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Building blocks for institutional preparation of CTL019 delivery
ARTICLE IN PRESS Cytotherapy, 2017; ■■: ■■–■■
Building blocks for institutional preparation of CTL019 delivery
JOSEPH MCGUIRK1, EDMUND K. WALLER2, MUNA QAYED2, SUNIL ABHYANKAR1, SOLVEIG ERICSON3, PETER HOLMAN3, CHRISTOPHER KEIR3 & G. DOUGLAS MYERS4 1
The University of Kansas Medical Center, Kansas City, KS, USA, 2Emory University School of Medicine, Atlanta, GA, USA, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, and 4University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA Abstract 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 on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient’s peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019. Key Words: blood component removal, clinical trial, genetic therapy, leukapheresis
Introduction to CAR T-cell therapy The field of immunocellular therapy aims to harness the power of a patient’s own immune system to fight malignancy. Although several components of the immune system can be involved in the immune response to cancer, many therapies take advantage of the cytotoxic potential of T cells. T cells can be manipulated to recognize and attack cancer cells through the use of vaccination, monoclonal antibodies, bispecific T-cell engagers and modification of T cells ex vivo. One therapeutic approach involving the activation and engineering of cytotoxic T cells is chimeric antigen receptor (CAR) T-cell therapy [1–3]. CARs are genetically engineered receptors consisting of antibodymediated antigen recognition,T-cell signaling, and T-cell costimulatory domains. CAR-modified T cells therefore combine T-cell cytotoxic activity with the antigen specificity of an antibody. CARs obviate the need for presentation of antigen in human leukocyte antigen (HLA), which may be down-regulated on many tumors [4], effectively “blinding” T cells to a tumor’s pres-
ence. Introduction of a CAR into a T cell endows the T cell with the ability to recognize and eliminate tumor cells expressing the antigen of interest via CAR T-cell– mediated killing, while the CAR T cells retain the cell’s endogenous T-cell receptor and capability to exert cytotoxic function toward HLA-bound antigen recognized by the endogenous T-cell receptor [5]. CARs are most commonly transduced into a patient’s T cells using a lentiviral or gammaretroviral vector [6,7]. After manufacture of the CAR T cells ex vivo, the patient receives lymphodepleting chemotherapy if needed, followed by CAR T-cell infusion (Figure 1) [8]. To date, clinical trials of CAR T cells have been primarily focused on CD19-expressing malignancies. CD19 antigen is expressed on B-cell precursor cells, most mature B cells, and several B-cell malignancies and, importantly, is not expressed on other vital tissues [9]. CD19-targeted CAR T-cell therapies have demonstrated high efficacy in clinical trials for a variety of hematologic malignancies. In pediatric and adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) who were
Correspondence: Joseph McGuirk, DO, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. E-mail: [email protected] (Received 16 March 2017; accepted 2 June 2017) ISSN 1465-3249 Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jcyt.2017.06.001
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1 Leukapheresis
5 Modified T-cell infusion
4 Chemotherapy Anbody-coated beads Bead removal
2 T-cell acvaon/ transducon
T-cell 3 Modified expansion
Copyright © 2015 Novars Corporaon.
Figure 1. 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.
heavily pretreated, complete response (CR) rates of up to approximately 90% have been reported in trials of CD19 CAR T-cell therapy [8,10,11]. In patients with r/r non-Hodgkin B-cell lymphoma, CR rates of approximately 50–70% have been achieved with CD19 CAR T-cell therapies [12–14]. Acute adverse events (AEs) resulting from CAR T-cell therapy have been observed, the most notable being cytokine release syndrome (CRS) [15]. Preparation for the early identification and expectant management of CRS and other potential toxicities is crucial to the safe delivery of CAR T-cell therapy at treating sites. Many clinical trials using CAR T cells are ongoing, and the potential exists for broader availability of CAR T-cell therapy in the near future; therefore, there is a great need to educate clinical staff members to adequately prepare them for delivering this type of therapy. In this review, we discuss logistics related to CAR T-cell therapy based on experience gained in multiinstitutional clinical trials investigating the CD19 CAR T-cell therapy CTL019. Here we focus on leukapheresis material, which is a fundamental and critical starting material for CAR T-cell product manufacturing, and discuss issues concerning the cryopreservation of
the leukapheresis material and related logistics. Furthermore, we highlight key points related to facilitating infusion of the product and managing potentially lifethreatening side effects post-CTL019 infusion. We believe that sites considering CAR T-cell therapies will find this review helpful in planning for and delivering this therapy safely to their patients. Obtaining the effector cells for CAR T-cell therapy Leukapheresis Apheresis is a widely used process whereby blood is removed from an individual, separated into select components and returned to the individual’s circulation after the component of interest has been collected [16]. Apheresis is currently used for the treatment of several diseases, including hematologic, metabolic and renal disorders, and is used in blood banks for collection of platelets and other blood components [16]. Apheresis is considered a safe procedure for both healthy donors and patients, including patients with r/r hematologic malignancies. A retrospective analysis of 15 763 apheresis procedures determined a moderate to severe
ARTICLE IN PRESS Building blocks for CTL019 delivery AE rate of 0.37%, which included dizziness, fainting, citrate toxicity, vascular injuries and other miscellaneous events [17]; most of the observed AEs were mild and easily reversed. Leukapheresis is the process in which white blood cells from the peripheral blood are collected. In peripheral blood stem cell (PBSC) leukapheresis, the target cell population is CD34+ cells, and these cells have typically been mobilized from the bone marrow [18]. PBSC collection is typically a 4- to 6-h outpatient procedure, and one to four collections are typically required to obtain sufficient CD34+ cells for one or more transplants; the optimal number of CD34+ cells collected depends on the number of planned transplants [18,19]. Similar to PBSC collections, the CAR T-cell therapeutic product begins with leukapheresis [20]; however, in this case, mononuclear cells are collected. Furthermore, the collections are nonmobilized, with the goal of obtaining CD3+ T cells, and take much less time than stem cell apheresis: often, a single 2to 3-h collection is sufficient to harvest the required number of cells [19]. In clinical trials for CTL019, we aim for a minimum absolute lymphocyte count of 500 cells/µL and a minimum CD3+ cell count of 150 cells/µL. The peripheral blood CD3+ cell count, along with collection efficiency for the site, can be used as a reference to predict the volume of blood needed to reach the target number of CD3+ cells. This can help inform whether an adequate number of cells will be harvested in a single collection. Obtaining collected leukapheresis material with adequate cell populations can be critical to the success of manufacturing CAR T-cells. The minimum required numbers of defined cell types must be collected. Limiting nontarget cell populations is critical but may be partially mitigated with advanced cell therapy manufacturing processes that have the capability to remove the unwanted cell types. Leukapheresis in pediatric patients Certain distinctions must be made between adults and children when performing leukapheresis (Table I)
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[21,22]. Pediatric patients have a much smaller total blood volume, resulting in a greater sensitivity to removal of blood during the leukapheresis procedure. Children may also be more susceptible to hypothermia or hypocalcemia during leukapheresis. For these reasons, the rate of leukapheresis should be slower in pediatric patients than in adults.These special considerations for the pediatric population are not unique to patients undergoing leukapheresis in preparation for CAR T-cell therapy; therefore, apheresis centers that manage both pediatric and adult patients will be familiar with these distinctions. An additional point of preparation for the leukapheresis procedure is ensuring proper venous access. In pediatric patients, this often involves insertion of a temporary or permanent dialysis-grade catheter. In adolescents and adults, evaluating antecubital veins before the procedure date is essential to determining whether a central venous catheter is needed and, if so, to properly plan catheter placement. Both the clinical staff and patients should be aware that catheter placement is a possibility before the scheduled leukapheresis appointment. Leukapheresis for CAR T-cell therapy Other concerns regarding leukapheresis for CAR T-cell therapy depend on the treatment history of the patient. Patients receiving CTL019 or other CD19 CAR T-cell therapies have often undergone several rounds of prior cytotoxic therapy, sometimes including allogeneic stem cell transplant (SCT) [8,11]. These prior treatments may affect the timing of leukapheresis, because T-cell number and function may be reduced by the prior therapy. Patients with a history of allogeneic SCT should stop immunosuppressive drug therapy and should have no evidence of acute graft-versus-host disease (GVHD) at the time of leukapheresis collection. For the CTL019 trials, it was determined that patients should not undergo leukapheresis for CAR T-cell therapy fewer than 3 months after allogeneic SCT because of the risk of harvesting allogeneicreactive T cells during this period, which could induce
Table I. Key leukapheresis considerations for CAR T-cell therapy. Key aspect of leukapheresis procedure Pediatric patients [21,22] Prior therapies
Smaller blood volume Susceptible to hypothermia or hypocalcemia Venous access may be challenging Allogeneic SCT Pegylated asparaginase Other cytotoxic chemotherapy Immunomodulatory drugs Steroids
How addressed or managed Slower rate of leukapheresis Insert temporary or permanent dialysis-grade catheter Allogeneic SCT must have been >3 months before leukapheresis Stop >4 weeks before leukapheresis Stop >2 weeks before leukapheresis Stop ≥2 weeks before leukapheresis Therapeutic doses must be stopped >72 hours before leukapheresis
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GVHD or exacerbate subclinical GVHD if used for CAR T-cell manufacture. Other chemotherapy or immunosuppressive medications should be stopped as early as possible before leukapheresis because these medications may result in the collection of low numbers of T cells or T cells that are unable to proliferate ex vivo. In the CTL019 clinical trials, we advised stopping cytotoxic chemotherapy 2 weeks before leukapheresis, with the exception of pegylated asparaginase, which we advised stopping 4 weeks before leukapheresis. Low-dose or weekly maintenance chemotherapy and immunomodulatory drugs, such as anti–tumor necrosis factor α, should be stopped 2 or more weeks and therapeutic doses of steroids must be stopped at least 72 h before leukapheresis. As with many steps in the CAR T-cell therapy process, there should be open communication among the treatment center, apheresis center and product manufacturing site staff so that concerns about product quality and questions related to the timing of leukapheresis and chemotherapy washout can be discussed.The external apheresis center and/or treatment center play key roles in handling the leukapheresis material after collection, such as cryopreservation and storage until it is shipped for manufacturing. Efficiency in obtaining leukapheresis material that can be used for CAR T-cell manufacture expedites the process of bringing CAR T-cell therapy to patients who may not have other therapeutic options. Institutional preparation for efficient leukapheresis procedures is one of many steps that must be taken to ensure that the site is working toward optimal safety and efficacy when treating patients with CAR T-cell therapies. In clinical trials using the CD19-targeted CAR T-cell therapy CTL019, several factors that influence a successful leukapheresis procedure are being investigated, including the CD3+ cell count targets necessary for CTL019 manufacturing, the history of prior
chemotherapy, the type of machine used for the leukapheresis procedure and the most appropriate timing for the patient to undergo leukapheresis. To further investigate and standardize leukapheresis, a clinical study is ongoing to examine the collection and use of leukapheresis products obtained from patients considering enrollment in a CTL019 clinical trial. Preparing the institution for CAR T-cell therapy Overview of institutional preparation As with all clinical trials, careful consideration should be taken when evaluating the staff resources and needs at the clinical trials office, the corresponding laboratories and the hospital before offering CAR T-cell therapy to patients. Attention must also be paid to the timing of when the patient is pre-screened for potential participation in the trial. Once the patient’s cells are collected by leukapheresis and sent for manufacturing, the timing of interim/bridging chemotherapy, lymphodepleting chemotherapy, and CAR T-cell infusion must be carefully planned to facilitate CAR T-cell expansion in vivo. Lymphodepleting chemotherapy is administered to facilitate CAR T-cell expansion in vivo [8,12] and reduces disease burden before infusion of the CAR T-cell product. In our experience, the coordination of trials using CTL019 demands special attention to the timing of events once the patient has been admitted for treatment (Table II). Before opening clinical trials of CAR T-cell therapy, a series of approvals are needed from the manufacturing site, the U.S. Food and Drug Administration (FDA) and the local institutional review board and institutional biosafety committee. If CAR T-cell therapy becomes commercially available, institutional resources will need to be available to comply with FDA oversight.
Table II. Key roles of the multidisciplinary team when treating patients who receive CAR T-cell therapy. Department Nursing
Emergency department and intensive care unit Pharmacy
Social workers
Key roles -
Become thoroughly educated in CAR T-cell therapy and AE management Effectively communicate all aspects of CAR T-cell therapy to patients and families and answer patient questions Undergo refresher training while on duty when patients are treated with CAR T cells Attend multidisciplinary team meetings Recognize the unique needs of patients receiving CAR T-cell therapy Do not administer steroids Follow CRS management algorithm and administer tocilizumab when needed Attend multidisciplinary team meetings Prepare plans for lymphodepleting chemotherapy, leukapheresis, and obtaining anti-cytokine therapy if needed Be aware of each patient being treated with CAR T-cell therapy to help ensure that side effects are managed properly Ensure that tocilizumab is available in the pharmacy Attend multidisciplinary team meetings Arrange lodging, transportation, and reimbursement Provide emotional support Attend multidisciplinary team meetings
From Callahan et al. [23] and McConville and Harvey [24].
ARTICLE IN PRESS Building blocks for CTL019 delivery Pre-screening patients before enrollment and therapy delivery A critical role of institutions involved in CAR T-cell therapy trials is the pre-screening of patients. Because many patients who are considered for clinical trials come from outside the institution, and possibly outside of the country, patients must be carefully examined and pre-screened before consent and initiation of screening procedures for the trial. Patients or the referring provider must submit the patient’s medical records, including recent pathology reports, historical imaging, laboratory values, treatment history and other physician notes or salient information for consideration during the pre-screening process. In particular, flow cytometry reports should be carefully reviewed to determine whether the patient’s leukemia cells are uniformly CD19+; in some cases, partial CD19 expression has been reported as CD19+. After being pre-screened for the CTL019 trials, patients are encouraged to come to the clinic to discuss all treatment options. Patients who are eligible and continue to express interest in the trial are then given ample time to review the consent form and meet with clinical staff to determine whether participation in the clinical trial is right for them. This pre-screening process can help expedite the next therapeutic option for the patient, be it proceeding with chemotherapy or undergoing leukapheresis in preparation for CAR T-cell therapy. Therefore, having the appropriate infrastructure within the center to take referral calls, obtain relevant information, set up physician evaluation and manage pre-leukapheresis requirements can streamline the enrollment of patients for CAR T-cell therapy. In our experience with pre-screening patients for the CTL019 clinical trials, it was determined that all study coordinators should have access to the electronic medical records of each patient to avoid the cumbersome process of scanning or faxing the records back and forth. Sites should designate a coordinator with appropriate credentials to coordinate the management of patient pre-screening procedures during clinical trials and the potential commercial use of CAR T cells.
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leukapheresis material is a critical starting material for CAR T-cell manufacturing and is typically collected, preprocessed and prepared by an apheresis center, which may be internal or external to the treatment center, for shipment to the manufacturing facility. Ensuring consistency of the leukapheresis starting material, cryopreservation and careful coordination of shipping to the manufacturing facility is critical. The objective is to have the CAR T cells produced and tested for safety within weeks of the leukapheresis collection. The timing of the shipment is critical because the patient’s disease must be managed appropriately during CAR T-cell manufacture. Sites will need to communicate with the manufacturing facilities to ensure that the cell product manufacturing will be completed at an appropriate time based on the patient’s disease management. To ensure no disruption to established processes, it is recommended that institutional apheresis and cellprocessing laboratories use their own labeling systems, ideally to International Society of Blood Transfusion (ISBT)-128 standards to address critical chain of identity controls.To ensure efficient transfer of leukapheresis material, additional labeling may be necessary, as defined by the CAR T-cell manufacturing facility, before it is shipped to the manufacturing facility. Couriers should also be well informed about the proper handling procedures for cellular therapy products, which are temperature and time sensitive. Correctly adhering to each of these details enables a smooth transition for the leukapheresis material and final CAR T-cell product between the treating institution and the manufacturing facility.To achieve optimal consistency of the leukapheresis material, it is beneficial for the centralized CAR T-cell manufacturing facility to publish guidelines and requirements concerning the collection, pre-processing, packing and shipment of the leukapheresis material. In the CTL019 clinical trials, study coordinators notified the hospital apheresis unit and cell-processing laboratory about upcoming patients, and a standard operating procedure (SOP) was developed to cover product handling, testing and processing requirements.
Coordination with the manufacturing facility
Preparation of the hospital pharmacy
Early clinical trials used CAR T cells that were manufactured at the same academic center where the patient underwent leukapheresis. However, this approach is challenging when planning broader accessibility of CAR T-cell therapy due to the potential for highly variable final CAR T-cell products. Industry partnerships with academic institutions leading the CAR T-cell field have allowed for the establishment of large, centralized facilities for the manufacture of CAR T cells with a high level of product consistency [20]. Patient
The hospital pharmacy is an integral part of the multidisciplinary team involved in CAR T-cell therapy. For example, at one institution treating patients with CTL019, clinical trial–specific requirements were followed in developing three treatment plans by the pharmacy: (i) lymphodepleting chemotherapy with fludarabine and cyclophosphamide with an alternative plan for cytarabine/vinorelbine and cisplatin (adult patients) or cytarabine/etoposide (pediatric patients), (ii) no lymphodepleting chemotherapy
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and (iii) lymphodepleting chemotherapy with bendamustine. Additionally, while adhering to specific requirements of clinical trials, two supportive care plans were also developed: one for leukapheresis and another for tocilizumab (tocilizumab can be used in the event of CRS, which is discussed in a later section). Each plan was checked and validated by multiple members of the multidisciplinary team before the plan was made available for use. Preparation of the hospital pharmacy staff therefore helps ensure patient safety both before and after CAR T-cell infusion. Non-medical team coordination Several non-medical aspects of clinical trials, including trials of CAR T-cell therapy, require careful planning and coordination. We recommend that social workers work closely with the multidisciplinary team to help arrange lodging and transportation for patients and families who need to travel to the site [23]. In addition, social workers should be available for other practical considerations, such as handicap access, reimbursement and emotional support [23]. During the CTL019 clinical trials, sites found that weekly team meetings including investigators, pharmacists, nurse coordinators, research coordinators, social workers, apheresis teams and others were helpful and ensured that the staff were aware of the status of each patient being treated. These meetings included discussions about patients in the pre-screening, screening, bridging therapy and post-infusion steps of the CTL019 protocol. Use of CAR T-cell therapy in the non–clinical trial setting The aspects of site training and multidisciplinary team coordination discussed thus far have implications for the potential use of commercially available CAR T-cell therapy. At the time of writing this review, CTL019 was under review by the FDA; if approved, several additional sites will need to be trained to administer CTL019. The steps just outlined can be applied not only to clinical trial sites but also to hospitals that may use CTL019 outside of a trial setting. The role of social media in clinical trials of CAR T-cell therapy Social media and data made available on the Internet can be important tools for increasing patient and physician awareness of clinical trials. Patients and their families can easily access press releases and other information on clinical trials and may be well informed about open trials and recently presented data when arriving at the clinic for an initial consultation. Some patients may post information on social media about
the clinical trial they are participating in and their personal outcome or experience with AEs. Because CAR T-cell therapy is a novel type of therapy, there may be more attention paid to social media posts regarding CAR T cells than would be expected for a new chemotherapy or monoclonal antibody therapy. From leukapheresis to CAR T-cell infusion Bridging chemotherapy Patients referred for CTL019 therapy are often in active relapse or have refractory disease; therefore, most patients require bridging chemotherapy after leukapheresis to control their disease until the CAR T-cell manufacturing process is complete [23]. For these patients, rapid access to leukapheresis is critical, and bridging therapy is initiated while they await completion of the CAR T-cell manufacturing process. The goal of bridging chemotherapy is to maximize disease control while minimizing organ toxicity, including cardiac toxicity in patients with heavy prior anthracycline exposure.The goal of controlling disease prior to CAR T-cell therapy is to avoid excessive organ toxicity during CRS—an expected AE following CAR T-cell infusion [15]. Bridging chemotherapy is typically coordinated with the referring institution, where the patients undergo treatment until the manufactured CAR T-cell product is ready. Bridging chemotherapy was also discussed with study sponsor personnel to ensure that the timing of bridging chemotherapy and manufacturing were coordinated. The teams considered the treatment history of the patient and which chemotherapy regimens could be used without delaying the infusion of CTL019. It was essential that the manufacturing team kept the site staff informed of the progress of CAR T-cell manufacture for each patient so that the clinical team could successfully bridge patients without causing harm, deviating from the protocol, or delaying infusion of CAR T cells. Bridging chemotherapy regimens are highly variable and depend on the diagnosis, the disease burden and whether patients are children or adults. Tentative CAR T-cell infusion dates are carefully planned to allow for appropriate cycles of bridging and lymphodepleting chemotherapies. Frequent communication with the CAR T-cell manufacturing site allows for adjustment, if necessary, of the bridging therapy timeline. Early notification of CAR T-cell manufacturing challenges, such as inadequate T-cell expansion or manufacturing failure, will allow institutions to adjust their plans for the patient. During this time, patients may also be informed about the status of their CAR T-cell products during meetings with the clinical team. Patients should be counseled at the start of the process that a manufacturing failure is possible and that they
ARTICLE IN PRESS Building blocks for CTL019 delivery may need to repeat the leukapheresis procedure if a second manufacturing attempt is made. Receipt of manufactured CAR T-cell products After manufacture of the patient’s autologous CAR T cells, it is important that the product be delivered efficiently to the treatment center. Because of the time and temperature sensitivity of the material, the institution delivery location must be very specifically defined to avoid any potential for lost or damaged product. On receipt of the manufactured CAR T-cell product, it is critical that the chain of identity be verified with the manufacturing facility. Infusion of CAR T cells Coordination between the multidisciplinary team is critical before and on the day of CAR T-cell infusion. The patient must have recently been examined by the treating physician to determine no change in performance status that would increase the risk of AEs associated with CAR T-cell therapy [23]. It is recommended that patients are screened for influenza approximately 10 days before the planned CAR T-cell infusion. Hospital staff trained in CAR T-cell therapy must be available on the date of infusion, as should other hospital staff not involved in the clinical care of the patient but whose activities are critical to the process, such as those responsible for thawing and disposing of the gene therapy products. Knowledge of the institutional biosafety requirements for these materials is necessary for their proper handling. Furthermore, all SOPs need to include proper thaw and disposal procedures for the CAR T-cell product before its use at an institution. Proper labeling of the products is also critical to maintaining the chain of custody for all trials of cell and gene therapy. In addition, a plan is needed to notify the pharmacy of the potential need for anti-cytokine therapies to manage side effects, such as CRS, on the day of infusion. The patient must be closely monitored per the institution’s SOPs for cryopreserved product infusion. This includes a requirement that families and patients remain close to the treating site for 21–28 days after infusion for monitoring of side effects, including CRS. Notifying the entire multidisciplinary team that a patient has been infused with CAR T cells will facilitate a timely response to any AEs experienced by the patient. Preparing the institution for a multidisciplinary approach to managing CAR T-cell therapy–related AEs Side effects have been observed after CAR T-cell infusion that require coordinated management by several
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health care teams. The most prominent and serious toxicity associated with CD19-targeted CAR T-cell therapy is CRS, which is caused by proinflammatory cytokine release during the activation and rapid expansion of CAR T cells within the patient’s body. High cytokine levels can lead to symptoms of CRS such as fever, nausea, chills, headache, myalgia, tachycardia, hypotension and dyspnea [8,15]. Recent reports have shown approximately 80–90% of pediatric patients with ALL developed CRS after therapy with CTL019; approximately 40–50% of these patients experienced grade 3/4 CRS [10,25,26]. CRS often occurs just days after the patient is infused [10].Therefore, initial management of patients with CAR T-cell therapy–associated CRS is often the responsibility of emergency department staff. Our experience with CRS has reinforced our policy that families remain close to the treating center for at least 21–28 days after CAR T-cell infusion. CRS severity may correlate with disease burden [8,27], but no assay is currently available for determining which patients will experience severe CRS requiring inpatient monitoring and treatment. In general, CRS should be managed with pain medications, antiemetics, intravenous nutrition, intubation, vasopressor support and/or the interleukin 6 receptor antagonist antibody tocilizumab [27,28]. A treatment algorithm provided through the clinical trials outlined and guided the management of CRS. The loss of vasomotor tone caused by severe CRS is similar to the effects of Gram-negative sepsis [29], including the similar potential for rapid decompensation. Most emergency department and intensive care unit (ICU) teams will respond to symptoms of CRS by administering intravenous fluid. Early vasopressor support is recommended during CAR T-cell therapy to avoid fluid overload. Importantly, steroids should not be administered to patients treated with CAR T-cell therapy—unless a patient is refractory to at least one dose of tocilizumab and does not improve with hemodynamic and respiratory support—because of the potential of steroids to induce CAR T-cell apoptosis [30]. However, a recent report showed that engraftment and persistence of CD19 CAR T cells were not affected when steroids were administered early after the onset of CRS symptoms [31]. Several approaches have been taken to avoid steroid use after CAR T-cell therapy. The electronic medical record is updated with an alert that the patient is participating in a clinical trial, and the clinical team must be contacted before ordering medication for the patient. Steroids may also be entered as an allergy on the patient’s electronic medical record, with a brief explanation, or the patient can be given a card indicating his or her status as a CAR T-cell therapy recipient to present to the emergency department if needed. In addition, ICU staff members are educated about CAR
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T-cell therapy and CRS management to prepare them for the proper management of patients with CRS. Investigators should also be aware that many pediatric patients are given steroids by anesthesia during extubation after apheresis catheter placement; therefore, it is advisable that steroids be temporarily recorded as an allergy in the patient’s medical record before line placement. Tocilizumab should be stocked in hospital pharmacies before a patient is treated with CAR T-cell therapy; at least two doses should be available. Tocilizumab is a proven effective treatment for managing patients with severe CRS, and—depending on the clinical response—some patients may require more than one dose of tocilizumab [8,11,32,33]. The interleukin 6 blocking antibody siltuximab has also been used to manage severe CRS, and siltuximab should be stocked in hospital pharmacies or a protocol should be developed to obtain it within 24 h after the first dose of tocilizumab is ordered. In clinical trials of CTL019, clear workflows were developed for obtaining tocilizumab either during pharmacy business hours or overnight, and pharmacy clinical staff members were made aware of the preparation instructions for tocilizumab and of the requirement for a quick turnaround. Each time a new patient was admitted for CTL019 infusion, the pharmacy clinical coordinator reminded all pharmacy staff of the patient’s name and the potential need for tocilizumab to manage severe CRS. The attending nursing staff must have clear instructions to ensure that tocilizumab is promptly administered when CRS occurs. Tocilizumab should be administered within 2 h of being ordered. This means that other therapies (e.g., antibiotics) may need to be interrupted because tocilizumab treatment should be the priority when patients experience CRS. Neurological side effects have also been observed as a result of CD19-targeted CAR T-cell therapies [8,11,12]. Although neurotoxicity is typically self-limiting, physicians, nurses, hospital staff and patients and their families should be educated on the symptoms of neurotoxicity, including delirium during high fevers and delayed encephalopathy [8]. Close attention should be paid to any concomitant medication that may alter mental status. Any changes in the patient’s neurological status should be immediately reported to the treating physician. Patients may also experience other AEs, such as tumor lysis syndrome and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) after CAR T-cell therapy, which should be managed according to institutional guidelines [2,28]. Management of MAS/ HLH is similar to management of CRS, with particular attention paid to coagulation studies [34]. The comprehensive education and preparation of patients, pharmacists, emergency department staff, ICU
staff and treating physicians and nurses are critical to the proper management of CRS and other AEs. Before the opening of the CTL019 trials, emergency department, ICU and neurology provider teams were familiarized with CAR T-cell therapy, specifically with CRS and its management and the importance of avoiding steroid use in these patients. Bone marrow transplant pharmacists were educated about the CTL019 protocol and were given documents detailing toxicity management, supportive care and the CRS management algorithm.Weekly multidisciplinary team meetings also served to educate all team members about CRS symptoms. For sites initiating CAR T-cell therapy trials, educational materials should be developed and individualized for the clinical staff of different departments (e.g., nurses, pharmacists, emergency department staff), and the staff should be thoroughly trained in CRS management. Staff should also have access to pertinent literature and other educational materials so that they can continue to familiarize themselves with CAR T-cell therapy, the associated AEs and AE management. It may also be helpful to post the CRS management algorithm in common areas of the treatment site or where other clinical practice guidelines are maintained. Patients and their families should also be educated about the symptoms of CAR T-cell therapy– associated AEs, such as CRS and neurotoxicity, and their severity to avoid a delay in seeking proper treatment. Effective communication not only improves patient safety but also typically leads to increased adherence to clinical trial protocols. Conclusion Novel immunocellular therapies, including CAR T-cell therapy, require a more complex patient-specific manufacturing and administration process than traditional therapies and are associated with a spectrum of AEs. Planning for the delivery of CAR T-cell therapy begins with a pre-screening assessment because the patient’s functional status and medical history will help facilitate the safety of leukapheresis, patient care before treatment, treatment delivery and AE management. Frequent and open communication between the treatment center, internal or external apheresis center and manufacturing sites is crucial to the successful implementation of CAR T-cell therapy. Although the optimal composition of a leukapheresis product destined for CAR T-cell manufacture is still under investigation, several patient factors need to be considered when determining optimal time for leukapheresis: prior cytotoxic therapy, temporal relationship to allogeneic SCT, disease burden and performance status. Data from ongoing studies will aid in the standardization of leukapheresis proto-
ARTICLE IN PRESS Building blocks for CTL019 delivery cols, which will be critical to improving the safety and efficacy of CAR T cells and other cellular therapies. Institutions should be thoroughly prepared for CAR T-cell therapy and management of its associated AEs. Although remission rates with CTL019 have shown potential, its toxicities can be life threatening. Understanding the mechanisms and management of AEs associated with immunocellular therapies will help make this novel therapy available to a broader patient population. Acknowledgments This work was supported in part by National Institutes of Health grants UL1TR000454 and KL2TR000455 (M. Qayed).We thank Judith Murphy, PhD, for medical editorial assistance. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. Disclosure of interests: S. Ericson, C. Keir and P. Holman are employees of Novartis Pharmaceuticals Corporation. M. Qayed reports personal fees from Novartis Pharmaceuticals Corporation, outside the submitted work. G.D. Myers reports nonfinancial support and other from Novartis Pharmaceuticals Corporation, outside the submitted work. The other authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References [1] Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011;3:95ra73. [2] Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725–33. [3] Porter DL, Kalos M, Zheng Z, Levine B, June C. Chimeric antigen receptor therapy for B-cell malignancies. J Cancer 2011;2:331–2. [4] Hicklin DJ, Marincola FM, Ferrone S. HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 1999;5:178–86. [5] Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 2008;14:1264– 70. [6] Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25. [7] Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17:1453–64.
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[8] Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med 2014;371:1507–17. [9] Scheuermann RH, Racila E. CD19 antigen in leukemia and lymphoma diagnosis and immunotherapy. Leuk Lymphoma 1995;18:385–97. [10] Fitzgerald JC, Weiss SL, Maude SL, Barrett DM, Lacey SF, Melenhorst JJ, et al. Cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Crit Care Med 2017;45:e124–31. [11] Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, et al. CD19 CAR-T cells of defined CD4+: CD8+ composition in adult B cell ALL patients. J Clin Invest 2016;126:2123–38. [12] Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, et al. Chemotherapyrefractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J Clin Oncol 2015;33:540–9. [13] Schuster SJ, Svoboda J, Nasta SD, Chong EA, Porter DL, Landsburg DJ, et al. Recovery of humoral immunity in patients with durable complete responses following chimeric antigen receptor modified T cells directed against CD19 (CTL019). J Clin Oncol 2016;34(Suppl.):abstract 7564. [14] Sauter CS, Riviere I, Bernal Y, Wang X, Purdon T, Yoo S, et al. Phase I trial of 19-28z chimeric antigen receptor modified T cells (19-28z CAR-T) post-high dose therapy and autologous stem cell transplant (HDT-ASCT) for relapsed and refractory (rel/ref) aggressive B-cell non-Hodgkin lymphoma (B-NHL). J Clin Oncol 2015;33(Suppl.):abstract 8515. [15] Lee DW, Gardner R, Porter DL, Louis CU, Ahmed N, Jensen M, et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 2014;124:188–95. [16] Schwartz J, Winters JL, Padmanabhan A, Balogun RA, Delaney M, Linenberger ML, et al. Guidelines on the use of therapeutic apheresis in clinical practice-evidence-based approach from the Writing Committee of the American Society for Apheresis: the sixth special issue. J Clin Apher 2013;28: 145–284. [17] Yuan S, Ziman A, Smeltzer B, Lu Q, Goldfinger D. Moderate and severe adverse events associated with apheresis donations: incidences and risk factors. Transfusion 2010;50:478–86. [18] Cottler-Fox MH, Lapidot T, Petit I, Kollet O, DiPersio JF, Link D, et al. Stem cell mobilization. Hematology Am Soc Hematol Educ Program 2003;419–37. [19] ASFA. American Society for Apheresis patient resource information sheets. Available from: http://www.apheresis.org/ ?page=FactSheets. [Accessed 16 August 2016]. [20] Levine BL, Miskin J, Wonnacott K, Keir C. Global manufacturing of CAR T cell therapy. Mol Ther Methods Clin Dev 2016;4:92–101. [21] Russell RT, Carney DE, Rescorla FJ. Peri-operative care of the general pediatric surgical patient. In: Wheeler DS, Wong HR, Shanley TP, editors. Pediatric Critical Care Medicine. London: Springer-Verlag; 2014. [22] Hunt EA, Jain NG, Somers MJ. Apheresis therapy in children: an overview of key technical aspects and a review of experience in pediatric renal disease. J Clin Apher 2013;28:36–47. [23] Callahan C, Baniewicz D, Ely B. CAR T-cell therapy: pediatric patients with relapsed and refractory acute lymphoblastic leukemia. Clin J Oncol Nurs 2017;21:22–8. [24] McConville H, Harvey M. Reprogramming the immune system to target cancer: chimeric antigen receptor T-cell therapy; 2016. Available from: http://www.oncologynurse advisor.com/leukemia/reprogramming-immune-system-totarget-cancer/article/461164. [Accessed 4 May 2017].
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[25] Grupp SA, Laetsch TW, Buechner J, Bittencourt H, Maude SL, Verneris MR, et al. Analysis of a global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL). Blood 2016;128:abstract 221. [26] Maude SL, Pulsipher MA, Boyer MW, Grupp SA, Davies SM, Phillips CL, et al. Efficacy and safety of CTL019 in the first US phase II multicenter trial in pediatric relapsed/refractory acute lymphoblastic leukemia: results of an interim analysis. Blood 2016;128:abstract 2801. [27] Teachey DT, Lacey SF, Shaw PA, Melenhorst JJ, Maude SL, Frey N, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov 2016;6:664–79. [28] Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR, et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013;368: 1509–18. [29] Brandtzaeg P, Mollnes TE, Kierulf P. Complement activation and endotoxin levels in systemic meningococcal disease. J Infect Dis 1989;160:58–65.
[30] Herold MJ, McPherson KG, Reichardt HM. Glucocorticoids in T cell apoptosis and function. Cell Mol Life Sci 2006;63:60–72. [31] Gardner R, Leger KJ, Annesley CE, Summers C, Rivers J, Gust J, et al. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. Blood 2016;128:abstract 586. [32] Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med 2015;7: 303ra139. [33] Lee DW, Kochenderfer JN, Stetler-Stevenson M, Cui YK, Delbrook C, Feldman SA, et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 2015;385:517–28. [34] Teachey DT, Rheingold SR, Maude SL, Zugmaier G, Barrett DM, Seif AE, et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 2013;121:5154–7.
Building blocks for institutional preparation of CTL019 delivery
JOSEPH MCGUIRK1, EDMUND K. WALLER2, MUNA QAYED2, SUNIL ABHYANKAR1, SOLVEIG ERICSON3, PETER HOLMAN3, CHRISTOPHER KEIR3 & G. DOUGLAS MYERS4 1
The University of Kansas Medical Center, Kansas City, KS, USA, 2Emory University School of Medicine, Atlanta, GA, USA, 3Novartis Pharmaceuticals Corporation, East Hanover, NJ, USA, and 4University of Missouri-Kansas City School of Medicine, Kansas City, MO, USA Abstract 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 on a broader scale in the future. CAR T-cell therapy begins with the collection of a sufficient number of T cells from a patient’s peripheral blood through leukapheresis. Several factors must be considered when patients undergo leukapheresis for CAR T-cell therapy, including age and prior therapies. The leukapheresis material is shipped to a manufacturing facility, followed by return of the CAR T cells to the treatment center. Careful coordination of a multidisciplinary team composed of physicians, nurses, pharmacists and other hospital personnel is critical for the proper care of the patient before, during and after CAR T-cell therapy. CAR T-cell therapy has been associated with adverse events (AEs) such as cytokine release syndrome, which requires rapid attention by the emergency department, intensive care unit and hospital pharmacy. In this review, we discuss several aspects of institutional preparation for leukapheresis, CAR T-cell infusion and AE management based on our experience with clinical trials of the CD19 CAR T-cell therapy CTL019. Key Words: blood component removal, clinical trial, genetic therapy, leukapheresis
Introduction to CAR T-cell therapy The field of immunocellular therapy aims to harness the power of a patient’s own immune system to fight malignancy. Although several components of the immune system can be involved in the immune response to cancer, many therapies take advantage of the cytotoxic potential of T cells. T cells can be manipulated to recognize and attack cancer cells through the use of vaccination, monoclonal antibodies, bispecific T-cell engagers and modification of T cells ex vivo. One therapeutic approach involving the activation and engineering of cytotoxic T cells is chimeric antigen receptor (CAR) T-cell therapy [1–3]. CARs are genetically engineered receptors consisting of antibodymediated antigen recognition,T-cell signaling, and T-cell costimulatory domains. CAR-modified T cells therefore combine T-cell cytotoxic activity with the antigen specificity of an antibody. CARs obviate the need for presentation of antigen in human leukocyte antigen (HLA), which may be down-regulated on many tumors [4], effectively “blinding” T cells to a tumor’s pres-
ence. Introduction of a CAR into a T cell endows the T cell with the ability to recognize and eliminate tumor cells expressing the antigen of interest via CAR T-cell– mediated killing, while the CAR T cells retain the cell’s endogenous T-cell receptor and capability to exert cytotoxic function toward HLA-bound antigen recognized by the endogenous T-cell receptor [5]. CARs are most commonly transduced into a patient’s T cells using a lentiviral or gammaretroviral vector [6,7]. After manufacture of the CAR T cells ex vivo, the patient receives lymphodepleting chemotherapy if needed, followed by CAR T-cell infusion (Figure 1) [8]. To date, clinical trials of CAR T cells have been primarily focused on CD19-expressing malignancies. CD19 antigen is expressed on B-cell precursor cells, most mature B cells, and several B-cell malignancies and, importantly, is not expressed on other vital tissues [9]. CD19-targeted CAR T-cell therapies have demonstrated high efficacy in clinical trials for a variety of hematologic malignancies. In pediatric and adult patients with relapsed or refractory (r/r) acute lymphoblastic leukemia (ALL) who were
Correspondence: Joseph McGuirk, DO, The University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS 66160, USA. E-mail: [email protected] (Received 16 March 2017; accepted 2 June 2017) ISSN 1465-3249 Copyright © 2017 International Society for Cellular Therapy. Published by Elsevier Inc. This is an open access article under the CC BYNC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). http://dx.doi.org/10.1016/j.jcyt.2017.06.001
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1 Leukapheresis
5 Modified T-cell infusion
4 Chemotherapy Anbody-coated beads Bead removal
2 T-cell acvaon/ transducon
T-cell 3 Modified expansion
Copyright © 2015 Novars Corporaon.
Figure 1. 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.
heavily pretreated, complete response (CR) rates of up to approximately 90% have been reported in trials of CD19 CAR T-cell therapy [8,10,11]. In patients with r/r non-Hodgkin B-cell lymphoma, CR rates of approximately 50–70% have been achieved with CD19 CAR T-cell therapies [12–14]. Acute adverse events (AEs) resulting from CAR T-cell therapy have been observed, the most notable being cytokine release syndrome (CRS) [15]. Preparation for the early identification and expectant management of CRS and other potential toxicities is crucial to the safe delivery of CAR T-cell therapy at treating sites. Many clinical trials using CAR T cells are ongoing, and the potential exists for broader availability of CAR T-cell therapy in the near future; therefore, there is a great need to educate clinical staff members to adequately prepare them for delivering this type of therapy. In this review, we discuss logistics related to CAR T-cell therapy based on experience gained in multiinstitutional clinical trials investigating the CD19 CAR T-cell therapy CTL019. Here we focus on leukapheresis material, which is a fundamental and critical starting material for CAR T-cell product manufacturing, and discuss issues concerning the cryopreservation of
the leukapheresis material and related logistics. Furthermore, we highlight key points related to facilitating infusion of the product and managing potentially lifethreatening side effects post-CTL019 infusion. We believe that sites considering CAR T-cell therapies will find this review helpful in planning for and delivering this therapy safely to their patients. Obtaining the effector cells for CAR T-cell therapy Leukapheresis Apheresis is a widely used process whereby blood is removed from an individual, separated into select components and returned to the individual’s circulation after the component of interest has been collected [16]. Apheresis is currently used for the treatment of several diseases, including hematologic, metabolic and renal disorders, and is used in blood banks for collection of platelets and other blood components [16]. Apheresis is considered a safe procedure for both healthy donors and patients, including patients with r/r hematologic malignancies. A retrospective analysis of 15 763 apheresis procedures determined a moderate to severe
ARTICLE IN PRESS Building blocks for CTL019 delivery AE rate of 0.37%, which included dizziness, fainting, citrate toxicity, vascular injuries and other miscellaneous events [17]; most of the observed AEs were mild and easily reversed. Leukapheresis is the process in which white blood cells from the peripheral blood are collected. In peripheral blood stem cell (PBSC) leukapheresis, the target cell population is CD34+ cells, and these cells have typically been mobilized from the bone marrow [18]. PBSC collection is typically a 4- to 6-h outpatient procedure, and one to four collections are typically required to obtain sufficient CD34+ cells for one or more transplants; the optimal number of CD34+ cells collected depends on the number of planned transplants [18,19]. Similar to PBSC collections, the CAR T-cell therapeutic product begins with leukapheresis [20]; however, in this case, mononuclear cells are collected. Furthermore, the collections are nonmobilized, with the goal of obtaining CD3+ T cells, and take much less time than stem cell apheresis: often, a single 2to 3-h collection is sufficient to harvest the required number of cells [19]. In clinical trials for CTL019, we aim for a minimum absolute lymphocyte count of 500 cells/µL and a minimum CD3+ cell count of 150 cells/µL. The peripheral blood CD3+ cell count, along with collection efficiency for the site, can be used as a reference to predict the volume of blood needed to reach the target number of CD3+ cells. This can help inform whether an adequate number of cells will be harvested in a single collection. Obtaining collected leukapheresis material with adequate cell populations can be critical to the success of manufacturing CAR T-cells. The minimum required numbers of defined cell types must be collected. Limiting nontarget cell populations is critical but may be partially mitigated with advanced cell therapy manufacturing processes that have the capability to remove the unwanted cell types. Leukapheresis in pediatric patients Certain distinctions must be made between adults and children when performing leukapheresis (Table I)
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[21,22]. Pediatric patients have a much smaller total blood volume, resulting in a greater sensitivity to removal of blood during the leukapheresis procedure. Children may also be more susceptible to hypothermia or hypocalcemia during leukapheresis. For these reasons, the rate of leukapheresis should be slower in pediatric patients than in adults.These special considerations for the pediatric population are not unique to patients undergoing leukapheresis in preparation for CAR T-cell therapy; therefore, apheresis centers that manage both pediatric and adult patients will be familiar with these distinctions. An additional point of preparation for the leukapheresis procedure is ensuring proper venous access. In pediatric patients, this often involves insertion of a temporary or permanent dialysis-grade catheter. In adolescents and adults, evaluating antecubital veins before the procedure date is essential to determining whether a central venous catheter is needed and, if so, to properly plan catheter placement. Both the clinical staff and patients should be aware that catheter placement is a possibility before the scheduled leukapheresis appointment. Leukapheresis for CAR T-cell therapy Other concerns regarding leukapheresis for CAR T-cell therapy depend on the treatment history of the patient. Patients receiving CTL019 or other CD19 CAR T-cell therapies have often undergone several rounds of prior cytotoxic therapy, sometimes including allogeneic stem cell transplant (SCT) [8,11]. These prior treatments may affect the timing of leukapheresis, because T-cell number and function may be reduced by the prior therapy. Patients with a history of allogeneic SCT should stop immunosuppressive drug therapy and should have no evidence of acute graft-versus-host disease (GVHD) at the time of leukapheresis collection. For the CTL019 trials, it was determined that patients should not undergo leukapheresis for CAR T-cell therapy fewer than 3 months after allogeneic SCT because of the risk of harvesting allogeneicreactive T cells during this period, which could induce
Table I. Key leukapheresis considerations for CAR T-cell therapy. Key aspect of leukapheresis procedure Pediatric patients [21,22] Prior therapies
Smaller blood volume Susceptible to hypothermia or hypocalcemia Venous access may be challenging Allogeneic SCT Pegylated asparaginase Other cytotoxic chemotherapy Immunomodulatory drugs Steroids
How addressed or managed Slower rate of leukapheresis Insert temporary or permanent dialysis-grade catheter Allogeneic SCT must have been >3 months before leukapheresis Stop >4 weeks before leukapheresis Stop >2 weeks before leukapheresis Stop ≥2 weeks before leukapheresis Therapeutic doses must be stopped >72 hours before leukapheresis
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GVHD or exacerbate subclinical GVHD if used for CAR T-cell manufacture. Other chemotherapy or immunosuppressive medications should be stopped as early as possible before leukapheresis because these medications may result in the collection of low numbers of T cells or T cells that are unable to proliferate ex vivo. In the CTL019 clinical trials, we advised stopping cytotoxic chemotherapy 2 weeks before leukapheresis, with the exception of pegylated asparaginase, which we advised stopping 4 weeks before leukapheresis. Low-dose or weekly maintenance chemotherapy and immunomodulatory drugs, such as anti–tumor necrosis factor α, should be stopped 2 or more weeks and therapeutic doses of steroids must be stopped at least 72 h before leukapheresis. As with many steps in the CAR T-cell therapy process, there should be open communication among the treatment center, apheresis center and product manufacturing site staff so that concerns about product quality and questions related to the timing of leukapheresis and chemotherapy washout can be discussed.The external apheresis center and/or treatment center play key roles in handling the leukapheresis material after collection, such as cryopreservation and storage until it is shipped for manufacturing. Efficiency in obtaining leukapheresis material that can be used for CAR T-cell manufacture expedites the process of bringing CAR T-cell therapy to patients who may not have other therapeutic options. Institutional preparation for efficient leukapheresis procedures is one of many steps that must be taken to ensure that the site is working toward optimal safety and efficacy when treating patients with CAR T-cell therapies. In clinical trials using the CD19-targeted CAR T-cell therapy CTL019, several factors that influence a successful leukapheresis procedure are being investigated, including the CD3+ cell count targets necessary for CTL019 manufacturing, the history of prior
chemotherapy, the type of machine used for the leukapheresis procedure and the most appropriate timing for the patient to undergo leukapheresis. To further investigate and standardize leukapheresis, a clinical study is ongoing to examine the collection and use of leukapheresis products obtained from patients considering enrollment in a CTL019 clinical trial. Preparing the institution for CAR T-cell therapy Overview of institutional preparation As with all clinical trials, careful consideration should be taken when evaluating the staff resources and needs at the clinical trials office, the corresponding laboratories and the hospital before offering CAR T-cell therapy to patients. Attention must also be paid to the timing of when the patient is pre-screened for potential participation in the trial. Once the patient’s cells are collected by leukapheresis and sent for manufacturing, the timing of interim/bridging chemotherapy, lymphodepleting chemotherapy, and CAR T-cell infusion must be carefully planned to facilitate CAR T-cell expansion in vivo. Lymphodepleting chemotherapy is administered to facilitate CAR T-cell expansion in vivo [8,12] and reduces disease burden before infusion of the CAR T-cell product. In our experience, the coordination of trials using CTL019 demands special attention to the timing of events once the patient has been admitted for treatment (Table II). Before opening clinical trials of CAR T-cell therapy, a series of approvals are needed from the manufacturing site, the U.S. Food and Drug Administration (FDA) and the local institutional review board and institutional biosafety committee. If CAR T-cell therapy becomes commercially available, institutional resources will need to be available to comply with FDA oversight.
Table II. Key roles of the multidisciplinary team when treating patients who receive CAR T-cell therapy. Department Nursing
Emergency department and intensive care unit Pharmacy
Social workers
Key roles -
Become thoroughly educated in CAR T-cell therapy and AE management Effectively communicate all aspects of CAR T-cell therapy to patients and families and answer patient questions Undergo refresher training while on duty when patients are treated with CAR T cells Attend multidisciplinary team meetings Recognize the unique needs of patients receiving CAR T-cell therapy Do not administer steroids Follow CRS management algorithm and administer tocilizumab when needed Attend multidisciplinary team meetings Prepare plans for lymphodepleting chemotherapy, leukapheresis, and obtaining anti-cytokine therapy if needed Be aware of each patient being treated with CAR T-cell therapy to help ensure that side effects are managed properly Ensure that tocilizumab is available in the pharmacy Attend multidisciplinary team meetings Arrange lodging, transportation, and reimbursement Provide emotional support Attend multidisciplinary team meetings
From Callahan et al. [23] and McConville and Harvey [24].
ARTICLE IN PRESS Building blocks for CTL019 delivery Pre-screening patients before enrollment and therapy delivery A critical role of institutions involved in CAR T-cell therapy trials is the pre-screening of patients. Because many patients who are considered for clinical trials come from outside the institution, and possibly outside of the country, patients must be carefully examined and pre-screened before consent and initiation of screening procedures for the trial. Patients or the referring provider must submit the patient’s medical records, including recent pathology reports, historical imaging, laboratory values, treatment history and other physician notes or salient information for consideration during the pre-screening process. In particular, flow cytometry reports should be carefully reviewed to determine whether the patient’s leukemia cells are uniformly CD19+; in some cases, partial CD19 expression has been reported as CD19+. After being pre-screened for the CTL019 trials, patients are encouraged to come to the clinic to discuss all treatment options. Patients who are eligible and continue to express interest in the trial are then given ample time to review the consent form and meet with clinical staff to determine whether participation in the clinical trial is right for them. This pre-screening process can help expedite the next therapeutic option for the patient, be it proceeding with chemotherapy or undergoing leukapheresis in preparation for CAR T-cell therapy. Therefore, having the appropriate infrastructure within the center to take referral calls, obtain relevant information, set up physician evaluation and manage pre-leukapheresis requirements can streamline the enrollment of patients for CAR T-cell therapy. In our experience with pre-screening patients for the CTL019 clinical trials, it was determined that all study coordinators should have access to the electronic medical records of each patient to avoid the cumbersome process of scanning or faxing the records back and forth. Sites should designate a coordinator with appropriate credentials to coordinate the management of patient pre-screening procedures during clinical trials and the potential commercial use of CAR T cells.
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leukapheresis material is a critical starting material for CAR T-cell manufacturing and is typically collected, preprocessed and prepared by an apheresis center, which may be internal or external to the treatment center, for shipment to the manufacturing facility. Ensuring consistency of the leukapheresis starting material, cryopreservation and careful coordination of shipping to the manufacturing facility is critical. The objective is to have the CAR T cells produced and tested for safety within weeks of the leukapheresis collection. The timing of the shipment is critical because the patient’s disease must be managed appropriately during CAR T-cell manufacture. Sites will need to communicate with the manufacturing facilities to ensure that the cell product manufacturing will be completed at an appropriate time based on the patient’s disease management. To ensure no disruption to established processes, it is recommended that institutional apheresis and cellprocessing laboratories use their own labeling systems, ideally to International Society of Blood Transfusion (ISBT)-128 standards to address critical chain of identity controls.To ensure efficient transfer of leukapheresis material, additional labeling may be necessary, as defined by the CAR T-cell manufacturing facility, before it is shipped to the manufacturing facility. Couriers should also be well informed about the proper handling procedures for cellular therapy products, which are temperature and time sensitive. Correctly adhering to each of these details enables a smooth transition for the leukapheresis material and final CAR T-cell product between the treating institution and the manufacturing facility.To achieve optimal consistency of the leukapheresis material, it is beneficial for the centralized CAR T-cell manufacturing facility to publish guidelines and requirements concerning the collection, pre-processing, packing and shipment of the leukapheresis material. In the CTL019 clinical trials, study coordinators notified the hospital apheresis unit and cell-processing laboratory about upcoming patients, and a standard operating procedure (SOP) was developed to cover product handling, testing and processing requirements.
Coordination with the manufacturing facility
Preparation of the hospital pharmacy
Early clinical trials used CAR T cells that were manufactured at the same academic center where the patient underwent leukapheresis. However, this approach is challenging when planning broader accessibility of CAR T-cell therapy due to the potential for highly variable final CAR T-cell products. Industry partnerships with academic institutions leading the CAR T-cell field have allowed for the establishment of large, centralized facilities for the manufacture of CAR T cells with a high level of product consistency [20]. Patient
The hospital pharmacy is an integral part of the multidisciplinary team involved in CAR T-cell therapy. For example, at one institution treating patients with CTL019, clinical trial–specific requirements were followed in developing three treatment plans by the pharmacy: (i) lymphodepleting chemotherapy with fludarabine and cyclophosphamide with an alternative plan for cytarabine/vinorelbine and cisplatin (adult patients) or cytarabine/etoposide (pediatric patients), (ii) no lymphodepleting chemotherapy
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and (iii) lymphodepleting chemotherapy with bendamustine. Additionally, while adhering to specific requirements of clinical trials, two supportive care plans were also developed: one for leukapheresis and another for tocilizumab (tocilizumab can be used in the event of CRS, which is discussed in a later section). Each plan was checked and validated by multiple members of the multidisciplinary team before the plan was made available for use. Preparation of the hospital pharmacy staff therefore helps ensure patient safety both before and after CAR T-cell infusion. Non-medical team coordination Several non-medical aspects of clinical trials, including trials of CAR T-cell therapy, require careful planning and coordination. We recommend that social workers work closely with the multidisciplinary team to help arrange lodging and transportation for patients and families who need to travel to the site [23]. In addition, social workers should be available for other practical considerations, such as handicap access, reimbursement and emotional support [23]. During the CTL019 clinical trials, sites found that weekly team meetings including investigators, pharmacists, nurse coordinators, research coordinators, social workers, apheresis teams and others were helpful and ensured that the staff were aware of the status of each patient being treated. These meetings included discussions about patients in the pre-screening, screening, bridging therapy and post-infusion steps of the CTL019 protocol. Use of CAR T-cell therapy in the non–clinical trial setting The aspects of site training and multidisciplinary team coordination discussed thus far have implications for the potential use of commercially available CAR T-cell therapy. At the time of writing this review, CTL019 was under review by the FDA; if approved, several additional sites will need to be trained to administer CTL019. The steps just outlined can be applied not only to clinical trial sites but also to hospitals that may use CTL019 outside of a trial setting. The role of social media in clinical trials of CAR T-cell therapy Social media and data made available on the Internet can be important tools for increasing patient and physician awareness of clinical trials. Patients and their families can easily access press releases and other information on clinical trials and may be well informed about open trials and recently presented data when arriving at the clinic for an initial consultation. Some patients may post information on social media about
the clinical trial they are participating in and their personal outcome or experience with AEs. Because CAR T-cell therapy is a novel type of therapy, there may be more attention paid to social media posts regarding CAR T cells than would be expected for a new chemotherapy or monoclonal antibody therapy. From leukapheresis to CAR T-cell infusion Bridging chemotherapy Patients referred for CTL019 therapy are often in active relapse or have refractory disease; therefore, most patients require bridging chemotherapy after leukapheresis to control their disease until the CAR T-cell manufacturing process is complete [23]. For these patients, rapid access to leukapheresis is critical, and bridging therapy is initiated while they await completion of the CAR T-cell manufacturing process. The goal of bridging chemotherapy is to maximize disease control while minimizing organ toxicity, including cardiac toxicity in patients with heavy prior anthracycline exposure.The goal of controlling disease prior to CAR T-cell therapy is to avoid excessive organ toxicity during CRS—an expected AE following CAR T-cell infusion [15]. Bridging chemotherapy is typically coordinated with the referring institution, where the patients undergo treatment until the manufactured CAR T-cell product is ready. Bridging chemotherapy was also discussed with study sponsor personnel to ensure that the timing of bridging chemotherapy and manufacturing were coordinated. The teams considered the treatment history of the patient and which chemotherapy regimens could be used without delaying the infusion of CTL019. It was essential that the manufacturing team kept the site staff informed of the progress of CAR T-cell manufacture for each patient so that the clinical team could successfully bridge patients without causing harm, deviating from the protocol, or delaying infusion of CAR T cells. Bridging chemotherapy regimens are highly variable and depend on the diagnosis, the disease burden and whether patients are children or adults. Tentative CAR T-cell infusion dates are carefully planned to allow for appropriate cycles of bridging and lymphodepleting chemotherapies. Frequent communication with the CAR T-cell manufacturing site allows for adjustment, if necessary, of the bridging therapy timeline. Early notification of CAR T-cell manufacturing challenges, such as inadequate T-cell expansion or manufacturing failure, will allow institutions to adjust their plans for the patient. During this time, patients may also be informed about the status of their CAR T-cell products during meetings with the clinical team. Patients should be counseled at the start of the process that a manufacturing failure is possible and that they
ARTICLE IN PRESS Building blocks for CTL019 delivery may need to repeat the leukapheresis procedure if a second manufacturing attempt is made. Receipt of manufactured CAR T-cell products After manufacture of the patient’s autologous CAR T cells, it is important that the product be delivered efficiently to the treatment center. Because of the time and temperature sensitivity of the material, the institution delivery location must be very specifically defined to avoid any potential for lost or damaged product. On receipt of the manufactured CAR T-cell product, it is critical that the chain of identity be verified with the manufacturing facility. Infusion of CAR T cells Coordination between the multidisciplinary team is critical before and on the day of CAR T-cell infusion. The patient must have recently been examined by the treating physician to determine no change in performance status that would increase the risk of AEs associated with CAR T-cell therapy [23]. It is recommended that patients are screened for influenza approximately 10 days before the planned CAR T-cell infusion. Hospital staff trained in CAR T-cell therapy must be available on the date of infusion, as should other hospital staff not involved in the clinical care of the patient but whose activities are critical to the process, such as those responsible for thawing and disposing of the gene therapy products. Knowledge of the institutional biosafety requirements for these materials is necessary for their proper handling. Furthermore, all SOPs need to include proper thaw and disposal procedures for the CAR T-cell product before its use at an institution. Proper labeling of the products is also critical to maintaining the chain of custody for all trials of cell and gene therapy. In addition, a plan is needed to notify the pharmacy of the potential need for anti-cytokine therapies to manage side effects, such as CRS, on the day of infusion. The patient must be closely monitored per the institution’s SOPs for cryopreserved product infusion. This includes a requirement that families and patients remain close to the treating site for 21–28 days after infusion for monitoring of side effects, including CRS. Notifying the entire multidisciplinary team that a patient has been infused with CAR T cells will facilitate a timely response to any AEs experienced by the patient. Preparing the institution for a multidisciplinary approach to managing CAR T-cell therapy–related AEs Side effects have been observed after CAR T-cell infusion that require coordinated management by several
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health care teams. The most prominent and serious toxicity associated with CD19-targeted CAR T-cell therapy is CRS, which is caused by proinflammatory cytokine release during the activation and rapid expansion of CAR T cells within the patient’s body. High cytokine levels can lead to symptoms of CRS such as fever, nausea, chills, headache, myalgia, tachycardia, hypotension and dyspnea [8,15]. Recent reports have shown approximately 80–90% of pediatric patients with ALL developed CRS after therapy with CTL019; approximately 40–50% of these patients experienced grade 3/4 CRS [10,25,26]. CRS often occurs just days after the patient is infused [10].Therefore, initial management of patients with CAR T-cell therapy–associated CRS is often the responsibility of emergency department staff. Our experience with CRS has reinforced our policy that families remain close to the treating center for at least 21–28 days after CAR T-cell infusion. CRS severity may correlate with disease burden [8,27], but no assay is currently available for determining which patients will experience severe CRS requiring inpatient monitoring and treatment. In general, CRS should be managed with pain medications, antiemetics, intravenous nutrition, intubation, vasopressor support and/or the interleukin 6 receptor antagonist antibody tocilizumab [27,28]. A treatment algorithm provided through the clinical trials outlined and guided the management of CRS. The loss of vasomotor tone caused by severe CRS is similar to the effects of Gram-negative sepsis [29], including the similar potential for rapid decompensation. Most emergency department and intensive care unit (ICU) teams will respond to symptoms of CRS by administering intravenous fluid. Early vasopressor support is recommended during CAR T-cell therapy to avoid fluid overload. Importantly, steroids should not be administered to patients treated with CAR T-cell therapy—unless a patient is refractory to at least one dose of tocilizumab and does not improve with hemodynamic and respiratory support—because of the potential of steroids to induce CAR T-cell apoptosis [30]. However, a recent report showed that engraftment and persistence of CD19 CAR T cells were not affected when steroids were administered early after the onset of CRS symptoms [31]. Several approaches have been taken to avoid steroid use after CAR T-cell therapy. The electronic medical record is updated with an alert that the patient is participating in a clinical trial, and the clinical team must be contacted before ordering medication for the patient. Steroids may also be entered as an allergy on the patient’s electronic medical record, with a brief explanation, or the patient can be given a card indicating his or her status as a CAR T-cell therapy recipient to present to the emergency department if needed. In addition, ICU staff members are educated about CAR
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T-cell therapy and CRS management to prepare them for the proper management of patients with CRS. Investigators should also be aware that many pediatric patients are given steroids by anesthesia during extubation after apheresis catheter placement; therefore, it is advisable that steroids be temporarily recorded as an allergy in the patient’s medical record before line placement. Tocilizumab should be stocked in hospital pharmacies before a patient is treated with CAR T-cell therapy; at least two doses should be available. Tocilizumab is a proven effective treatment for managing patients with severe CRS, and—depending on the clinical response—some patients may require more than one dose of tocilizumab [8,11,32,33]. The interleukin 6 blocking antibody siltuximab has also been used to manage severe CRS, and siltuximab should be stocked in hospital pharmacies or a protocol should be developed to obtain it within 24 h after the first dose of tocilizumab is ordered. In clinical trials of CTL019, clear workflows were developed for obtaining tocilizumab either during pharmacy business hours or overnight, and pharmacy clinical staff members were made aware of the preparation instructions for tocilizumab and of the requirement for a quick turnaround. Each time a new patient was admitted for CTL019 infusion, the pharmacy clinical coordinator reminded all pharmacy staff of the patient’s name and the potential need for tocilizumab to manage severe CRS. The attending nursing staff must have clear instructions to ensure that tocilizumab is promptly administered when CRS occurs. Tocilizumab should be administered within 2 h of being ordered. This means that other therapies (e.g., antibiotics) may need to be interrupted because tocilizumab treatment should be the priority when patients experience CRS. Neurological side effects have also been observed as a result of CD19-targeted CAR T-cell therapies [8,11,12]. Although neurotoxicity is typically self-limiting, physicians, nurses, hospital staff and patients and their families should be educated on the symptoms of neurotoxicity, including delirium during high fevers and delayed encephalopathy [8]. Close attention should be paid to any concomitant medication that may alter mental status. Any changes in the patient’s neurological status should be immediately reported to the treating physician. Patients may also experience other AEs, such as tumor lysis syndrome and macrophage activation syndrome/hemophagocytic lymphohistiocytosis (MAS/HLH) after CAR T-cell therapy, which should be managed according to institutional guidelines [2,28]. Management of MAS/ HLH is similar to management of CRS, with particular attention paid to coagulation studies [34]. The comprehensive education and preparation of patients, pharmacists, emergency department staff, ICU
staff and treating physicians and nurses are critical to the proper management of CRS and other AEs. Before the opening of the CTL019 trials, emergency department, ICU and neurology provider teams were familiarized with CAR T-cell therapy, specifically with CRS and its management and the importance of avoiding steroid use in these patients. Bone marrow transplant pharmacists were educated about the CTL019 protocol and were given documents detailing toxicity management, supportive care and the CRS management algorithm.Weekly multidisciplinary team meetings also served to educate all team members about CRS symptoms. For sites initiating CAR T-cell therapy trials, educational materials should be developed and individualized for the clinical staff of different departments (e.g., nurses, pharmacists, emergency department staff), and the staff should be thoroughly trained in CRS management. Staff should also have access to pertinent literature and other educational materials so that they can continue to familiarize themselves with CAR T-cell therapy, the associated AEs and AE management. It may also be helpful to post the CRS management algorithm in common areas of the treatment site or where other clinical practice guidelines are maintained. Patients and their families should also be educated about the symptoms of CAR T-cell therapy– associated AEs, such as CRS and neurotoxicity, and their severity to avoid a delay in seeking proper treatment. Effective communication not only improves patient safety but also typically leads to increased adherence to clinical trial protocols. Conclusion Novel immunocellular therapies, including CAR T-cell therapy, require a more complex patient-specific manufacturing and administration process than traditional therapies and are associated with a spectrum of AEs. Planning for the delivery of CAR T-cell therapy begins with a pre-screening assessment because the patient’s functional status and medical history will help facilitate the safety of leukapheresis, patient care before treatment, treatment delivery and AE management. Frequent and open communication between the treatment center, internal or external apheresis center and manufacturing sites is crucial to the successful implementation of CAR T-cell therapy. Although the optimal composition of a leukapheresis product destined for CAR T-cell manufacture is still under investigation, several patient factors need to be considered when determining optimal time for leukapheresis: prior cytotoxic therapy, temporal relationship to allogeneic SCT, disease burden and performance status. Data from ongoing studies will aid in the standardization of leukapheresis proto-
ARTICLE IN PRESS Building blocks for CTL019 delivery cols, which will be critical to improving the safety and efficacy of CAR T cells and other cellular therapies. Institutions should be thoroughly prepared for CAR T-cell therapy and management of its associated AEs. Although remission rates with CTL019 have shown potential, its toxicities can be life threatening. Understanding the mechanisms and management of AEs associated with immunocellular therapies will help make this novel therapy available to a broader patient population. Acknowledgments This work was supported in part by National Institutes of Health grants UL1TR000454 and KL2TR000455 (M. Qayed).We thank Judith Murphy, PhD, for medical editorial assistance. Financial support for medical editorial assistance was provided by Novartis Pharmaceuticals Corporation. Disclosure of interests: S. Ericson, C. Keir and P. Holman are employees of Novartis Pharmaceuticals Corporation. M. Qayed reports personal fees from Novartis Pharmaceuticals Corporation, outside the submitted work. G.D. Myers reports nonfinancial support and other from Novartis Pharmaceuticals Corporation, outside the submitted work. The other authors have no commercial, proprietary, or financial interest in the products or companies described in this article. References [1] Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A, et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011;3:95ra73. [2] Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011;365:725–33. [3] Porter DL, Kalos M, Zheng Z, Levine B, June C. Chimeric antigen receptor therapy for B-cell malignancies. J Cancer 2011;2:331–2. [4] Hicklin DJ, Marincola FM, Ferrone S. HLA class I antigen downregulation in human cancers: T-cell immunotherapy revives an old story. Mol Med Today 1999;5:178–86. [5] Pule MA, Savoldo B, Myers GD, Rossig C, Russell HV, Dotti G, et al. Virus-specific T cells engineered to coexpress tumor-specific receptors: persistence and antitumor activity in individuals with neuroblastoma. Nat Med 2008;14:1264– 70. [6] Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med 2014;6:224ra25. [7] Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, et al. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther 2009;17:1453–64.
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