Article

CAR T-Cell Advances in Lymphoma: Implications for Managed Care

To claim CE credit for this activity, please visit https://www.pharmacytimes.org/courses/car-t-cell-therapy-advances-in-lymphoma-implications-for-managed-care

Chimeric Antigen Receptor T-Cell Therapy

Non-Hodgkin lymphomas (NHLs) are a heterogeneous group of lymphoproliferative disorders originating in B, T, and natural killer cells.1 NHL is the seventh leading cause of cancer in the United States, with an estimated 80,470 newly diagnosed individuals and 20,250 deaths in 2022.2 B-cell lymphomas may have an aggressive or indolent rate of progression and therefore, treatment and prognosis may be multifactorial and highly variable based on the disease classification, immunophenotype, and genetic and clinical features.1 Mature B-cell lymphomas account for approximately 85% to 90% of all NHL cases, with diffuse large B-cell lymphoma being the most common, followed by follicular lymphoma (FL) and mantle cell lymphoma (MCL).3 Currently, the estimated 5-year survival rate for individuals with NHL is 73.8%.2 Despite initial response to frontline chemoimmunotherapy or chemotherapy, many patients will demonstrate disease progression and become refractory to other treatment options.

The development of chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment paradigm for patients with aggressive relapsed/refractory (R/R) B-cell NHL who have progressed on the standard of care that includes high-dose chemotherapy, chemoimmunotherapy, and/or autologous stem cell transplant (ASCT). CAR T-cell therapy is FDA approved for a variety of B-cell lymphomas, including R/R large B-cell lymphoma (LBCL), R/R FL, R/R MCL, R/R B-cell acute lymphoblastic leukemia, and R/R multiple myeloma, and is being studied in other R/R indolent lymphomas and in chronic lymphocytic leukemia.4

CAR T-cell therapy is a novel immune-mediated therapy designed to modify, enhance, and activate T cells to recognize and target a specific tumor cell in the body.5,6 Autologous T cells are genetically modified through a process known as transduction to produce a new antigen recognition domain on the T-cell surface that effectively transforms the T cells into a “living drug” that persists in oncolytic activity for months or even years after administration.7

The CAR is comprised of 3 distinct components: (1) an extracellular single-chain variable fragment with a hinge region, also called the antibody-binding domain; (2) a transmembrane domain; and (3) an intracellular signaling domain, CD3 zeta with or without a costimulatory domain comprising either CD28 or 4-1BB (Figure 18). The first-generation CAR T-cell therapies lacked the costimulatory domain and, as a result, exhibited poor efficacy and persistence in the early clinical studies. The currently available FDA-approved CAR T-cell products are considered “second generation” because they include an additional costimulatory domain such as CD28 or 4-1BB to improve persistence and potency.9,10 Third- and fourth-generation CAR T cells are currently under development.

Figure 1. Chimeric Antigen Receptor T Cells8

Republished from Stock S, Schmitt M, Sellner L. Optimizing manufacturing protocols of chimeric antigen receptor T cells for improved anticancer immunotherapy. Int J Mol Sci. 2019;20(24):6223. doi:10.3390/ijms20246223, under the terms and conditions of the Creative Commons Attribution (CC BY) license.

Currently, 4 anti-CD19 CAR T-cell agents are FDA approved for the treatment of various R/R B-cell lymphomas. The approved indications are listed in Table 1.11-14

Table 1. FDA-Approved Chimeric Antigen Receptor T-Cell Therapies for Lymphoma11-14

Tisagenlecleucel ([tisa-cel] Kymriah) and brexucabtagene autoleucel ([brexu-cel] Tecartus) are FDA approved for the treatment of R/R B-cell acute lymphoblastic leukemia in pediatric populations, young adults, and adult patients, respectively.13,14 Two additional CAR T-cell therapies targeting B-cell maturation antigen, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), have received FDA approval for the treatment of R/R multiple myeloma after 4 or more lines of therapy.15,16 However, the focus of this educational article will be on CD19 CAR T-cell therapies approved for the treatment of B-cell lymphomas.

CAR T-cell manufacturing is a multistep process that begins with the collection of peripheral blood mononuclear cells via leukapheresis, genetic modification through viral transduction, and expansion of the T cells conducted ex vivo in a manufacturing facility and then administered to the patient (Figure 217).18,19 The manufacturing times for CAR T cells vary by product manufacturer, ranging from 3 to 6 weeks, and are contingent on the quality of the T cells collected and the time ex vivo to reach the full quantity of cells to meet the target CAR-positive T-cell dose.10

Figure 2. Autologous Chimeric Antigen Receptor T-Cell Therapy Process17

Republished with permission from ©Fran Milner 2017.


Current Treatment Landscape and Clinical Evidence

Chimeric Antigen Receptor T-Cell Therapies in Non-Hodgkin Lymphoma

Large B-Cell Lymphoma

Initial CAR T-cell therapies axicabtagene ciloleucel (axi-cel), tisa-cel, and lisocabtagene maraleucel (liso-cel) were approved for aggressive R/R LBCLs after at least 3 lines of therapy based on results from single-arm, open-label studies ZUMA-1, JULIET, and TRANSCEND (Table 24,10,20-32).20-25 Long-term outcomes from these trials reported a significant proportion of durable remissions greater than 1 year. Both liso-cel and tisa-cel have a 4-1BB costimulatory domain, while axi-cel has a CD28 costimulatory domain. This difference could potentially impact CAR T-cell persistence and relapse. For example, some studies have noted a more durable persistence in CARs with the 4-1BB domain. Conversely, relapses occur less frequently with CD28 CARs; however, the long-term impact has yet to be determined. The 3 CAR T-cell products for LBCL have not been directly studied in head-to-head clinical trials; therefore, preferences are primarily provider, patient, and manufacturer dependent. Sometimes the choice of product depends on the manufacturer slot availability and the clinical needs of the patient due to prolonged manufacturing times.33-36 While head-to-head trials of these products have not been completed, a recent retrospective report evaluating real-world use of 260 patients receiving either tisa-cel or axi-cel noted similar progression-free and overall survival. The 2 constructs differed significantly with respect to safety and resource utilization.37,38

Recently, 3 phase 3 trials were completed that compared CAR T-cell therapy with ASCT in patients with aggressive R/R LBCL in the second-line setting: the BELINDA trial with tisa-cel, the ZUMA-7 trial with axi-cel, and the TRANSFORM trial with liso-cel. Event-free survival benefit was observed in the CAR T-cell group in both the ZUMA-7 (8.3 vs 2.0 months) and TRANSFORM (10.1 vs 2.3 months) trials but was not observed in the BELINDA trial. In BELINDA, the 2 groups experienced similar response rates and an event-free survival of 3 months. The complete response rate was higher in the axi-cel (66% vs 39%) and liso-cel groups (65% vs 32%) compared with the ASCT group, while no difference in complete response was observed between tisa-cel and the ASCT group (28.4% vs 27.5%, respectively). Based on results from ZUMA-7 and TRANSFORM, axi-cel and liso-cel were granted FDA approval for the second-line treatment of adult patients with R/R LBCL.27,28,38 Differences in trial design may account for some variability between BELINDA and the other 2 trials. In BELINDA, bridging chemotherapy was allowed, and was defined as chemotherapy given after T-cell collection to control disease prior to lymphodepleting chemotherapy. In addition, impending organ-compromising disease was not an exclusion, so patients included in this trial may have had more aggressive disease; however, additional assessment should be completed. The ZUMA-7 and TRANSFORM results represent a clinically meaningful advancement in the second-line treatment of R/R LBCL, where salvage chemoimmunotherapy, followed by chemotherapy and ASCT, has remained the standard of care for decades.27,28,38 The appropriate sequencing of CAR T-cell therapies with transplant and other available treatment options in LBCL remains to be investigated.

Table 2. Summary of Major Trials Evaluating Efficacy of CAR T-Cell Therapy in Lymphoma4,10,20-32

Follicular Lymphoma

FL is generally considered a slowly progressing or indolent cancer. Although median overall survival has improved with chemoimmunotherapy as the standard of care, approximately 20% of patients will eventually progress within 2 years. Progression-free survival has been shown to decrease from 6.6 years after first-line treatment to 1.5 years and 10 months after second and third lines of therapy.29

Currently, 2 CAR T-cell agents, axi-cel and tisa-cel, are approved for use in patients with R/R FL in the third or later lines of therapy based on results from ZUMA-5 and ELARA. Axi-cel was the first to be approved for R/R FL based on ZUMA-5, a single-arm, open-label, multicenter, phase 2 trial that enrolled 146 patients with R/R FL or marginal zone lymphoma whose disease failed to respond to at least 2 prior therapies.30

More recently, tisa-cel was approved for R/R FL in the second or later lines of therapy based on results from ELARA, a phase 2, multinational trial evaluating efficacy of tisa-cel in adults with R/R FL after 2 or more lines of treatment or who relapsed after ASCT.13 The primary end point was met at interim analysis, with a median follow-up of 9.9 months.29

Mantle Cell Lymphoma

Patients with R/R MCL are recognized as having high-risk disease with generally poor prognosis.1 The National Comprehensive Cancer Network guidelines recommend that CAR T-cell therapy be considered in patients who have received chemoimmunotherapy and a Bruton tyrosine kinase inhibitor.1 Brexu-cel is an anti-CD19 CAR T-cell product that removes circulating CD19-expressing malignant cells during the manufacturing process, allowing it to be used in patients with leukemia or MCL, and is the only CAR T-cell therapy approved for R/R MCL.14,31 FDA approval for brexu-cel was based on results from ZUMA-2, a single-arm, open-label, phase 2 trial.31

Managing Chimeric Antigen Receptor T-Cell−Associated Toxicities

Despite the advances in personalized immunotherapy and the promising benefits of CAR T-cell therapy in the treatment of difficult-to-treat cancers, there are serious adverse effects (AEs) that may occur with the use of these treatments. Overall, the likelihood of CAR T-cell−associated toxicities is high, and not all patients can tolerate therapy.39 The more serious, life-threatening toxicities associated with CAR T-cell therapies are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). The incidence and severity of CRS and ICANS vary with CAR T-cell product and by disease (Table 34,10,20,22,23,25-29,31,32).40

Table 3. Summary of Select Adverse Effects From CAR T-Cell Therapy Clinical Trials4,10,20,22,23,25-29,31,32

Cytokine Release Syndrome

CRS is an acute systemic inflammatory response resulting from overactivation of immune effector cells and the subsequent release of inflammatory cytokines. The circulating cytokines lead to endothelial injury and capillary leak which presents clinically as hemodynamic instability and organ dysfunction resulting in severe and fatal consequences. Symptoms include fever, hypotension, hypoxia, and chills and may accompany cardiac, hepatic, and/or renal dysfunction.40 It has an acute onset, often occurring within 3 to 5 days of CAR T-cell infusion, with a duration of 5 to 8 days.11-14 Multiple cytokines have been implicated in CRS including interleukin (IL)-6, IL-1, interferon-gamma, and tumor necrosis factor-alpha. IL-6 is considered a central mediator of CRS and under elevated levels may induce a proinflammatory response. In general, management of CRS consists of targeting both direct and nonspecific immunosuppressive strategies and includes the combination of tocilizumab, an IL-6 receptor antagonist, and corticosteroids along with supportive care (ie, hydration, antipyretics, vasopressors) as needed. Proposed alternatives to tocilizumab include siltuximab, an anti-IL-6 antibody, and anakinra, an IL-1 receptor antagonist.40 The prevention and mitigation of CRS continues to evolve and is an active area of research. Strategies include the use of prophylactic corticosteroids as well as early use of tocilizumab. Recently, the FDA approved a label update to include prophylactic corticosteroids across all its indications for the prevention of CRS.41,42

Immune Effector Cell-Associated Neurotoxicity Syndrome

Neurotoxicity, also known as ICANS, is also frequently observed after CAR T-cell infusion and is defined as a pathologic process involving the central nervous system that results in activation or engagement of endogenous or infused T cells and/or immune effector cells. ICANS may present as encephalopathy, delirium, aphasia, ataxia, seizures, tremors, and cerebral edema and may be life-threatening.40 Typical time to onset of neurotoxicity is 4 to 8 days after CAR T-cell infusion, with a duration of 7 to 21 days.11-14 Neurotoxicity may occur in the presence or absence of CRS; however, CRS is a strong risk factor for ICANS. Management includes corticosteroids, careful monitoring, and supportive care. Tocilizumab is not recommended because it is unable to cross the blood-brain barrier when given intravenously and has not demonstrated significant clinical impact with ICANS. Patients with elevated intracranial pressure may require a lumbar puncture. Mold-active antifungal prophylaxis should be considered in patients receiving steroids for CRS or neurotoxicity.40

Other toxicities that may occur with CAR T-cell therapy include hemophagocytic lymphohistiocytosis (HLH), B-cell aplasia, and prolonged cytopenia. HLH is a severe immunologic syndrome caused by uncontrolled immune activation resulting in hyperactivation of macrophages and lymphocytes and an increase in proinflammatory cytokines, which ultimately leads to immune-mediated multi-organ failure. Treatment begins with steroids and, if there is no improvement within 48 hours, the addition of anakinra. Etoposide or intrathecal cytarabine can be considered for HLH with central nervous system involvement. B-cell aplasia or hypogammaglobulinemia is another potential AE associated with CAR T-cell therapy and may be a long-term consequence of the modified T-cell activity. It is characterized by low antibody levels in the blood and an increased risk of infection due to extremely low B cells or plasma cells from the on-target/off-target activity of CAR T-cell therapy. Hypogammaglobulinemia may be treated with intravenous immunoglobulin infusion until serum immunoglobulin G levels normalize and infection is resolved. Patients who receive CAR T-cell therapy are also at risk of hematologic toxicities, including prolonged cytopenia, and are generally managed with transfusion or growth factor support.40

Risk Evaluation and Mitigation Strategy

Currently, all approved CAR T-cell therapies have their own Risk Evaluation and Mitigation Strategy (REMS) programs and require facility enrollment and staff training prior to CAR T-cell administration. A minimum of 2 doses of tocilizumab must be available on-site for each patient undergoing treatment to ensure appropriate treatment is available to treat CRS. The REMS program also requires patients to remain within 2 hours of the treatment facility for at least 4 weeks following CAR T-cell infusion and receive education on CAR T-cell therapy.43,44

Understanding the Costs and Value Associated With Chimeric Antigen Receptor T-Cell Therapy

Access Considerations for Chimeric Antigen Receptor T-Cell Therapy

CAR T-cell therapy has ushered the way for personalized immune-mediated cancer therapy in the 21st century and despite its promising efficacy, access continues to be a significant concern. Patients’ disease status, performance status, comorbidities, and caregiver support are all essential considerations. Disparities exist for minority populations and patients with a lower socioeconomic status.45 Additionally, this new technology is not without considerable cost to the health care system. As the cellular therapy space continues to grow and evolve so will the need to understand the financial impact these therapies will have on the health care system, patients, and providers.

Direct Costs

Despite the growth of the CAR T-cell market, there are still many barriers to optimal uptake and effective administration of treatment. The cost of CAR T-cell therapy presents one of the biggest challenges, with drug wholesale acquisition costs (WAC) ranging from $399,100 to $465,000 depending on the specific product and indication.46

However, costs associated with CAR T-cell treatment are not limited to acquisition cost. Hospital services including costs associated with leukapheresis, lymphodepleting chemotherapy, and toxicity management are the most significant drivers of cost for CAR T-cell therapies, especially for patients who experience toxicities.47 According to a multicenter historical cohort study of 111 patients receiving CAR T-cell treatment who were admitted to the intensive care unit, the primary cause of admission was CAR T-cell−related toxicities. CRS and ICANS were observed in 77% and 83% of patients, respectively, with 60% of patients experiencing both toxicities. Median time from CAR T-cell infusion to intensive care unit admission was 5 (0-74) days, and length of stay was 4 (1-22) days.48 Treatment-related ancillary services have significant impact on health care expenditures, and costs may vary by hospital type. Among those costs are lymphodepleting chemotherapy and bridging therapies, which may be required to slow the disease progression while the CAR T cells are being manufactured.49 The costs associated with lymphodepletion therapy, acquisition and infusion of CAR T cells, and management of AEs in site-of-care setting were examined by Lyman et al. The estimated total cost of care associated with administration of CAR T-cell therapy was $454,611 in an academic hospital inpatient setting compared with $421,624 in a nonacademic specialty oncology network setting. After excluding the cost of CAR T-cell acquisition ($373,000), total hospital and office visit costs were $53,360 (65.3% of total costs) in an academic inpatient hospital and $23,526 (48.4% of total costs) in a nonacademic specialty oncology network: a cost differential of over $30,000.47 The site-of-care influence on cost is greatest when CAR T-cell therapy is administered at a nonhospital-affiliated site.47

While the acquisition cost of CAR T-cell therapy has received much attention, real-world evidence on the total cost of care beyond drug cost continues to be investigated. Recently, 2 separate retrospective, real-world analyses utilizing US commercial medical and pharmacy claims data were conducted to determine the total health care resource utilization and total cost of care associated with CAR T-cell therapy. Within the first 3 months after CAR T-cell infusion, the mean total inpatient hospital days among all patients ranged from 17 to 22 days and was slightly longer for patients who experienced severe CRS (19-27 days) or severe neurologic events (22-29 days). In the 3 months following treatment, the mean total cost of care for all patients ranged from $379,627 to $525,722, with health care expenditures higher for patients who experienced severe CRS ($475,875-$565,931) and severe neurologic events ($406,428-$679,195).50 These findings were supported by an analysis conducted on integrated pharmacy and medical claims data of 15 million members by Sahli et al. The analysis identified 74 patients with a lymphoma diagnosis who received CAR T-cell therapy between January 2018 and June 2020; costs were evaluated over a period of 86 days (30 days before and 56 days after infusion). The median total cost of care was $610,999 ($358,980-$2,235,658), with 12% of episodes exceeding $1 million in total cost. Despite CAR T-cell therapy, 39% of members did not have a durable response and 30% of patients went on to receive subsequent chemotherapy.51

Indirect Costs

Less recognized are significant indirect costs associated with CAR T-cell therapy borne by the patient and their families. While treatment costs may be covered by the patients’ medical carrier, the out-of-pocket costs, which include transportation, hotel accommodations, and potential lost wages, are not always accounted for when considering total cost of care. Per REMS requirements, patients are required to remain within a 2-hour radius of the treating medical center for up to 4 weeks after CAR T-cell infusion. Due to the restricted number of medical centers certified to provide treatment, some patients may have to travel significant distances for treatment. One study noted that approximately 33% of patients must travel more than 120 minutes from the treatment facility, and another study described 37% of patients having to travel at least 1 hour for treatment.4,52

Site of Care

Traditionally, CAR T-cell therapy has been administered in the inpatient setting and usually at a large academic medical center. Costs associated with CAR T-cell therapy may decrease substantially if access can be expanded to nonacademic and community centers; however, administration of these therapies continues to be very complex.53 More recently, efforts to improve access to treatment for patients and reduce treatment cost associated with inpatient stay has generated interest in outpatient administration with appropriate threshold for hospital admission for treatment-related toxicities.54 Although outpatient administration can result in lower costs, patients may still be admitted to the hospital due to toxicity. Approximately 10% of patients in the TRANSCEND trial and 18% in the ELARA trial received CAR T-cell therapy in the outpatient setting. Of those patients, 72% and 65%, respectively, were subsequently hospitalized for AE management.25,29 In the Medicare population, CAR T-cell therapy is covered under Part B; however, if the patient is admitted to the hospital within 72 hours, then the outpatient costs will be bundled with the claim for an inpatient stay and the provider loses the ability to claim Part B benefits.55 Hospital outpatient administration is unlikely to benefit payers because it is the more costly site of service for Part B drugs billed under the medical benefit.47

Value and Cost-Effectiveness of Chimeric Antigen Receptor T-Cell Therapy

The staggering cost of CAR T-cell therapy requires the health care system and payers to examine the value of these potentially curative therapies relative to previous standards of care. Value is assessed through cost-effectiveness analysis of health outcomes gained and is commonly measured as quality-adjusted life-years (QALYs) per dollar spent. QALYs are composite estimates of morbidity and mortality calculated by multiplying life-years gained by a utility value for specific health states derived from studies conducted in patients with specific medical conditions of interest. By comparing the cost and QALYs of existing standard-of-care therapies, an incremental cost-effectiveness ratio can be derived. Decision makers can determine the acceptability to fund therapy by comparing costs per QALY against a predetermined willingness-to-pay (WTP) threshold. In the United States, the implied WTP for oncology is in the range of $100,000 to $150,000.56

Recent peer-reviewed studies have reported cost-effectiveness of tisa-cel and axi-cel in comparison with the standard of care for LBCL. The cost-effectiveness of axi-cel compared with chemotherapy for the treatment of R/R B-cell lymphoma was modeled in 2 different studies. Lifetime survival gains for treatment with axi-cel ranged from 1.52 to 6.54 more QALYs at a cost-effective estimate of $58,000 to $289,000 per QALY gained.57,58 A cost-effectiveness analysis for tisa-cel yielded increases of 2.82 to 3.92 QALYs at a cost-effective estimate of $168,000 to $337,000 per QALY gained.59 The Institute for Clinical and Economic Review (ICER) conducted a value assessment of axi-cel for the treatment of B-cell lymphoma in 2018; the only FDA-approved CAR T-cell treatment at the time of assessment. The ICER panel determined that axi-cel had a low-to-intermediate long-term value based on a cost-effectiveness estimate of $136,078 per QALY gained and was below or within the WTP threshold of $50,000 to $150,000 per QALY over lifetime horizon. The panel also determined that further analysis suggested the cost-effectiveness finding would be less favorable if the possibility of late relapses or price increases were included. Budget impact analyses have found that short-term cost of axi-cel for R/R NHL could exceed ICER’s $915 million threshold for annual budget impact at its current price and that only 38% of the estimated 5900 eligible patients could be treated in 1 year before crossing the threshold. In another budget impact estimate, administration of axi-cel or tisa-cel to all indicated patients with R/R B-cell lymphoma would increase US health care costs by $12 to $9 billion, respectively.59,60

Reimbursement Strategies and Innovative Payment Models

Reimbursement challenges have been at the forefront of the CAR T-cell therapy discussion since the FDA first approved treatment in 2017. The Centers for Medicare & Medicaid Services inpatient prospective payment system proposes a reimbursement structure comprising 2 components: (1) Medicare Severity Diagnosis Related Group and (2) New Technology Add-On Payments (NTAP). For fiscal year 2023, the reimbursement rate for Medicare Severity Diagnosis Related Group-18 will be $247,938, with 1 new NTAP for ciltacabtagene autoleucel added to the existing NTAP for idecabtagene vicleucel and brexu-cel for a maximum total of $272,675 and a fixed-loss outlier payment of $38,859. Both the NTAP and outlier are dependent on total billed charges for the case and hospitals overall operating and capital cost-to-charge ratios. An outlier payment and fixed-loss threshold amount is allowed for extremely costly cases; however, despite these allowances, the reimbursements for CAR T-cell treatment still fall short of the minimum estimated total cost of care.54,61

Commercial payers require a prior authorization process before a patient may be authorized to receive treatment with CAR T-cell therapy, which can be a very time-consuming and rate-limiting step to timely treatment. Reimbursement for commercial payers is often based on single-case rate agreements.54

Alternative payment strategies are continually being explored to address gaps in the US payment model. One of the more common strategies includes a bundle payment system that includes packaging all costs of care as a one-time payment, or an outcomes-based agreement or value-based payment. A Centers of Excellence model has been proposed which will concentrate services solely to facilities recognized as Centers of Excellence.62 One advantage of this model is the existing framework from stem cell transplant specialty networks that could be used as a guide; however, a disadvantage includes further limiting access to care for patients living in rural communities.63 The Academy of Managed Care Pharmacy convened a group of national and regional payers to explore new payment models for high-investment medications. Several innovative payment models were considered and included annuity payment, reinsurance markets, performance-based contracts, and milestone-based contracts. Annuity payments and reinsurance markets provide financial mechanisms for mitigating risk, while performance-based and milestone-based contracts base payment on outcomes.64 Progressive strategies that monetize health using a currency called HealthCoin that could be traded among public and private payers are also being considered as viable payment strategies to tackle the staggering costs of these new innovative pharmaceutical treatments.65

Future Directions for Chimeric Antigen Receptor T-Cell Therapy

With the anticipated growth of the cell therapy market expected to exceed $20 billion by 2031, the future of cell therapy continues to evolve with the development of more effective targets and less toxic AEs.66 Academic medical centers are poised to decentralize the CAR T-cell production from the pharmaceutical manufacturer to in-house laboratories to reduce the time from leukapheresis to infusion and decrease costs but are limited by burdensome regulatory pathways that are currently in effect.67,68 Pharmaceutical manufacturers are searching for ways to improve the CAR T-cell manufacturing process, including the development of “off-the-shelf” allogenic CAR T-cell therapies and further developing other immune effector cell therapies, such as bispecific T-cell engagers that may impact overall demand for CAR T cells. Several next-generation CAR designs are in various stages of clinical development that aim to improve safety and efficacy, such as switchable, armored, tandem, and universal CARs.6,69

Conclusions

CAR T-cell therapy is rapidly evolving with the advent of additional FDA-approved indications, new cancer targets, and next-generation CARs in development. The total cost of care approaches $1 million for some patients who experience serious toxicities, and some patients will relapse and require additional therapies. The total cost of care and an insufficient reimbursement structure present major challenges to the effective implementation of CAR T-cell therapy. While cost-effectiveness studies suggest intermediate value at their current prices, budget impact models demonstrate that fewer than 40% of eligible patients could be treated before the ICER’s budget threshold is crossed. Innovative payment models are being considered among national and regional payers to increase access to and affordability of these novel, high-cost therapies.

References

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