, leading to cytokine storm syndrome. Cytokine storm, a violent inflammatory immune response, reveals the devastating effect of immune dysregulation and the critical role of an effective host immune response.
Methods
Scientometric analysis summarizes the literature related to cytokine storm in recent decades and provides a valuable and timely approach to track the development of new trends. In this review, the pathogenesis and treatment of diseases associated with cytokine storm are summarized comprehensively on the basis of scientometric analysis.
Results
Field distribution, knowledge structure, and research topic evolution correlated with cytokine storm are revealed, and the occurrence, development, and treatment of disease relevant to cytokine storm are illustrated.
Conclusion
Cytokine storm can be induced by pathogens and iatrogenic causes, and can also occur in the context of autoimmune diseases and monogenic diseases as well. These reveal the multidisciplinary nature of cytokine storm and remind the complexity of the pathophysiological features, clinical presentation and management. Overall, this scientometric study provides a macroscopic presentation and further direction for researchers who focus on cytokine storms.
... As discussed earlier, for patients that do proceed to CAR T cell therapy, optimizing the timing of apheresis, in particular with respect to the patient's lymphocyte count, is an important consideration. For the clinical trials of tisagenlecleucel, a minimum absolute lymphocyte count of 500 cells/µl and CD3-positive cell count of 150 cells/µl was recommended 65 . Most centres require a treatmentfree period following certain therapies prior to apheresis, especially from previous HSCT (ideally >100 days), immunosuppressive therapies for grafts-versus-host disease treatment or prophylaxis without either new onset or recurrent grafts-versus-host disease (ideally >30 days), and/or immune-targeted therapies (ideally 1 month or several half-lives). ...
Chimeric antigen receptor (CAR) T cells have emerged as a potent therapeutic approach for patients with certain haematological cancers, with multiple CAR T cell products currently approved by the FDA for those with relapsed and/or refractory B cell malignancies. However, in order to derive the desired level of effectiveness, patients need to successfully receive the CAR T cell infusion in a timely fashion. This process entails apheresis of the patient’s T cells, followed by CAR T cell manufacture. While awaiting infusion at an authorized treatment centre, patients may receive interim disease-directed therapy. Most patients will also receive a course of pre-CAR T cell lymphodepletion, which has emerged as an important factor in enabling durable responses. The time between apheresis and CAR T cell infusion is often not a simple journey, with each milestone being a critical step that can have important downstream consequences for the ability to receive the infusion and the strength of clinical responses. In this Review, we provide a summary of the many considerations for preparing patients with B cell non-Hodgkin lymphoma or acute lymphoblastic leukaemia for CAR T cell therapy, and outline current limitations and areas for future research.
... The evaluation of the number of circulating lymphocytes or T-cells is important for planning the apheresis (a minimum of 500 total lymphocytes/mm 3 and/or 150 CD3+ lymphocytes/ mm 3 is recommended, although apheresis can be performed with lower counts). 22,23 For patients previously submitted to HSCT, it is recommended the absence of acute or chronic graft versus host disease (GVHD) in activity before the apheresis and infusion of the CAR-T cells. 24 A period without hematol transfus cell ther. ...
Chimeric antigen receptor T (CAR-T) cell therapy is a novel therapeutic modality for acute lymphoblastic leukemia (ALL) with robust outcomes in patients with refractory or relapsed disease. At the same time, CAR-T cell therapy is associated with unique and potentially fatal toxicities, such as cytokine release syndrome (CRS) and neurological toxicities (ICANS). This manuscript aims to provide a consensus of specialists in the fields of Hematology Oncology and Cellular Therapy to make recommendations on the current scenario of the use of CAR-T cells in patients with ALL.
... Tisagenlecleucel is a CD19-directed, genetically modified, autologous T-cell immunotherapy through which a patient's own T cells are reprogrammed with a transgene encoding an anti-CD19 CAR using the 4-1BB (CD137) co-stimulatory domain. 9 Use of the 4-1BB co-stimulatory domain augments T-cell antitumor activity and enhances CAR-T proliferation and persistence. 10 In contrast, current BiTEs do not provide co-stimulatory molecule engagement to the T cell, perhaps highlighting a key difference in the mechanism of action between these two immunebased therapies. ...
In the absence of head-to-head trials, an indirect-treatment comparison can estimate the treatment effect of tisagenlecleucel in comparison with blinatumomab on rates of complete remission (CR) and overall survival (OS) in patients with relapsed or primary refractory (R/R) acute lymphoblastic leukemia (ALL). Patient-level data from two pivotal trials, ELIANA (tisagenlecleucel; n = 79) and MT103-205 (blinatumomab; n = 70), were used in comparisons of CR and OS, controlling for cross-trial difference in available patient characteristics. Five different adjustment approaches were implemented: stabilized inverse probability of treatment weight (sIPTW); trimmed sIPTW; stratification by propensity score quintiles; adjustment for prognostic factors; and adjustment for both prognostic factors and propensity score. Comparative analyses indicate that treatment with tisagenlecleucel was associated with a statistically significant higher likelihood of achieving CR and lower hazard of death than treatment with blinatumomab. The tisagenlecleucel group exhibited a higher likelihood of CR than the blinatumomab group in every analysis regardless of adjustment approach (odds ratios: 6.71-9.76). Tisagenlecleucel was also associated with a lower hazard of death than blinatumomab in every analysis, ranging from 68% to 74% lower hazard of death than with blinatumomab, determined using multiple adjustment approaches (hazard ratios: 0.26-0.32). These findings support the growing body of clinical trial and real-world evidence demonstrating that tisagenlecleucel is an important treatment option for children and young adults with R/R ALL.
