Hematologic Malignancies—Leukemia, Myelodysplastic Syndromes, and Allotransplant
The Other Side of CAR T-Cell Therapy: Cytokine Release Syndrome, Neurologic Toxicity, and Financial Burden
2Sarah Cannon Center for Blood Cancer, Nashville, TN
3The University of Texas MD Anderson Cancer Center, Houston, TX
Immune effector cells, including T cells and natural killer cells, which are genetically engineered to express a chimeric antigen receptor (CAR), constitute a powerful new class of therapeutic agents to treat patients with hematologic malignancies. Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity. With more experience and collaboration, hopefully the toxicities and the costs will come down, increasing the availability of CAR T cells to patients in need.
Summarize the logistics and financial hurdles required to perform CAR T-cell therapy.
Describe the most current consensus grading system for CRS and ICANS.
Discuss the possible pathophysiologic mechanism for the development CRS and ICANS.
Report on the current management strategies to treat CRS and ICANS.
Give an overview of the FACT guidelines for IEC therapy to guide institutions and clinicians on how to optimally treat patients with CAR T-cell therapy and other immune cell therapy.
Immune effector cells (IECs), including T cells and natural killer cells, which are genetically engineered to express a chimeric antigen receptor (CAR), constitute a powerful new class of therapeutic agents to treat patients with hematologic malignancies. Several CAR T-cell trials have shown impressive remission rates in patients with relapsed/refractory hematologic cancers, including acute lymphoblastic leukemia (ALL),1,2 non-Hodgkin lymphoma,3,4 chronic lymphocytic leukemia,5 and multiple myeloma.6 More than 1,000 patients have received CAR T cells in the United States alone, with more than 250 CAR T-cell trials listed on ClinicalTrials.gov, primarily from the United States and China.7 CAR T cells targeting CD19 have produced impressive responses in young patients up to age 26 with refractory ALL.1,8 In adults, CAR T-cell therapies have produced substantial long-term remissions in patients with refractory B-cell lymphomas.3 In both settings, the responses associated with these CAR T-cell therapies appeared to be superior to what could be achieved with standard therapies, leading to the U.S. Food and Drug Administration (FDA) approval of tisagenlecleucel for refractory ALL in August 2017 and for refractory lymphoma in May 2018, with approval of axicabtagene ciloleucel for refractory lymphoma in October 2017. Although the clinical responses of these agents in hematologic malignancies have been very encouraging, they have also produced substantial morbidity and occasionally mortality resulting from toxicity. The FDA has therefore required a Risk Evaluation and Mitigation Strategy program for the two approved products, and the Foundation for Accreditation of Cell Therapy (FACT) has published standards for the clinical and quality infrastructure needed for safe administration of therapy.9 Over the years, several groups developed systems to grade toxicity and guide intervention.10-13 Major differences in the scoring of toxicities made comparisons between different IEC therapy products and trials challenging. To address this limitation, the American Society of Blood and Marrow Transplantation (ASBMT) has recently published consensus guidelines to establish a global standard for the grading of cytokine release syndrome (CRS) and iIEC–associated neurologic syndrome (ICANS), which are included in Table 1, Table 2, and Table 3.14
Pioneering work by Zelig Eshhar at the Weizmann Institute on redirecting the specificity of genetically engineered T cells to target antigens on tumor cells led to the development of CAR T cells.15 Eshhar joined Steven Rosenberg in 1990 at the National Institutes of Health and developed first-generation CARs targeting melanoma cells. Work by Michel Sadelain on the addition of costimulatory domains to CAR T cells led to better T-cell receptor signaling with potent and sustained activity of engineer cells.16,17 These early discoveries and research over the subsequent decades led to the recent clinical trials showing impressive responses in patients with refractory lymphomas and acute leukemias.3,18
CAR T-cell therapies typically use autologous T lymphocytes, although clinical trials are evaluating allogeneic products, to treat patients with hematologic malignancies and selected solid tumors.19 These adoptive cell therapies consist of T cells manipulated ex vivo to target tumor antigens before infusion back into the patient. CARs have two important roles: (1) to recognize and bind to a tumor cell via a ligand and (2) to transfer intracellular signals that result in T-cell activation.20
CAR T cells consist of an extracellular target-binding domain, a hinge region, a transmembrane domain that anchors the CAR to the cell membrane, and an intracellular signaling domain (Fig. 1). These T-cell signaling domains include a signaling region of the CD3ζ molecule or the FcRγ chain as well as costimulatory domains to provide additional signaling after ligand engagement.
First-generation constructs had only one signaling domain (CD3ζ) to induce T-cell activation.21 These first-generation constructs had limited activation and expansion capabilities. Understanding the role of costimulatory molecules led to development of CAR T cells with more potent cytokine production and proliferation. Second-generation CAR T cells, which are the most common constructs in the clinic, incorporate intracellular domains including CD28 or 4-1BB in tandem with CD3ζ as shown in Fig. 1.22-24 Clinical and laboratory studies suggest differences in T-cell composition, expansion, and persistence of CAR T cells depending on the construct costimulatory moiety.25,26 The costimulatory molecule CD28 stimulates the B7 signaling pathway, whereas 4-1BB triggers the tumor necrosis factor receptor–associated factor pathway, which results in activation of nuclear factor-kappa B27,28 CAR T cells with CD28 expand rapidly, whereas those with 4-1BB expand more slowly, which may contribute to the different toxicity profiles seen with the various CAR T-cell constructs. Third-generation CAR T cells are now under investigation involving two costimulatory domains (CD28 and 4-1BB or OX40), whereas fourth-generation constructs called T cells redirected for universal cytokine-mediated killing are armored second-generation CARs with additional genetic modifications to enhance antitumor activity via expression and secretion of cytokines upon engagement of CAR T cells with tumor antigens.29 CAR T-cell transduction methods currently use retroviral or lentiviral transduction. These result in permanent genome modification and gene expression.30,31 Long-term gene expression has the potential advantage for more sustained disease control but can also lead to persistent on-target toxicity and the theoretical risk of malignant transformation, which fortunately has not been reported to date in any CAR T-cell recipients.7 Other transduction technologies under investigation include use of electroporation associated with increase replicative capacity but with short-term expression.32
The process for collection and administration of CAR T cells is outlined in Fig. 2 and begins with identification of appropriate candidates for either commercial CAR T-cell products or clinical trials. Early referral to centers providing these therapies is important because data suggest tumor burden, prior therapies, and performance status affect outcomes after CAR T-cell therapies. If not candidates for clinical trials, patients with indications for treatment with commercial products undergo evaluation by financial coordinators with submission to insurance companies and, in most centers, internal hospital financial clearance.
After identifying appropriate candidates, patients undergo mononuclear cell collection via apheresis. Currently active clinical trials and trials that led to approved commercial products required an absolute lymphocyte count > 100–200/µL and that > 2 weeks has elapsed from the last salvage regimen.3,19 After apheresis, cells are cryopreserved or delivered fresh to a manufacturing facility for processing. Processing includes T-cell expansion, genetic manipulation via retroviral or lentiviral transduction, quality control testing, and cryopreservation of the final expanded T-cell product. This process can take 2–4 weeks, during which patients at the clinical site may receive bridging therapies for control of their malignancy. Patients then undergo lymphodepleting chemotherapy to create a favorable in vivo immune environment for expansion of infused CAR T cells.33 Following infusion, patients are monitored for toxicities associated with CAR T cells.
The other side of the impressive antitumor activity produced by CAR T-cell therapies is their unique toxicities. Unlike chemotherapy-associated side effects, which are often nonspecific and can cause permanent multiorgan damage,34 many of the CAR T-cell–mediated toxicities are on-target and reversed when the CAR T cells are done expanding, eradicated, or exhausted.7 The most commonly observed CAR T-cell–associated toxicity is CRS.10 Fever is usually the first symptom of CRS. The time of onset of fever can be quite variable, ranging from a few hours to more than a week after CAR T-cell infusion. Temperatures can exceed 40°C and may be accompanied by rigors, malaise, headaches, myalgias, arthralgias, and anorexia, which can progress rapidly to life-threatening capillary leakage tachycardia, hypotension, and hypoxia, associated with marked elevations in serum cytokine levels.13 As shown in Fig. 3, CRS typically occurs within the first week following CAR T-cell infusion.3,4 Peak CAR T-cell levels and serum interleukin-6 (IL-6) levels in patients have strongly correlated with the severity of CRS after CAR T-cell therapy.35-37 Patients at high risk for severe CRS include those with large tumor burdens, with comorbidities, and who develop early onset CRS within 3 days of infusion, although occasionally severe CRS can occur outside of these parameters.8,12
The CRS rates of any grade range from 37% to 93% for patients with lymphoma (Table 4)3,4,38 and 77% to 93% for those with leukemia (Table 5).1,2,39 For CRS up to grade 3, the rates are 1%–23% for patients with lymphoma3,4,38 and 23%–46% for patients with ALL.1,2,39 The higher, serious CRS rates in patients with ALL may be due to the tumor burden, disease distribution, or proliferative activity of the disease. The median time to develop CRS for both diseases is within the first week following CAR T-cell infusion and typically resolves within 7–8 days but has been documented to persist beyond 30 days. Approximately 45%–50% of patients enrolled in the early CAR T-cell trials required intensive care management.3,8 With more experience and earlier interventions in CRS management, this rate may be decreasing.
Pathophysiological CRS is triggered by the activation of T cells when their CARs engage the designated antigens on the malignant cells. The activation leads to proliferation of CAR T cells and release of cytokines and chemokines from antigen-redirected T cells including IL-6, soluble IL-6 receptor, soluble IL-2 receptor a, interferon gamma (IFN-γ), and granulocyte-macrophase colony-stimulating factor.35-37,40 Activation of bystander immune cells such as monocytes/macrophages, dendritic cells, and others is common. The most commonly reported cytokine elevations include IFN-γ, IL-6, IL-8, IL-10, monocyte chemoattractant protein-1 (MCP-1), and macrophage inflammatory protein-1b with similar kinetics across B-cell ALL, chronic lymphocytic leukemia, and non-Hodgkin lymphoma.8,12,35,41,42 Many groups are studying additional biomarkers that would predict severe toxicity.35,43,44
The first step for those managing patients undergoing CAR T-cell or natural killer cell therapy is to diagnose the grade of CRS. The ASBMT consensus group published the simple grading system shown in Table 1, in which fever is a prerequisite for diagnosis and hypotension and hypoxia are the principal determinants of the consensus grading scale.14 The major changes from the previous scoring systems are that any requirement for vasopressor support is now a grade 3 as opposed to either grade 2 or 3 depending upon vasopressor dose(s). Similarly, the oxygen requirements for grading have been simplified. Low-flow oxygen requirements are now grade 2, high-flow oxygen grade 3, and positive pressure including intubation grade 4. Organ toxicities no longer contribute to the CRS score. These logical changes have markedly simplified the CRS grading process.
As discussed previously, elevated IL-6 levels in patients undergoing CAR T-cell therapy are associated with severe CRS. Tocilizumab, an anti–IL-6 receptor antagonist was approved by the FDA in August 2017 to treat CRS when the first CAR T-cell product was approved. Tocilizumab has induced rapid reversal of CRS and has become the standard of care for this complication.1,3,13 Corticosteroids are also effective in the management of toxicities after CAR T-cell therapies because they suppress inflammatory responses. Corticosteroids are often promptly administered if the patient does not have a rapid response to IL-6 receptor blockade.13 Preliminary data suggest that the use of IL-6 receptor blockade and/or steroids is not associated with higher rates of cancer relapse compared with patients undergoing CAR T-cell therapy who do not receive them.7 Many centers are giving tocilizumab and, if ineffective, a dose of steroids for grade 2 or higher CRS. Given the lack of negative effect on relapse, both tocilizumab and steroids are being used earlier in the course and severity of both CRS and ICANS, although additional data are needed regarding the optimal timing of these therapies. Patients with grade 3 or higher CRS, rapid deterioration, and vital sign instability are often transferred to the intensive care unit until stabilized.3,8,13
Other therapeutic options include the anti–IL-6 monoclonal antibody siltuximab, which has not been used extensively to treat CRS to date.45 Animal studies in xenogeneic mice have shown that CRS may be associated with macrophage secretion of IL-1-b,46 and investigators have been exploring the use of the IL-1 antagonist anakinra47 in CRS, with no definite answer yet on clinical efficacy.
Other toxicities associated with CAR T-cell CD19 products that require careful clinical follow-up and management included prolonged B-cell aplasia with hypogammaglobulinemia.48 Although not typically life-threatening, it can result in repeated infectious complications. Some centers routinely administer intravenous immunoglobulin, whereas others restrict usage to patients who have repeated infections. Febrile neutropenia during CAR T-cell therapy is not uncommon, with infections documented in 10%–20% of patients.4 Prolonged pancytopenia beyond 28 days is also reported in up 32% of patients, underscoring the importance of longer-term follow-up and antibiotics as clinically indicated.4 Although leukemia from oncogenic transformation of genetically manipulated hematopoietic stem cells has been observed,49 there have been no such cases reported following CAR T-cell therapy to date.7
Neurologic toxicity is the second major side effect developing in a substantial proportion of patients treated with CD19-targeted CAR T cells. Although it is typically self-limited, it can be potentially life-threatening or fatal. Previously referred to as CAR T-cell–related encephalopathy syndrome,13 neurotoxicity is now referred to as ICANS14 to reflect that other cellular therapies and bispecific antibodies can produce a similar set of neurologic symptoms.
ICANS symptom presentation and prevalence varies among studies. As summarized in Table 4 and Table 5, the rates of ICANS of any grade associated with CD19-targeted CAR T-cell therapies range from 23%–67% for patients with lymphoma3,4,38 and 40%–62% for those with leukemia.1,2,39 Rates of ICANS up to grade 3 are 12%–30% for patients with lymphoma and 13%–42% for patients with leukemia. ICANS may be affected by patient-specific factors including disease type, disease burden, treatment history, and patient age,1,2,41,50,51 as well as product-specific factors such as CAR design, cell manufacturing conditions, CAR T-cell dose, preconditioning regimen, and product potency.51,52 Grading schemas also differed among trials, which likely affected the reported prevalence and severity for both neurotoxicity and CRS.
ICANS has also been reported in clinical trials of CAR T cells directed against targets other than CD19. In a trial of patients with ALL treated with CD22-targeted CAR T-cell therapy, 25% developed ICANS of any grade but none had severe ICANS or CRS.53 ICANS also appears to be overall less prevalent with B-cell maturation antigen–targeted CAR T-cell therapy,6,54 although severe cases have been reported, including a case of reversible cerebral edema.55 Whether the difference in toxicity profile is related to target antigen or differences in construct design is unknown, but the occurrence of ICANS with a growing list of immunotherapies makes direct targeting of CD19 antigen on central nervous system (CNS) elements less likely, a hypothesis that had been considered previously.
Clinical manifestations of ICANS are diverse and include encephalopathy (confusion or delirium), expressive aphasia or language disturbance, motor weakness, tremor, headache, seizures, depressed level of consciousness, and, rarely, diffuse cerebral edema.13,50,51,56,57 Some neurologic sign/symptoms such as expressive aphasia appear to be very specific to ICANS. In one study, expressive aphasia, starting as impaired naming of objects, or hesitant/stuttering and perseverative speech, was an early neurologic symptom developing in 85% of patients who went on to develop severe ICANS.50 Impairments of attention, cognitive processing, and changes in handwriting are other early and common signs of ICANS.1,13,53 Symptoms may progress to seizures or depressed level of consciousness/obtundation to the point of requiring intubation for airway protection. Rare cases of diffuse cerebral edema have occurred, often developing rapidly over hours with few antecedent clinical warning signs; however, most ICANS symptoms are transient and fully reverse within the first 3–4 weeks of treatment with persistent abnormalities being uncommon.1,50,51
Severe ICANS occurs almost exclusively in patients who develop CRS and almost always after the first fever.50,51 ICANS can occur at the same time as CRS or days later after CRS abates.50,51 ICANS can occur as early as the day following CAR T-cell infusion or up to the third or fourth week after infusion, demonstrating a highly variable course. As such, close monitoring for ICANS is required throughout the treatment course. Multiple studies have shown an association of higher ICANS grade with higher grade CRS, although severe cases of ICANS can also occur after fever alone.1,39,50,51 There are likely independent mechanisms for CRS and ICANS but with common predisposing and causative factors.
The pathogenesis of ICANS is less clear than for CRS, but advancement in understanding has been made through analysis of patients treated and preclinical studies. Similar to CRS, ICANS occurs in situations in which higher peak in vivo CAR T-cell numbers develop.2,3,50-52 Higher peak CAR T-cell numbers can occur with higher infused cell dose, higher pretreatment bone marrow disease burden, or other factors that lead to greater in vivo CAR T-cell expansion such as fludarabine-containing preconditioning regimens. Risk-adapted dosing of CAR T-cells, with lower cell doses given to patients with higher disease burden, may reduce both CRS and neurotoxicity.36,41
Severe ICANS is associated with higher levels of C-reactive protein, early peak of IL-6, and higher levels by day 3 following infusion of multiple other cytokines such as IL-15, IFN-γ, IL-2, IL-8, MCP-1 granzyme B, granulocyte-macrophase colony-stimulating factor, and tumor necrosis factor-alpha.3,50,51 None of these cytokines appear to be specific for ICANS because they are also observed to be elevated in severe CRS. Patients with severe ICANS and severe CRS also were found to have elevated ANG2 in the blood, suggesting that endothelial cell activation may be an underlying process in both.51,58 Models to predict the development of severe neurologic toxicity based on serum cytokine levels have been developed and may be able to guide early intervention studies; however, they are currently limited by the difficulty in obtaining cytokine levels in real time.41,50,51
It has been suggested that greater neurotoxicity risk exists with CD28-containing constructs, especially after five cases of fatal cerebral edema developed after treatment with a CAR with a CD28 costimulatory domain, leading to the termination of a clinical trial in adults with ALL.59 However, fatal cerebral edema and other fatal neurologic events after CAR T-cell therapy have also occurred with a CAR construct containing 41BB.51 CAR T-cell products incorporating a CD28 costimulatory domain are associated with earlier CRS compared with CAR T cells with 41BB-containing constructs, perhaps setting the stage for neurotoxicity. Although higher rates of severe neurotoxicity have been seen in some trials of CD28-containing CAR T-cell therapy,2,3,52 other trials have had much lower rates60 and other construct design factors such as the hinge and transmembrane domain may also play a role.54,61 There is no conclusive evidence of an association of a particular costimulatory domain and the risk of ICANS.
Severe ICANS is associated with elevated cerebrospinal fluid (CSF) protein levels, likely reflecting increased blood–CSF barrier permeability.50,51 In addition, patients with neurotoxicity have substantially elevated levels of multiple cytokines in CSF during neurotoxicity. This is thought to be due to the combination of increased barrier permeability, which allows the influx of cytokines from the blood and local production by cells within the CNS.50,51 Disproportionately high concentrations of MCP-1, inducible protein-10, IL-6, and IL-8 have been found in the CSF of patients with severe neurotoxicity, suggesting CNS-specific production by activated myeloid, astrocyte, and/or endothelial cells.50 The additional finding of elevated levels of the excitatory NMDA receptor agonists glutamate and quinolinic acid in patients with acute neurotoxicity may explain the seizures and myoclonus that occurs.50 Finally, CAR T cells are detected in the CSF of most patients during neurotoxicity but can also be detected in those without neurotoxicity.8,50,51 A nonhuman primate model of CAR neurotoxicity using autologous CD20-targeting CAR T cells demonstrated CAR T-cell but also non–CAR T-cell accumulation in the CSF and brain parenchyma consistent with encephalitis.62 It is unclear if the T cells are bystanders or active contributors to the development and maintenance of neurotoxicity. The presence of CAR T cells in the CSF does not appear sufficient to cause neurotoxicity in and of itself, although CSF profiling may not reflect the amount of brain parenchymal infiltration that may be contributing to pathology. Autopsy studies after cases of fatal neurotoxicity have revealed variable findings including infrequent non–CAR T cells in the brain parenchyma and CSF, white matter injury with macrophage infiltration and microglial activation,63 and endothelial activation with thrombotic microangiopathy and multifocal vascular disruption.51 Although lymphocytes can be seen in the parenchyma and CSF, there is no vasculitis or evidence of direct targeting of neural elements.
Once considered in aggregate with CRS, ICANS is now recognized as a separate but related process from CRS requiring separate grading. Most centers initially used Common Terminology Criteria for Adverse Events for grading neurologic adverse events, with some departing from it for seizure grading. Grading of cognitive impairment was challenged by the subjectivity inherent in defining the degree of impairment of activities of daily living in hospitalized patients. The CARTOX consensus group published a grading system for CAR T-cell neurologic toxicity that included a 10-point scoring system incorporating key elements of the Mini-Mental State Examination to evaluate the degree of encephalopathy by alterations in speech, orientation, handwriting, and concentration.13 This tool made assessing encephalopathy easier and more reproducible by assigning an objective score for grading; however, the other aspects of CARTOX grading, namely measurement of opening pressure and of papilledema, were too cumbersome and potentially inaccurate to expand to broad use. The new ASBMT consensus guidelines for grading ICANS builds on past grading schema and provides an objective, easy to apply, and more accurate way to categorize ICANS severity.14 It uses an updated encephalopathy screening tool, termed Immune Effector Cell Encephalopathy (ICE) score, which is similar to the CARTOX-10 but includes an element for assessing receptive aphasia commonly seen in these patients (Table 2). The new 10-point scale is easy to administer and can also be used as a screening tool. To grade ICANS, the ICE score is calculated along with an evaluation of level of consciousness, seizure, motor findings, and elevated intracranial pressure/cerebral edema. ICANS grade is determined by the most severe event (Table 3). For example, a patient with an ICE score of 3 who has a generalized seizure is classified as grade 3 ICANS. For children younger than age 12, the grading is the same except for the Cornell Assessment of Pediatric Delirium taking the place of the ICE score.14
The role of immune suppressive interventions for ICANS is debated with thresholds for intervention varying greatly among centers. Some have used supportive care alone because of the finding that most neurotoxicity resolves on its own within 3–4 weeks after CAR T-cell infusion.1 Others use aggressive treatment with immunosuppressive agents.13,64 Most patients with ICANS also experience CRS,50,51 which may be treated with tocilizumab or steroids in refractory cases of CRS not responding to tocilizumab.10,12,37,64 It has been postulated that tocilizumab may increase the incidence and severity of ICANS by leading to increased circulating IL-6 in the CNS.40,65 Studies found that, although early treatment with tocilizumab decreased the incidence of severe CRS, it was not associated with a decreased incidence or severity of ICANS; in fact, severe ICANS rates may have been slightly higher.3 Tocilizumab therefore is generally not recommended for isolated ICANS. Most centers are using corticosteroids as first-line therapy for isolated ICANS with tocilizumab plus corticosteroids given for ICANS that develops concurrently with CRS, although therapy remains largely empirical and there are no clinical trial data yet comparing the various approaches. Different corticosteroids are used depending on institutional standards, although dexamethasone use is most common because it has excellent CNS penetration and improves the integrity of the blood–brain barrier. High pulse-dose methylprednisolone is used in the more severe cases of ICANS based on experience with fulminant neuroinflammatory disorders.13 Patients receiving corticosteroids for immunosuppression appear to have similar antitumor responses; however, whether there might be effects on disease remission durability is undetermined.66 Thresholds for the administration of anti–IL-6 therapy and corticosteroids as well as the dosing regimens have not been prospectively compared. The recent development of a universal grading scale for ICANS and CRS14 is an essential step in building more generalizable guidelines for toxicity management.
Risk-adapted strategies for adjusting CAR T-cell dose based on disease burden and expected in vivo CAR expansion should be evaluated. Early intervention studies using the biologics siltuximab and anakinra are planned. Siltuximab is a monoclonal antibody that directly binds IL-6, which has been used to manage severe CRS and neurotoxicity40,67 but has not yet been evaluated as an early intervention. The IL-1 receptor antagonist anakinra is another promising approach. In a mouse model of CAR T-cell–associated CRS and neurotoxicity, administration of the IL-1 receptor antagonist at the time of CAR T-cell infusion prevented both CRS and neurotoxicity.47 Other therapeutic approaches including inhibition of other cytokine pathways by antibodies, small molecule inhibitors, or strategies to prevent CNS excitotoxicity or promote endothelial cell health might be useful, but human data are lacking. It is critical that preventive strategies be evaluated in clinical trials.
CAR T-cell therapies require infrastructure, processes, and workflows different from those in a general oncology practice. Cell products must be temperature controlled at all times, including during preparation, shipping, and administration. Programs administering CAR T cells must have access to apheresis for mononuclear cell collections and cell processing facilities for temporary storage. Just as important is the chain of custody and identification of product from collection through shipping to manufacturing facility, back to clinical site, and through infusion. Also, although considered “living drugs,” kinetics of expansion are not as predictable as traditional drugs. CAR T cells also have the potential for severe toxicities, including CRS and neurologic toxicities that require specialized teams both in the inpatient and outpatient settings. These include nursing, coordinators, physicians with expertise in CAR T-cell–associated toxicities, intensivists, and neurologists.
Safe administration of these therapies also requires appropriate education, competencies, standard operating procedures, processes, and administrative oversight. While we are learning how to better identify patients at risk for toxicities and prevent and manage side effects, patients undergoing CAR T-cell therapy should only receive these therapies in centers with skilled personnel, established processes and procedures, and appropriate infrastructure. Whether these therapies should be administered by physicians in stem cell transplant programs, by disease focus or general oncologists, or physicians in other specialties is evolving at different institutions.
FACT developed peer-reviewed standards that have been used for more than 20 years for the accreditation of hematopoietic cell therapy (HCT) programs. The existing standards include areas of cellular therapy manufacturing and administration, processing, and clinical aspects of HCT. FACT more recently developed IEC standards given the unique requirements and similarities of IECs to HCT and after the expressed interest from cellular therapy programs, regulatory agencies, and commercial manufacturers. FACT IEC standards include areas of staff education and competencies, chain of custody and labeling, management of toxicities, data management, and outcome analysis.68 FACT IEC standards and accreditation allow different models for integration of different clinical teams including leukemia, lymphoma, solid tumors, and HCT programs. Most programs accredited to date use the quality and operational infrastructure of their HCT programs to comply with IEC standards with different levels of integration of other programs depending on the institution.
Commercial CAR T-cell therapy continues to be a financial risk to hospitals, creating a barrier for patients who could benefit from this novel therapy. The quick approval by the FDA of the first two commercial CAR T-cell products caught the payer community off guard. CAR T-cell products are classified as a drug but are similar to cellular therapies such as stem cell transplantations.
Even though CAR T-cell therapy is a covered indication by the Centers for Medicare and Medicaid Services, this does not mean the reimbursement covers the costs a hospital providing the therapy incurs. On October 1, 2018, the 2019 Inpatient Prospective Payment System rule went into effect, giving CAR T-cell therapy a diagnosis-related group with higher payment, MS-DRG 16, and the ability to receive additional reimbursement for the CAR T-cell product through a New Technology Add on Payment (NTAP). To capture the full amount of the NTAP ($186,500), the CAR T-cell product charge must be set high enough that when it is reduced by the facility’s cost-to-charge ratio, the NTAP can be recovered.18 Hospitals also have the ability to receive an outlier payment if the charges are high enough to hit the threshold.
Medicaid is also a barrier for patients who could benefit from receiving CAR T-cell therapy. Because Medicaid varies from state to state, a state’s Medicaid plan may only cover CAR T-cell therapy if performed as an outpatient, whereas another state may require an inpatient admission. Some Medicaid plans provide reimbursement on a per diem basis only that is inadequate to cover hospitals’ costs; others reimburse only a percentage of the CAR T-cell product cost.
Most commercial payers are reimbursing on a case rate payment structure; this is currently requiring a Single Case Agreement to be negotiated for each patient. Because this therapy is so new, most payers and hospitals do not have the data needed to determine what the rate should be for the Single Case Agreement. Hospitals also must understand what payers are including in the case rate and how they will reimburse for the cell product.
Because CAR T-cell therapy is potentially available to more patients for more disease indications, the cost of the CAR T-cell product must be re-evaluated by the manufacturing companies. Although the initial cost of intellectual property generation, research and development, and creation of manufacturing facilities is substantial, the cost to further expand the manufacturing capacities will not be as great. If CAR T-cell therapy is to be widely used across hematologic malignancies, the price of the product will need to be lowered to compare more closely to existing therapeutic options.
Because of all of these issues, reimbursement continues to be a barrier for patients who could benefit from receiving CAR T-cell therapy. Hospitals must reach out to the payer as soon as possible after a patient is identified as a candidate because the negotiations could range from a few days to a several weeks, depending on the experience and knowledge of the negotiators.
In summary, we have seen extremely encouraging results with CAR T-cell therapy, recognizing there are toxicity and financial issues that underscore the complexity of this valuable approach. With more experience and collaboration, hopefully the toxicities and the costs will come down, increasing the availability of CAR T cells to patients in need.
Disclosures provided by the authors and data availability statement (if applicable) are available with this article at DOI https://doi.org/10.1200/EDBK_238691.
The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc.
Honoraria: Magenta Novartis
Consulting or Advisory Role: Adaptimmune Magenta Novartis Velos (I)
Travel, Accommodations, Expenses: Magenta Novartis
Employment: HCA Healthcare
Honoraria: Juno Therapeutics Kite Pharma
Consulting or Advisory Role: Incyte Juno Therapeutics Kite Pharma Novartis
Travel, Accommodations, Expenses: Juno Therapeutics Kite Pharma
|1.||Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378:439-448. Crossref, Medline, Google Scholar|
|2.||Park JH, Rivière I, Gonen M, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N Engl J Med. 2018;378:449-459. Crossref, Medline, Google Scholar|
|3.||Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N Engl J Med. 2017;377:2531-2544. Crossref, Medline, Google Scholar|
|4.||Schuster SJ, Bishop MR, Tam CS, et al; JULIET Investigators. Tisagenlecleucel in adult relapsed or refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56. Crossref, Medline, Google Scholar|
|5.||Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733. Crossref, Medline, Google Scholar|
|6.||Ali SA, Shi V, Maric I, et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood. 2016;128:1688-1700. Crossref, Medline, Google Scholar|
|7.||June CH, Sadelain M. Chimeric antigen receptor therapy. N Engl J Med. 2018;379:64-73. Crossref, Medline, Google Scholar|
|8.||Maude SL, Frey N, Shaw PA, et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014;371:1507-1517. Crossref, Medline, Google Scholar|
|9.||Foundation for the Accreditation of Cellular Therapy. FACT standards for immune effector cells. https://www.factweb.org/forms/store/ProductFormPublic/first-edition-v1-1-fact-standards-for-immune-effector-cells-free-download. Accessed March 14, 2019. Google Scholar|
|10.||Lee DW, Gardner R, Porter DL, et al. Current concepts in the diagnosis and management of cytokine release syndrome [published correction appears in Blood. 2015;126:1048]. Blood. 2014;124:188-195. Crossref, Medline, Google Scholar|
|11.||Porter D, Frey N, Wood PA, et al. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel [published correction appears in J Hematol Oncol. 2018;11:81]. J Hematol Oncol. 2018;11:35. Crossref, Medline, Google Scholar|
|12.||Davila ML, Riviere I, Wang X, 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. Crossref, Medline, Google Scholar|
|13.||Neelapu SS, Tummala S, Kebriaei P, et al. Chimeric antigen receptor T-cell therapy - assessment and management of toxicities. Nat Rev Clin Oncol. 2018;15:47-62. Crossref, Medline, Google Scholar|
|14.||Lee DW, Santomasso BD, Locke FL, et al. ASBMT consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells. Biol Blood Marrow Transplant. 2018;15:47-62. Google Scholar|
|15.||Gross G, Waks T, Eshhar Z. Expression of immunoglobulin-T-cell receptor chimeric molecules as functional receptors with antibody-type specificity. Proc Natl Acad Sci USA. 1989;86:10024-10028. Crossref, Medline, Google Scholar|
|16.||Maher J, Brentjens RJ, Gunset G, et al. Human T-lymphocyte cytotoxicity and proliferation directed by a single chimeric TCRzeta /CD28 receptor. Nat Biotechnol. 2002;20:70-75. Medline, Google Scholar|
|17.||Sadelain M, Brentjens R, Rivière I. The basic principles of chimeric antigen receptor design. Cancer Discov. 2013;3:388-398. Crossref, Medline, Google Scholar|
|18.||Schuster SJ, Svoboda J, Chong EA, et al. Chimeric antigen receptor T cells in refractory B-cell lymphomas. N Engl J Med. 2017;377:2545-2554. Crossref, Medline, Google Scholar|
|19.||Rosenberg SA, Restifo NP. Adoptive cell transfer as personalized immunotherapy for human cancer. Science. 2015;348:62-68. Crossref, Medline, Google Scholar|
|20.||Gill S, June CH. Going viral: chimeric antigen receptor T-cell therapy for hematological malignancies. Immunol Rev. 2015;263:68-89. Crossref, Medline, Google Scholar|
|21.||Eshhar Z, Waks T, Gross G, et al. Specific activation and targeting of cytotoxic lymphocytes through chimeric single chains consisting of antibody-binding domains and the gamma or zeta subunits of the immunoglobulin and T-cell receptors. Proc Natl Acad Sci USA. 1993;90:720-724. Crossref, Medline, Google Scholar|
|22.||Imai C, Mihara K, Andreansky M, et al. Chimeric receptors with 4-1BB signaling capacity provoke potent cytotoxicity against acute lymphoblastic leukemia. Leukemia. 2004;18:676-684. Crossref, Medline, Google Scholar|
|23.||Kowolik CM, Topp MS, Gonzalez S, et al. CD28 costimulation provided through a CD19-specific chimeric antigen receptor enhances in vivo persistence and antitumor efficacy of adoptively transferred T cells. Cancer Res. 2006;66:10995-11004. Crossref, Medline, Google Scholar|
|24.||Finney HM, Akbar AN, Lawson AD. Activation of resting human primary T cells with chimeric receptors: costimulation from CD28, inducible costimulator, CD134, and CD137 in series with signals from the TCR zeta chain. J Immunol. 2004;172:104-113. Medline, Google Scholar|
|25.||Kawalekar OU, O’Connor RS, Fraietta JA, et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells [published correction appears in Immunity. 2016;44:380-390]. Immunity. 2016;44:712. Medline, Google Scholar|
|26.||Wilkins O, Keeler AM, Flotte TR. CAR T-cell therapy: progress and prospects. Hum Gene Ther Methods. 2017;28:61-66. Crossref, Medline, Google Scholar|
|27.||Rudd CE, Schneider H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol. 2003;3:544-556. Medline, Google Scholar|
|28.||Li G, Boucher JC, Kotani H, et al. 4-1BB enhancement of CAR T function requires NF-κB and TRAFs. JCI Insight. 2018;3:3. Google Scholar|
|29.||Chmielewski M, Abken H. TRUCKs: the fourth generation of CARs. Expert Opin Biol Ther. 2015;15:1145-1154. Medline, Google Scholar|
|30.||Biffi A, Bartolomae CC, Cesana D, et al. Lentiviral vector common integration sites in preclinical models and a clinical trial reflect a benign integration bias and not oncogenic selection. Blood. 2011;117:5332-5339. Medline, Google Scholar|
|31.||Scholler J, Brady TL, Binder-Scholl G, et al. Decade-long safety and function of retroviral-modified chimeric antigen receptor T cells. Sci Transl Med. 2012;4:132ra53. Medline, Google Scholar|
|32.||Riet T, Holzinger A, Dörrie J, et al. Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy. Methods Mol Biol. 2013;969:187-201. Medline, Google Scholar|
|33.||Hay KA, Turtle CJ. Chimeric antigen receptor (CAR) T cells: lessons learned from targeting of CD19 in B-cell malignancies. Drugs. 2017;77:237-245. Medline, Google Scholar|
|34.||Muller PY, Milton MN. The determination and interpretation of the therapeutic index in drug development. Nat Rev Drug Discov. 2012;11:751-761. Medline, Google Scholar|
|35.||Teachey DT, Lacey SF, Shaw PA, et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T-cell therapy for acute lymphoblastic leukemia. Cancer Discov. 2016;6:664-679. Crossref, Medline, Google Scholar|
|36.||Brentjens RJ, Davila ML, Riviere I, et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med. 2013;5:177ra38. Crossref, Medline, Google Scholar|
|37.||Porter DL, Hwang WT, Frey NV, et al. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015;7:303ra139. Crossref, Medline, Google Scholar|
|38.||Abramson J, Gordon L, Lia Palomba M . Updated safety and long term clinical outcomes in TRANSCEND NHL 001, pivotal trial of lisocabtagene maraleucel (JCAR017) in R/R aggressive NHL. Presented at: 23rd European Hematology Association Congress. Stockholm, Sweden: June 16, 2018. Abstract S800. Google Scholar|
|39.||Gardner RA, Finney O, Annesley C, et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood. 2017;129:3322-3331. Crossref, Medline, Google Scholar|
|40.||Chen F, Teachey DT, Pequignot E, et al. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J Immunol Methods. 2016;434:1-8. Crossref, Medline, Google Scholar|
|41.||Turtle CJ, Hanafi LA, Berger C, et al. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016;126:2123-2138. Crossref, Medline, Google Scholar|
|42.||Turtle CJ, Hanafi LA, Berger C, et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8+ and CD4+ CD19-specific chimeric antigen receptor-modified T cells. Sci Transl Med. 2016;8:355ra116. Crossref, Medline, Google Scholar|
|43.||Hay KA, Gauthier J, Hirayama AV, et al. Factors associated with durable EFS in adult B-cell ALL patients achieving MRD-negative CR after CD19 CAR-T cells. Blood. Epub 2019 Feb 6. Google Scholar|
|44.||Wang Z, Han W. Biomarkers of cytokine release syndrome and neurotoxicity related to CAR-T cell therapy. Biomark Res. 2018;6:4. Medline, Google Scholar|
|45.||van Rhee F, Fayad L, Voorhees P, et al. Siltuximab, a novel anti-interleukin-6 monoclonal antibody, for Castleman’s disease. J Clin Oncol. 2010;28:3701-3708. Link, Google Scholar|
|46.||Giavridis T, van der Stegen SJC, Eyquem J, et al. CAR T cell-induced cytokine release syndrome is mediated by macrophages and abated by IL-1 blockade. Nat Med. 2018;24:731-738. Crossref, Medline, Google Scholar|
|47.||Norelli M, Camisa B, Barbiera G, et al. Monocyte-derived IL-1 and IL-6 are differentially required for cytokine-release syndrome and neurotoxicity due to CAR T cells. Nat Med. 2018;24:739-748. Crossref, Medline, Google Scholar|
|48.||Doan A, Pulsipher MA. Hypogammaglobulinemia due to CAR T-cell therapy. Pediatr Blood Cancer. 2018;65:65. Google Scholar|
|49.||Hacein-Bey-Abina S, von Kalle C, Schmidt M, et al. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003;348:255-256. Medline, Google Scholar|
|50.||Santomasso BD, Park JH, Salloum D, et al. Clinical and biological correlates of neurotoxicity associated with CAR T-cell therapy in patients with B-cell acute lymphoblastic leukemia. Cancer Discov. 2018;8:958-971. Crossref, Medline, Google Scholar|
|51.||Gust J, Hay KA, Hanafi LA, et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 2017;7:1404-1419. Crossref, Medline, Google Scholar|
|52.||Kochenderfer JN, Somerville RPT, Lu T, et al. Lymphoma remissions caused by anti-CD19 chimeric antigen receptor T cells are associated with high serum interleukin-15 levels. J Clin Oncol. 2017;35:1803-1813. Link, Google Scholar|
|53.||Fry TJ, Shah NN, Orentas RJ, et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat Med. 2018;24:20-28. Crossref, Medline, Google Scholar|
|54.||Brudno JN, Maric I, Hartman SD, et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J Clin Oncol. 2018;36:2267-2280. Link, Google Scholar|
|55.||Alfred L, Garfall EL, Edward A. Posterior reversible encephalopathy syndrome (PRES) after infusion of anti-Bcma CAR T Cells (CART-BCMA) for multiple myeloma: successful treatment with cyclophosphamide. Blood. 2016;128:5702. Google Scholar|
|56.||Brudno JN, Kochenderfer JN. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood. 2016;127:3321-3330. Crossref, Medline, Google Scholar|
|57.||Hu Y, Sun J, Wu Z, et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J Hematol Oncol. 2016;9:70. Medline, Google Scholar|
|58.||Hay KA, Hanafi LA, Li D, et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017;130:2295-2306. Crossref, Medline, Google Scholar|
|59.||JCAR015 in ALL: a root-cause investigation. Cancer Discov. 2018;8:4-5. Google Scholar|
|60.||Lee DW, Kochenderfer JN, Stetler-Stevenson M, 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;385:517-528. Crossref, Medline, Google Scholar|
|61.||Brudno JN, Kochenderfer JN. Recent advances in CAR T-cell toxicity: mechanisms, manifestations and management. Blood Rev. 2019;34:45-55. Crossref, Medline, Google Scholar|
|62.||Taraseviciute A, Tkachev V, Ponce R, et al. Chimeric antigen receptor T cell-mediated neurotoxicity in nonhuman primates. Cancer Discov. 2018;8:750-763. Crossref, Medline, Google Scholar|
|63.||Torre M, Solomon IH, Sutherland CL, et al. Neuropathology of a case with fatal CAR T-cell-associated cerebral edema. J Neuropathol Exp Neurol. 2018;77:877-882. Medline, Google Scholar|
|64.||Teachey DT, Bishop MR, Maloney DG, et al. Toxicity management after chimeric antigen receptor T cell therapy: one size does not fit ‘ALL’. Nat Rev Clin Oncol. 2018;15:218. Medline, Google Scholar|
|65.||Nishimoto N, Terao K, Mima T, et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood. 2008;112:3959-3964. Crossref, Medline, Google Scholar|
|66.||Gardner R, Leger KJ, Annesley CE, et al. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. Blood. 2016;128:586. Google Scholar|
|67.||Shah B, Huynh V, Sender LS, et al. High rates of minimal residual disease-negative (MRD−) complete responses (CR) in adult and pediatric and patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with KTE-C19 (anti-CD19 chimeric antigen receptor [CAR] T cells): preliminary results of the ZUMA-3 and ZUMA-4 trials. Blood. 2016;128:2803. Google Scholar|
|68.||Maus MV, Nikiforow S. The why, what, and how of the new FACT standards for immune effector cells. J Immunother Cancer. 2017;5:36. Crossref, Medline, Google Scholar|