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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.
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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...
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Citations
... 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.
... 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.
... CAR-T cell therapy has been associated with a number of potentially severe complications, such as cytokine release syndrome (CRS) and the immune effector cell-associated neurotoxicity syndrome (ICANS), which require coordinated management by a diverse multidisciplinary team (hematologists, intensivists, neurologists and pharmacists) (4,5). CRS is a systemic inflammatory response caused by cytokines released by infused CAR-T cells and can lead to widespread reversible organ dysfunction. ...
... The hospital CAR-T Multidisciplinary Committee, integrated by hematologists, oncologists, critical care specialists, immunologists, neurologists, radiologists, hospital pharmacists and nursing staff (21), evaluates candidate patients for CAR-T cell therapy. After patient acceptance, this board coordinates their clinical management in a comprehensive way, before, during and after CAR-T cell therapy (5). As part of this committee, hospital pharmacists check that CAR-T cell drugs are going to be used for an approved indication (10) and according to the therapeutic protocol that defines its use in the NHS (22,23). ...
... Patients and their families should be given, before being discharged from hospital, appropriate education about early signs and symptoms of CRS and ICANS and their severity to avoid a delay in seeking medical attention (5). Most importantly, patients treated with CAR-T cells should be instructed to immediately alert all providers that they have received this therapy, especially if presenting to a facility outside of their original treatment center (32). ...
Purpose
The use process for chimeric antigen receptor T (CAR-T) cell drugs is complex and has been associated with a number of potentially severe complications, which requires management by a multidisciplinary team. Pharmacists are a key element in the team and have roles and responsibilities. Our objective was to develop a structured and practical guide that supports hospital pharmacist responsibilities and defines specific activities in a CAR-T cell therapy program, specifically in Europe.
Methods
A literature review was performed, and the recommendations related to pharmacy practice in CAR-T therapy programs were analyzed. A multidisciplinary team was assembled, and meetings were held to address the key tasks in the CAR-T cells’ management process and to create the guide, based on national and international recommendations and in expert’s opinions.
Results
The multidisciplinary team defined the following key tasks and issued recommendations to improve patient safety, treatment efficacy, and quality: patient selection and evaluation, CAR-T cell drug order to manufacturer, apheresis and material shipment, reception of CAR-T cell drug and storing, CAR-T cell drug prescription and pharmacy verification, CAR-T cell drug thawing and dispensing, CAR-T cell drug administration, patient education, pharmacovigilance and monitoring and outcomes’ record and evaluation. In each task the pharmacist’s role and how it can improve patient care are defined. A checklist was created to guarantee the compliance of standard operating procedures approved in the institution to manage CAR-T cell therapy and as a tool to collect required data for outcomes’ record and evaluation.
Conclusion
This article provides a consensus set of safety recommendations regarding CAR-T therapy management in clinical practice, easily implementable by other institutions in the European setting. The guide identifies key steps where the involvement of hospital pharmacists would improve the safety and quality of the process and is a support guide to standardize hospital pharmacists’ responsibilities within the multidisciplinary team.
... Personalized cellular products require small-scale manufacturing of N = 1 batch numbers. For example, in the case of cancer treatments using TILs, only one batch of TIL product formulated as one infusion bag of approximately 300 mL volume is produced and administered at one time to the patient (autologous treatment) [12]. Over the past years, the manufacturing process of personalized treatments has been improved by growing technological advances in the field of closed-system technologies combined with single use disposable consumables. ...
... Figure 2 outlines the use of some of the currently available closed system equipment for cell processing steps in the manufacturing of cellular therapy products such as TILs at our center in Lausanne Switzerland (Harari et al. 2020 manuscript submitted). Equipment such as the Xuri TM from GE, the Lovo TM from Fresenius Kabi and the CliniMACS1 Prodigy from Miltenyi are now well-established closed systems that can be elegantly integrated into the manufacturing strategy for personalized cell therapy products [5,12,13]. Since each batch will require the use of such equipment at a Academic GMP facility for cancer immunotherapy Iancu and Kandalaft 235 time, the capacity of a facility will largely depend on the number of available closed system equipment. These closed systems have several advantages, including increased automation of the process, require less operator intervention and allow the concurrent manufacturing of multiple small batches destined for multiple patients. ...
Academic medicine serves to advance the scientific field and provide the highest quality of clinical care. This applies to cancer where there is a continuous unmet need for innovation. In the last decade, we have observed a significant development of commercial cell and gene-therapy products with a rapid growth of the industry. Hospital-based Good Manufacturing Practice (GMP) facilities which support primarily investigator-initiated clinical trials, are increasingly involved in interactions with industry. Although the missions of academic and commercial GMP facilities are different, both are bound by industry standards and often engage in technology transfer with industry partners. The successful set-up of an academic GMP facility requires striking a unique balance between commercial and academic priorities. Here we review the role of academic facilities in the development of cellular therapies with a focus on cancer immunotherapy and we highlight some of the most challenging operational aspects and point to potential solutions.
... The transport errors can occur in two levels: (1) transfer of leukapheresis materials from apheresis and cell-processing laboratories to the manufacturing company and (2) from the manufacturing company to the treating center. After the delivery of manufactured CAR T cells to the hospital, hospital staff should control the chain of identity to be in concordance to the manufacturing facility [50]. So far, product identifiers employed by hospitals may differ from the manufacturing company, which may result in uncertainty and loss of information [43]. ...
Recent advances in basic immunology have revealed impressive breakthroughs in the field of cancer immunotherapy, inspiring oncologists to translate this knowledge to the treatment of different types of cancers. However, several hurdles limit the efficiency of immunotherapy in increasing the overall survival of patients (Fig. 31.1). These hurdles rank from practical and economic issues such as feasibility and cost-effectiveness of immunotherapy and design of the clinical trials to the several immunological hurdles. In the immunological hurdles, tumor cells possess several mechanisms to evade the immune system response. A combination of factors such as the production of inhibitory cytokines and soluble factors such as the expression of inhibitory markers and conversion of cellular infiltrates into the tolerizing cells contribute to evasion of the immune system. Moreover, some tumor cells acquire apoptosis resistance through different strategies, and some cause the immune system to autoreact to host tissue. All these mechanisms inhibit tumor regression and the effectiveness of immunotherapy. Moreover, immunotherapy-related toxicities have proven to be a major issue in cancer immunotherapies, which required timely and properly management. Therefore, efforts for minimizing the side effects in parallel to maximizing the efficiency of immunotherapies are still warranted. In this chapter, we discuss the potential hurdles that confront cancer immunotherapy and the potential strategies to overcome these challenges and achieve a successful immune response against tumor.
... Each institution that initiates a CAR T-cell therapy program will face both clinical and administrative challenges before offering this new therapy to patients. This process involves complex logistics that cover the collection of cells at the apheresis center, shipping them to the manufacturer for production, coordinating receipt of the product, and defining an ideal workflow for CAR T-cell administration and patient management (266)(267)(268)(269). ...
Research on CAR T cells has achieved enormous progress in recent years. After the impressive results obtained in relapsed and refractory B-cell acute lymphoblastic leukemia and aggressive B-cell lymphomas, two constructs, tisagenlecleucel and axicabtagene ciloleucel, were approved by FDA. The role of CAR T cells in the treatment of B-cell disorders, however, is rapidly evolving. Ongoing clinical trials aim at comparing CAR T cells with standard treatment options and at evaluating their efficacy earlier in the disease course. The use of CAR T cells is still limited by the risk of relevant toxicities, most commonly cytokine release syndrome and neurotoxicity, whose management has nonetheless significantly improved. Some patients do not respond or relapse after treatment, either because of poor CAR T-cell expansion, lack of anti-tumor effects or after the loss of the target antigen on tumor cells. Investigators are trying to overcome these hurdles in many ways: by testing constructs which target different and/or multiple antigens or by improving CAR T-cell structure with additional functions and synergistic molecules. Alternative cell sources including allogeneic products (off-the-shelf CAR T cells), NK cells, and T cells obtained from induced pluripotent stem cells are also considered. Several trials are exploring the curative potential of CAR T cells in other malignancies, and recent data on multiple myeloma and chronic lymphocytic leukemia are encouraging. Given the likely expansion of CAR T-cell indications and their wider availability over time, more and more highly specialized clinical centers, with dedicated clinical units, will be required. Overall, the costs of these cell therapies will also play a role in the sustainability of many health care systems. This review will focus on the major clinical trials of CAR T cells in B-cell malignancies, including those leading to the first FDA approvals, and on the new settings in which these constructs are being tested. Besides, the most promising approaches to improve CAR T-cell efficacy and early data on alternative cell sources will be reviewed. Finally, we will discuss the challenges and the opportunities that are emerging with the advent of CAR T cells into clinical routine.
... Chimeric antigen receptor-T (CAR-T) cell therapy uses reprogrammed T cells to target and kill cancer cells, and thus has become a promising treatment for patients with advanced hematologic malignancies. [1][2][3][4][5][6][7][8][9][10] Patients with relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL) or r/r transformed follicular lymphoma may receive CD19-directed CAR-T cell therapy after 2 systemic therapy options such as R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). 11,12 Two such CD19-directed CAR-T cell therapies are currently commercially available: tisagenlecleucel and axicabtagene ciloleucel. ...
Chimeric antigen receptor-T (CAR-T) cell therapy achieves durable responses in patients with relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL), but may be associated with neurological toxicity (NT). We retrospectively assessed differences and concordance among 3 available grading scales (the National Cancer Institute Common Terminology Criteria for Adverse Events v4.03 [CTCAE], modified CAR-T Related Encephalopathy Syndrome [mCRES], and American Society for Transplantation and Cellular Therapy [ASTCT] scales) applied to the same set of NT data from the JULIET (A Phase 2, Single Arm, Multicenter Trial to Determine the Efficacy and Safety of CTL019 in Adult Patients With Relapsed or Refractory DLBCL) trial. Individual patient-level NT data from the phase 2, single-group, global, pivotal JULIET trial (NCT02445248) were retrospectively and independently graded, using CTCAE, ASTCT, and mCRES, by 4 medical experts with experience managing patients with 3 different CD19-targeted CAR constructs. According to the US Food and Drug Administration definition of NT using CTCAE, 62 of 106 patients infused with tisagenlecleucel had NT as of September 2017. Among 111 patients infused with tisagenlecleucel (as of December 2017), the 4 experts identified 50 patients (45%) who had any-grade NT per CTCAE, 19 (17%) per mCRES, and 19 (17%) per ASTCT. Reevaluation according to the mCRES/ASTCT criteria downgraded 31 events deemed NT by CTCAE to grade 0. This is the first study to retrospectively apply CTCAE, mCRES, and ASTCT criteria to the same patient data set. We conclude that CTCAE v4.03 was not designed for, and is suboptimal for, grading CAR-T cell therapy-associated NT. The CRES and ASTCT scales, which measure immune effector cell-associated neurotoxicity syndrome, offer more accurate assessments of NT after CAR-T cell therapy.
... The model did not include apheresis because this procedure is primarily performed in an outpatient setting, regardless of the site in which the patient receives CAR T-cell therapy infusion. 25 The decision-tree model, conceptual approach, and patient flow are presented in Figure 1. ...
Importance
Chimeric antigen receptor (CAR) T-cell therapies are currently administered at a limited number of cancer centers and are primarily delivered in an inpatient setting. However, variations in total costs associated with these therapies remain unknown.
Objective
To estimate the economic differences in the administration of CAR T-cell therapy by the site of care and the incidence of key adverse events.
Design, Setting, and Participants
A decision-tree model was designed to capture clinical outcomes and associated costs during a predefined period (from lymphodepletion to 30 days after the receipt of CAR T-cell infusion) to account for the potential incidence of acute adverse events and to evaluate variations in total costs for the administration of CAR T-cell therapy by site of care. Cost estimates were from the health care practitioner perspective and were based on data obtained from the literature and publicly available databases, including the Healthcare Cost and Utilization Project National Inpatient Sample, the Medicare Hospital Outpatient Prospective Payment System, the Medicare physician fee schedule, the Centers for Medicare and Medicaid Services Healthcare Common Procedure Coding System, and the IBM Micromedex RED BOOK. The model evaluated an average adult patient with relapsed or refractory large B-cell lymphoma who received CAR T-cell therapy in an academic inpatient hospital or nonacademic specialty oncology network.
Intervention
The administration of CAR T-cell therapy.
Main Outcomes and Measures
Total cost of the administration of CAR T-cell therapy by site of care. The costs associated with lymphodepletion, acquisition and infusion of CAR T cells, and management of acute adverse events were also examined.
Results
The estimated total cost of care associated with the administration of CAR T-cell therapy was $454 611 (95% CI, $452 466-$458 267) in the academic hospital inpatient setting compared with $421 624 (95% CI, $417 204-$422 325) in the nonacademic specialty oncology network setting, for a difference of $32 987. After excluding the CAR T-cell acquisition cost, hospitalization and office visit costs were $53 360 (65.3% of the total cost) in academic inpatient hospitals and $23 526 (48.4% of the total cost) in nonacademic specialty oncology networks. The administration of CAR T-cell therapy in nonacademic specialty oncology networks was associated with a $29 834 (55.9%) decrease in hospitalization and office visit costs and a $3154 (20.1%) decrease in procedure costs.
Conclusions and Relevance
The potential availability of CAR T-cell therapies that are associated with a lower incidence of adverse events and are suitable for outpatient administration may reduce the total costs of care by enabling the use of these therapies in nonacademic specialty oncology networks.
