Abstract: Enthusiasm for immunotherapy has spread throughout the oncology community in recent years, as therapies harnessing the body’s ability to fight cancers have offered the potential for remission and even cure in patients with otherwise few options. Chimeric antigen receptor–modified T cells (CAR-Ts) have emerged as a new entity in the treatment armamentarium for several hematologic malignancies, including non-Hodgkin lymphoma. CAR-T therapies are expected to begin receiving approvals from the US Food and Drug Administration as early as 2017. Although commercial pricing data for CAR-T therapies are not currently available, these treatment regimens are anticipated to carry a large financial burden, due to complex manufacturing requirements and the high associated toxicity profile. In this article, the authors review the foundational research in CAR-T therapy, including pricing estimates, in order to determine how best to integrate this new branch of immuno-oncology into clinical pathways for patients with B-cell malignancies.
Citation: Journal of Clinical Pathways. 2017;3(2):41-47.
Received January 26, 2017; accepted March 7, 2017
Practicing oncologists have generally used expert opinions, published guidelines, and consensus statements as the basis for making therapeutic decisions that balance efficacy with toxicity while factoring patient choices and comorbidities.1 This evidence-based decision-making process has led to the use of clinical pathways, governed by oncologists and/or payers, which are hypothesized to help providers deliver more efficient, more streamlined, and better care.2 The principles underlying clinical pathway development are that the most effective therapy be selected when available; when regimens are equally effective, the one with the most favorable toxicity profile is recommended; and, if efficacy and toxicity are comparable, the most cost-effective therapy is suggested.1
The past decade has witnessed significant improvements in the prognosis of patients with non-Hodgkin lymphoma (NHL), regardless of histology. Patients are now expected to experience better overall response rates (ORR), longer disease-free intervals, and improved overall survival.3 These improvements are multifactorial, owing to better therapeutics, monoclonal antibodies, supportive care, and personalized therapy.3 Despite these improvements, a significant proportion of patients will relapse or develop refractory disease.
Genetically engineered T cells, often referred to as “living drugs”, are emerging as a new modality in the fight against cancer.4 Enthusiasm for harnessing the immune system to treat malignancies has been reinforced since the recognition of the graft-versus-leukemia effect and the curative potential of allogeneic hematopoietic stem cell transplantation (allo-HSCT).5 The potential role of immunotherapy in treatment, augmenting and perhaps bypassing the role of traditional or targeted chemotherapy and/or radiation, may benefit patients with refractory or relapsed disease.
Innate and adaptive immunity are equally important host defense mechanisms against pathogens and malignancy. Main components of the innate immune system are epithelial barriers, phagocytic leukocytes, dendritic and natural killer cells, and circulating plasma proteins.6 Components of the adaptive immune system are usually silent but are activated when needed.7 The two subtypes of the adaptive system are humoral immunity, mediated by antibodies produced by B lymphocytes (B cells), and cell-mediated immunity, led by T lymphocytes (T cells).7 T cells identify cancer cells through antigen recognition, mediated by T-cell receptors (TCRs). These receptors are linked to peptides presented by the major histocompatibility complex; binding of the antigen complex to the receptor initiates T-cell activation and elicits an antitumor response.8 Graft-versus-host-disease (GVHD), one of the most hazardous complications of allo-HSCT, is the immune response of donor T-cells in reaction to the recipient’s alloantigens. Manipulation of donor T cells to prevent major histocompatibility complex antigen recognition has been commonly utilized as a strategy to reduce GVHD complications while maintaining graft effectiveness.9
Our understanding of the etiology of GVHD, and the resulting development of T-cell manipulation, has led to the hypothesis that autologous T cells could be manipulated to recognize malignant cells in a way that allows tumor control without the negative sequelae of GVHD.8 This requires that the T cells be harvested via apheresis and transported to a laboratory where they are chemically modified by linking the extracellular antigen recognition domain from a monoclonal antibody fragment to the T cell’s intracellular signaling domain.10 This newly modified autologous T cell–antigen receptor complex is a chimera of two proteins. The newly created chimeric antigen receptor–modified T cells (CAR-Ts) are then incubated to expand their number. Once adequately expanded, the CAR-Ts can be infused into the patient, but only after administering chemotherapy that depletes the patient’s own circulating lymphocytes to maximize the therapeutic effectiveness of the CAR-Ts.11
Hematologic malignancies that are defined by the expression of unique antigens on their cells have become the disease prototype for this form of targeted immunotherapy. Several CAR-T therapies are being investigated in clinical trials, and regulatory approval of one or more of these CAR-Ts is projected in 2017. Relapsed/refractory NHL is the most studied of all hematologic malignancies in clinical trials evaluating the role of CAR-T therapy. For this reason, early CAR-T therapy approval is most likely to be seen in this setting or in the pediatric acute lymphoblastic leukemia (ALL) setting.
Available data have demonstrated CAR-T therapy to have remarkable activity (Table 1), but with moderate to excessive toxicity. Additionally, costs are anticipated to be high. How this novel therapeutic modality will be adopted in a value-based care environment is therefore controversial. For CAR-T therapies to be incorporated into any clinical pathway, they will have to be value tested, which necessitates a thorough understanding of their efficacy, toxicity, and cost.
Efficacy
Other than stem cells, B cells ubiquitously express CD19 on their surfaces throughout their development; as such, this antigen has become an ideal target for CAR-Ts. Several studies of therapies targeting this receptor have been conducted in patients with relapsed and/or refractory CD19-positive disease. Original studies in chronic lymphocytic leukemia (CLL) have shown complete responses (CRs) in heavily pretreated patient populations, with some attaining minimal residual disease (MRD) negativity, a hallmark of efficacy.12-14 In relapsed/refractory ALL, where salvage therapies are considered a bridge to allo-HSCT,15 CAR-Ts showed rapid responses and MRD negativity.16 In fact, Maude et al17 treated 30 adult and children patients with escalating doses of CAR-Ts and found a CR in 27 patients (90%), including 15 who failed prior transplantation; MRD negativity was attained in 22 patients (73%). Collectively, these results confirmed that CAR-Ts targeting CD19 have activity in hematologic malignancies and paved the way for studies in a variety of other CD19-expressing B-cell malignancies, mostly NHL histologies.
These studies of CLL also established the role of lymphodepleting chemotherapy with fludarabine and cyclophosphamide (Flu/Cy) by suggesting that depletion of circulating T cells prior to CAR-T infusion increases effectiveness. The trial results also showed that a conditioning regimen of Flu/Cy is superior to single-agent cyclophosphamide conditioning.12-14 The role of lymphodepleting chemotherapy with Flu/Cy was also confirmed by initial NHL studies, in which negative trial results were attributed to lack of conditioning therapy.18
The National Cancer Institute (NCI) conducted a study of CAR-T therapy in 15 patients with advanced B-cell malignancies, 9 of whom had diffuse large B-cell lymphoma (DLBCL); of this group, 4 patients had primary mediastinal B-cell lymphoma (PMBCL).13 Of the entire cohort, 12 patients responded (ORR, 80%) and 8 patients (53%) attained a CR. Of the 7 patients with refractory DLBCL, 4 (57%) achieved a CR with durations ranging from 9 to 22 months. To mitigate treatment-related toxicities, de-intensifying the conditioning program was suggested; however, it is yet unknown how this strategy impacts efficacy.
Kochenderfer et al19 treated 9 patients with B-cell NHL (8 with DLBCL) with low-dose Flu/Cy before CAR-T infusion; one patient with DLBCL attained a CR (13%), and 4 patients showed a partial response (PR; ORR, 62%). In another study that included patients with a variety of B-cell malignancies (18 patients with DLBCL, 6 patients with follicular lymphoma [FL], and 4 patients with mantle cell lymphoma [MCL]), participants were conditioned with either cyclophosphamide alone or Flu/Cy. Flu/Cy-treated patients had a significantly better CR than those treated with cyclophosphamide alone (42% vs 8%), and, among patients with DLBCL treated with Flu/Cy, 38% achieved a CR. Moreover, 2 of 3 patients with FL receiving Flu/Cy conditioning attained a CR.20
Schuster et al21 reported on a trial of 38 patients with refractory B-cell NHL (21 patients with DLBCL, 14 patients with FL, and 3 patients with MCL). All enrolled patients had no curative options and anticipated survival times of < 2 years. Lymphodepleting regimens varied based on disease burden, histology, and previous therapies. Importantly, the median number of prior therapies was 4 (range, 1-10), and 32% of enrolled patients had undergone prior transplantation. The ORR at 3 months was 68% (DLBCL, 54%; FL, 100%; MCL, 50%); at a median follow up of 11.7 months, at the time of this report, progression-free survival (PFS) for the entire cohort was 62% (DLBCL, 43%; FL, 100%).
In the first multicenter trial of CAR-T in relapsed/refractory NHL (ZUMA-1), patients with either DLBCL or PMBCL received 3 days of Flu/Cy conditioning before a single CAR-T infusion. In total, 111 patients from 22 institutions were enrolled; an analysis was recently presented on 51 patients with DLBCL by Neelapu et al.22 The average turnaround time from apheresis to receiving the infusion was 17.4 days. The ORR was 76% (CR, 47%; PR, 29%), with 92% of responses occurring within the first month of infusion. At the time of this report, 39% of patients had ongoing responses at 3 months (CR, 33%). While PFS was 92% at 1 month, 56% of patients were progression-free at 3 months. Only 6 patients with PMBCL were treated in a similar fashion.23 At a median follow up of 3.2 months, ORR was 100% for these patients, and all of these responses were CRs. Strategies to understand how these responses can be sustained are ongoing. However, ZUMA-1 demonstrates that studies of CAR-T therapies can be safely conducted in a multicenter setting, a critical component to ensure marketing and commercial success.
Toxicity
Cytokine Release Syndrome
Cytokine release syndrome (CRS) is a constellation of inflammatory symptoms that result from cytokine elevations associated with T-cell engagement and proliferation.24 Multiple studies have shown elevated cytokine levels after patients receive CAR-Ts, and some have suggested that the severity of CRS correlates to the level of cytokines in the patient’s serum.25,26 The incidence of CRS varies in published studies, given the heterogeneity of treated patients and their disease burden. Patients present initially with high fever, chills, hypotension, tachycardia, and tachypnea. When CRS is severe, patients can develop severe vascular leakage, hypotension, and coagulopathy, all of which may lead to multiorgan failure.24 As such, CRS is the most serious and lethal adverse event associated with CAR-T therapy. Therefore, early identification and intervention is essential.25
Fevers and chills are usually the first sign of a host response when a patient develops CRS; these symptoms typically occur hours to days after CAR-T infusion. In a study of patients with relapsed/refractory ALL, Lee et al27 reported that 16 patients (76%) developed CRS but only 3 patients overall (14%) experienced grade 4 events. Similar scenarios were observed in other studies of relapsed/refractory ALL. Brentjens et al16 noted significant cytokine elevations in patients who had morphologic evidence of disease upon CAR-T infusion. Other studies in ALL patients reported CRS incidences between 43% and 73%.17,28 In B-cell NHL patients, acute toxicities of fever, hypotension, and delirium were observed even after 3 weeks of infusion, with 1 death possibly attributed to adverse events.13
Almost all organ systems are affected in patients developing CRS; infectious complications,25 coagulopathy,29 and sepsis,24 are among the most severe and life-threatening complications. Recognizing whether these developing signs and symptoms are related to CRS or to another etiology is essential for optimal management.
Patients must be observed closely and managed aggressively when suspecting CRS. In the absence of neutropenia, fever is managed conservatively with acetaminophen. Broad-spectrum antibiotics are administered when fevers occur in the setting of cytopenias. Hypotension is managed with fluid resuscitation, while recognizing that low blood pressure can occur due to vascular leakage, which requires vasopressors and intensive care monitoring.25
Brudno et al25 identified CRS-related toxicity criteria that require pharmacologic intervention (Table 2). Tocilizumab is an IL-6 receptor antagonist that has been shown to abrogate CRS, although there remain some concerns as to whether tocilizumab might mitigate the antimalignancy effect of CAR-Ts.14 While most of the published data for tocilizumab pertains to use in patients with ALL, this antagonist is commonly used in patients receiving CAR-Ts for other indications. If symptoms are not improved with one dose of tocilizumab, another dose is usually administered with consideration to corticosteroids if symptoms persist.25,28,30 Despite concerns that corticosteroids might mitigate the efficacy of CAR-Ts, they are effective in abrogating CRS toxicities12,14; most published guidelines recommend reserving steroids to tocilizumab nonresponders.25,30
Grading of CRS-related toxicities has not been universally agreed upon. Two proposed grading systems are shown in Table 3. Davila et al28 proposed a grading system that combines clinical signs and symptoms with cytokine levels, but wide adaptation of this scale is limited because obtaining timely cytokine serum levels might not be practical. Other proposed systems that modify Common Terminology Criteria for Adverse Events version 4.031 to meet CAR-T specific toxicities, such as that developed by Lee at al,30 have also been used and are being incorporated into ongoing clinical trials.
Neurologic Toxicities
Neurologic events occur in up to 50% of patients, independently of CRS incidence.25 Etiology of these toxicities is unclear, although some have suggested that they emerge as a result of an inflammatory response mediated by T cells.17 Lee et al showed that IL-6 levels are elevated in the cerebrospinal fluid (CSF) of patients experiencing neurotoxicity after CAR-T infusions. CAR-Ts also have been found in the CSF of patients experiencing neurologic events, suggesting a plausible role in developing neurotoxicity.17,27,28
Patients with neurotoxicity experience a variety of symptoms, ranging from mild headache to generalized seizures requiring mechanical ventilation. Commonly, patients have localized signs such as cranial nerve palsies, cerebellar toxicities, or stroke-like presentation.18 In most instances, neurologic events are self-limiting, and there are no clear guidelines regarding best management of these events. The NCI group recommends managing neurotoxicity in a similar fashion to CRS, as summarized in Table 2, although some have advocated early initiation of steroids when neurologic toxicities emerge; responses to these various interventions are not well documented.18
Other Adverse Events
All organs (cardiac, pulmonary, renal, etc) can be adversely affected by CAR-Ts. Anaphylactic reactions have been reported, and some studies have reported tumor lysis syndrome as a serious event, especially when lymphodepleting regimens are not administered prior to CAR-Ts.29,32 Research regarding the predictability, prevention, and management of toxicities associated with CAR-Ts is essential for this therapy to succeed.
Cost and Pricing
Because cost drives value-based shared decision discussions, it has become the third essential component determining the positioning of treatment options within the clinical pathway. The complexity of preparing CAR-Ts, and the unique toxicities encountered with this therapy, challenge traditional health care market formulas and test the predictability of global costs. Additionally, patients should be treated in a center with strong immunotherapy or transplantation acumen and with immediate access to intensive care monitoring should the need arise. The operational aspects of delivering CAR-Ts suggest that pricing and cost also depend on logistics such as apheresis and cryogenic transport, which is available by a limited number of vendors. Patient-specific manufacturing adds another element of cost that is rarely applicable to other therapies and poses the question of scalability.
Actual cost of CAR-T therapy has not yet been determined because none of the current CAR-Ts are commercially available. However, all processes in manufacturing CAR-Ts require Good Manufacturing Practice facilities or a similarly accredited environment. Given the complexity of therapy and the rigorous training required for physicians, nurses, pharmacists, and other health care providers, one could speculate that CAR-Ts would be priced similarly to allo-HSCT. Media sources have reported manufacturing companies estimating the cost of developing CAR-Ts for each individual patient to be between $500,000 and $750,000,33 although this does not necessarily forecast the market price.
The first approved indication will likely be pediatric and young adult ALL followed by relapsed/refractory DLBCL. Market models also expect commercially viable approvals for relapsed/refractory CLL and MCL, although some of these approvals will likely depend on postapproval success after initial indications.
How payers will react to market price is less predictable. If approved, insurers will look to similar models in order to determine reimbursement for CAR-Ts. It would not be unreasonable if a bundled payments approach is proposed, which would encompass outpatient therapy, inpatient hospitalization, and posttherapy monitoring.
Discussion
As the primary endpoints of clinical trials of CAR-T therapies are met or exceeded, and as manufacturers publically announce FDA filings, it is likely that the US Food and Drug Administration (FDA) will accelerate approval of at least one CAR-T product in the next 12 to 18 months. As CAR-Ts gain approval, the traditional process of building pathways based on the interplay between efficacy, safety, and cost may be challenging to apply in the CAR-T setting.
First, incorporating this technology into treatment pathways will depend on the labeled indication. Notably, responses achieved in DLBCL have not proven sustainable, while the converse is true in ALL. The three compounds currently being studied appear similar in efficacy and toxicity, and they are unlikely to be compared with one another. Given the lack of comparative efficacy data and similar toxicities between various CAR-Ts, equated values might be part of the process in how CAR-Ts are positioned in a clinical pathway and how coverage determinations are made. In DLBCL, the most common NHL in the United States, 30% of patients are expected to fail traditional therapies, of whom 30% to 35% are cured with autologous HSCT.34 Patients relapsing after HSCT and those deemed ineligible for autologous HSCT have no known standard of care, and some could be excellent candidates for CAR-Ts.
Whether cure is attained with CAR-Ts, or if this strategy is a bridge to another therapy, remains to be determined. Results reviewed herein suggest excellent remission rates in refractory patients, but the ZUMA-1 study, described above, showed suboptimal duration of response. Moreover, while clinical trials enroll highly selected patients, data in the “real world” are likely to be less robust. Monitoring patients after completion of therapy for possible late complications will likely be part of a mandatory Phase 4 postmarketing surveillance required by the FDA given the likely fast-track status of first indications. These challenges, coupled with cost of therapy, will possibly have a major impact on positioning CAR-Ts into clinical pathways for managing disease.
As efficacy and toxicities appear equal, cost of therapy might be the most differentiating factor between therapies. We suspect CAR-T payment will be akin to HSCT where bundled payments are the payment method of choice. Patients, providers, and treatment centers will need education and coordination in reimbursement from payers and manufacturers.
Some of the incurred cost depends on emerging adverse events and how they are managed and may resemble costs associated with managing patients undergoing stem cell transplantation. Cost will likely be lower with early identification of adverse events so that they are managed properly. Thus, we anticipate payers to be fully engaged in strategies to minimize serious adverse events. One strategy may be applying restrictions as to where patients may be administered CAR-T therapy by mandating quality and clinical certifications to CAR-T–providing institutions, analogous to accreditation status for stem cell transplantation programs. Payers may also mandate that facilities where CAR-Ts are administered have ongoing educational platforms that ensure awareness of incidence and management of these events. Manufacturers will likely work jointly with payers and providers to assure proper training and may even extend their engagement by endorsing any required certifications or other best practices. Manufacturers may help to disseminate information regarding such “centers of excellence” for CAR-T to community oncologists so that eligible patients are identified and referred accordingly.
As we enter a value-based care environment, balancing efficacy results with potential costly toxicities becomes an essential part of the reimbursement equation and in how payers determine coverage. This delicate balance between outcome and cost, defined as value, has led several national organizations to apply various principles to compute an actual value on a proposed therapy.35-38 These value-based conversations are poised to become a critical part of the shared-decision making process between providers and patients when deciding on CAR-T.
Conclusion
CAR-T therapies are a continuation of the immuno-oncology approach to cancer treatment; this modality has demonstrated activity across a variety of tumor types. Yet, the complexity of developing CAR-Ts, their unprecedented production cost, and their distinctive adverse events position them uniquely within the treatment landscape, as several of these compounds are poised to enter the market. With reimbursement models changing rapidly to reward quality of care over quantity of care, and as value-based calculators are increasingly being used to define value of administered therapy, payers and providers will need to closely monitor the outcomes of their enrollees and patients, respectively, to determine whether achieved outcomes justify the incurred cost. Only at that juncture can optimal positioning of CAR-Ts into clinical care pathways be successfully determined.
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