Barriers to patient access of CAR T cell therapies in Austria

Chimeric antigen receptor (CAR) T cell therapies offer a promising new therapeutic option for treating B cell malignancies, for instance relapsed or refractory diffuse large B cell lymphoma (DLBCL). However, patient access to this type of cellular immunotherapy may be limited due to systemic barriers even in wealthy Western countries. In Austria, the CAR T eligible DLBCL population is estimated to encompass approximately 56 patients based on the criteria applied for CAR T registrational trials. However, less than 40% of these DLBCL patients eligible for commercial standard-of-care CAR T cell therapy were finally treated with CAR T cell therapy in 2021 based on our analysis. This report discusses potential barriers that may impede current patient access to CAR T cell therapy and provides recommendations for systemic solutions to address these barriers and improve the CAR T access situation in Austria.


Introduction
Chimeric antigen receptor (CAR) T cell therapy, a novel type of treatment for hematological malignancies, utilizes genetically modified T cells expressing synthetic CARs that can subsequently trigger an immune response against cancer cells carrying a specific target surface protein [1]. CAR T cell therapies are most advanced in B cell neoplasia, with licensed therapies directed against CD19 or B cell maturation antigen (BCMA) antigens in lymphoma, leukemia, or multiple myeloma indications respectively. When infused back into the patient, the CAR T cells bind the CD19 or BCMA antigens expressed in B cell-derived malignancies in a major histocompatibility complex (MHC)-independent manner, thus bypassing tumorinduced downregulation of the MHC complex [2]. The CAR construct also contains a zeta chain of the T cell receptor (TCR) in combination with costimulatory molecules like IBB4 or CD28, which together stimulate a very strong immune response against CD19-or BCMA-positive cells [2]. While the majority of CAR constructs today apply autologous T cells as a basis [1], allogeneic CAR constructs are also in development [3].
The first two CAR T cell therapies were approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in 2017/2018 for relapsed/refractory diffuse large B cell lymphoma (DLBCL) patients after two lines of systemic therapy (axicabtagene ciloleucel and tisagenlecleucel), for primary mediastinal large B cell lymphoma (PMBCL) after two lines of systemic therapy (axicabtagene ciloleucel), and for relapsed/refractory B cell acute lymphoblastic leukemia (ALL) in patients up to 25 years (tisagenlecleucel) [4][5][6][7]. Since April 2022, in total six CAR T cell therapies have received regulatory approvals for different hematological malignancies, including DLBCL and PMBCL [4][5][6][7][8][9], ALL [5,6,10], mantle cell lymphoma (MCL) [10,11] follicular lymphoma (FL) [4][5][6][7], and multiple myeloma [12][13][14], and further indications are under investigation for CAR T cell therapies [2]. The side effect profile of these CAR T cell therapies varies substantially according to the targeted antigens, the costimulatory molecules used and probably the type of malignant disease. Side effects comprise cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, and immunosuppression with infection [15], which can be well handled in experienced CAR T centers.
DLBCL constitutes the largest indication among non-Hodgkin lymphomas globally with an estimated share of about 30-40% of cases [16]. Relapsed or refractory DLBCL patients after two lines of systemic therapy have previously been characterized by very poor clinical outcomes with only limited therapeutic options [17]. Recently, however, long-term CAR T cell therapy studies have demonstrated improved outcome, with 44% of DLBCL patients in third line surviving beyond 4 years after having received CAR T cell therapy [18]. More recent studies also demonstrate promising results of CAR T cell therapies in DLBCL patients after first relapse in direct comparison with the current standard of care high-dose chemotherapy and autologous stem cell transplant [19,20], with one of these CAR T cell therapies having been approved by the FDA [7].
In Austria, the first DLBCL patient received CAR T cell therapy within a clinical trial in the Vienna General Hospital AKH in 2016 [21]. As of 2021, six CAR T centers are qualified/certified by an industrydriven process mandated by the EMA to perform licensed CAR T cell therapy for DLBCL patients (Vienna General Hospital AKH and St Anna Children Hospital Vienna, Paracelsus Medical University Salzburg/ Salzburg Cancer Research Institute, Medical University Innsbruck, Medical University Graz, and Ordensklinikum Linz) and an additional one is planned in Lower Austria. Currently, five of nine Austrian federal provinces have a CAR T center [21], whereas the provinces Burgenland, Kärnten and Vorarlberg rely on cross-province referral of DLBCL patients for CAR T cell therapy. Besides routine treatment, the centers also carry out research of CAR T cell therapies, with more than eight separate studies active or in the recruitment process in Austria in 2021 [22][23][24][25][26][27][28][29]. The CAR T centers' strong participation in CAR T cell therapy studies has helped to build deep expertise for this novel therapy in Austria already from an early stage.
The CAR T centers cooperate within a national CAR T network that focuses on coordinating the implementation of CAR T cell therapy in Austria [30]. As part of this initiative, the members of the CAR T network specified quality requirements for CAR T centers, encompassing structural (e.g., hygiene, outpatient care), personnel as well as work-processesrelated aspects [31]. These are highly similar to the criteria defined by the Austrian Ministry of Health which together with the health platforms of the individual provinces is finally responsible for approving quality criteria for the remuneration of therapies. While the only listed contraindications in the summary of product characteristics (SmPC) for all approved CAR T therapies are hypersensitivity to the active substance or to any of the excipients or contraindications of the lymphodepleting chemotherapy [4,5,8], the CAR T network also introduced a national CAR T algorithm for assessing eligibility of DLBCL patients for licensed CAR T cell therapies (Table 1; [31]), with selection criteria closely matching the inclusion criteria used for the registrational clinical trials ZUMA-1 and JULIET [32,33]. However, this algorithm is a recommendation only and according to Austrian law treatment decisions are made independently by the responsible physicians at the treating centers.
The key steps along the treatment sequences of a DLBCL patient in Austria from diagnosis to eventual CAR T cell therapy may be as follows: in most patients with DLBCL with the exception of primary central nervous system (CNS) lymphoma and without contraindications and/or special molecular findings, diagnosis will be followed by a risk-adapted, anthracycline-based rituximab-containing chemoimmunotherapy in first line [38]. Due to the recent EMA approval of polatuzumab vedotin (Polivy) for treatment of newly diagnosed DLBCL patients on April 4, 2022 [39] based on the POLRAIX data [40], therapy in the frontline setting should be stratified based on age and/or the International Prognostic Index (IPI). Approximately 60% of patients will achieve a complete remission under R-CHOP; however, about 30% of patients relapse and 10% of patients are primary refractory to first-line therapy [41,42]. Relapsed/ refractory DLBCL patients are then usually treated with salvage therapy as well as subsequent autologous hematopoietic stem cell transplantation if possible [38]. However less than 40% of relapsed/refractory patients will proceed to stem cell transplantation due to lack of response to salvage chemotherapy [43].
Durable remissions with stem cell transplantation have been achieved in 31% of DLBCL patients in one series [44] and 2-year event-free survival was lower than 20% in another series [43] highlighting a significant unmet need for effective therapeutic options. Patients with DLBCL who relapsed or were refractory after the two lines of therapy would become eligible for a CAR T cell therapy based on the EMA-approved indications [4,5,8] and the Austrian CAR T algorithm criteria [31]. In light of promising clinical results [19,20] and the recent approval of a CAR T cell therapy in primary refractory and relapsed DLBCL patients by the FDA [7,9], it is expected CAR T cell therapies will soon also be approved by the EMA for use after first relapse and Austrian hemato-oncologists are already entitled by legislation for off-label use to apply CAR T cell therapy in this indication. The identification of DLBCL patients eligible for CAR T cell therapy should occur by the treating hemato-oncologist at an early stage due to an often very rapid progression of the disease. Confirmation of eligibility for CAR T cell therapy may happen directly within a CAR T cell center, particularly when these centers also regularly serve for first-line therapy for aggressive lymphomas or in a virtual regional tumor board in discussion with the referring hospital when treatment is more decentralized. The CAR T center then arranges the leukapheresis and the transfer of the patient's cells to the pharmaceutical manufacturer for CAR T cell production. In most cases, patients will receive an individualized bridging chemo-or radiotherapy to limit disease progression followed by a lymphodepleting conditioning therapy to support CAR T cell expansion [45,46]. Patients are closely monitored to manage potential adverse events for as long as necessary due to the individual course, with regular follow-up visits at the CAR T center required after discharge. However, outpatient strategies are also under investigation [47], which could reduce the requirement for a hospital stay by the patients after CAR T cell therapy.

Materials and methods
To analyze the CAR T cell therapy access situation in Austria and identify potential barriers for patients, a systematic analysis of the DLBCL patient numbers in 2021 along with the treatment sequence was conducted. The analysis covers a typical CAR T DLBCL patient treatment pathway in Austria, ranging from initial diagnosis to CAR T cell therapy. The critical parameters defining the treatment sequence include (i) DLBCL incidence, (ii) treatment success and numbers of patients requiring second-and third-line therapy, (iii) proportion of third-line DLBCL patients that are eligible for CAR T therapy based on the Austrian Algorithm criteria, (iv) numbers of third-line DLBCL CAR T eligible patients treated within clinical trials, and (v) numbers of third-line DLBCL CAR T eligible patients successfully infused with a licensed CAR T therapy in the routine setting.
Since at the time of writing both recent and specific public data on DLBCL incidence and treatment patterns were not available in Austria, published estimations from France [35] and Germany [34] were used to approximate the DLBCL incidence in Austria, as well as patient flow in first, second and third line. The proportion of CAR T eligible patients in Austria was estimated based on estimations for France [35], the Netherlands, Austria, Spain, and Italy [36,37] as well as recent real-world analyses [48][49][50][51]. Data on the use of CAR T cell therapies in Austria have been retrieved from recently published reports. In a recent manuscript by the European Society for Blood and Marrow Transplantation (EBMT), estimated data on CAR T use in 2019 in Austrian was presented [52] Unfortunately, this publication does not define how these data were obtained and controlled for correct coverage. Furthermore, since the approved products received an EC marketing authorization by mid-August 2018, it is very likely that the reported numbers in 2019 reflect patients treated in both clinical trials and in the routine setting, since a considerable number of Austrian DLBCL patients during this time were treated with CAR Ts in clinical trials [22][23][24]26]. In a recently published analysis performed by the Austrian CAR T Network, retrospective data on patients receiving CAR T therapy in the routine setting have been presented [53].
Details and results of the full analysis plan are available in Table 1.

Analysis of CAR T cell therapy access for Austrian DLBCL patients
Results of a detailed analysis on estimations of the treatment landscape for patients with DLBCL in Austria are presented in Table 1.
Our analysis estimates that in Austria approximately 556 are diagnosed with DLBCL every year, assuming an estimated incidence rate of approximately 6 in 100,000 persons based on the average DLBCL population incidence estimation for the USA [54], the UK [55], Germany [34], and France [35]. This is in line with data provided by Statistik Austria in 2020 [56], reporting 1438 cases of Non-Hodgkin lymphoma (NHL) and assuming a proportion of 36% DLBCL [54].
Around 16% (89 of 556) of DLBCL patients are estimated to be refractory or in relapse after 2 previous lines of therapy based on the estimations for Germany [34], France [35], and the USA [54], which would represent the EMA-approved DLBCL CAR T population of 89 patients per year in Austria [4,5]. When also applying eligibility criteria as used in the registrational trials and specified by the Austrian CAR T algorithm, approximately 10% (56 of 556) of all incident DLBCL patients are estimated to qualify for CAR T cell therapy per year based on the estimation for France [35], the Netherlands, Austria, Spain, Italy, and recent realworld data [36,37,48,50,51,57].
Initial data on the use of CAR T cell therapies in Austria as compared to other European countries were published by the EBMT for the year 2019 [52]. In this survey, Austria was characterized by a number of CAR T cell centers of > 3-4 per 10 million inhabitants, which was only higher in Switzerland and Belgium. In terms of number of patients treated, an estimate of > 30/10 million people was given for Austria. Based on this assessment and assuming a total population of 8,858,775 in Austria in 2019 (https://ec.europa.eu/ eurostat/data/database), a minimum of 27 patients in 2019 would have been treated with CAR T therapy. Since this report did not differentiate between the indication for treatment and discriminate between patients treated within clinical trials or the routine setting, numbers remain questionable and difficult to control for their origin and quality. In addition, these numbers may not be representative for the current situation in 2021 or reflect a realistic estimation of the number of patients treated with CAR T therapies in the approved setting.
Recently, data from a national CAR T registry provided by the Austrian CAR T Network on Austrian patients that have received CAR T therapy have been presented [53]. Between September 2019 and February 2022, 52 Austrian patients received CAR T therapy in the routine setting. Of these, 45 Austrian patients selected strictly based on the Austrian selection algorithm received commercially available CAR T therapy for DLBCL in the approved setting, while the rest received a commercial CAR T therapy for the treatment of ALL. While this entails that roughly 19 DLBCL patients per year have been treated with commercially available CAR Ts, a slight rise in deliveries per year over this timespan can be assumed based on recently presented real-world data from other European countries [58][59][60] Based on this data, 21% (19 of 89) of the estimated EMA approved population and 34% (19 of 56) of the estimated population considered eligible under the Austrian CAR T algorithm have received a commercial CAR T cell therapy. While it is difficult to estimate the number of DLBCL patients treated within clinical trials in 2021 in Austria, it is likely that some proportions of potentially eligible patients have not been considered for licensed CAR T cell therapies due to participation in a clinical CAR T trial since a number of studies in third-line DLBCL were actively recruiting in Austria at this timepoint [24,28,61]. Based on the recruitment of Austrian patients into the JULIET trial, the pivotal study of tisagenlecleucel in DLBCL [62], it can be assumed that at least 9% of CAR T eligible patients in Austria will have been enrolled into clinical CAR T trials in the 82  third-line setting. Furthermore, CAR T cell therapies are directly competing with bispecific antibodies used in clinical trials which seem more rapidly accessible even in their earliest clinical trial phases and may also cause slower implementation of CAR T cell therapies in Austria. Bispecific antibodies share at least partly the mechanisms of action and some toxicity aspects of CAR T cell therapies, like cytokine release syndrome (CRS), neurotoxicity, and increased rates of severe infection, but are more readily accessible due to the absence of a long manufacturing process unlike CAR T cell therapies [63]. Interestingly, these results are similar to the finding of a recent Italian analysis, reporting that from a population of 638 potentially eligible patients, only 110 patients (17%) finally received CAR T therapy [64]. However, it highlights the existence of a clear data gap that needs to be addressed by further research (Fig. 1). Assuming a 35-40% 5 year progression-free survival with CAR T cell therapies, Lin et al. [65] previously estimated that in relapsed/refractory DLBCL patients 6.4 (4.6-8.2) life years can be saved when treated with CAR T cell therapies as compared to other types of therapy [65]. Our analysis indicates that in 2020 and 2021 79% (N = 70) of DLBCL patients of the EMAapproved population and 66% (N = 37) of patients of the population considered eligible under the Austrian CAR T algorithm have not been treated with a licensed CAR T cell therapy. If at least 9% of Austrian DLBCL patients have been treated within a clinical CAR T trial in the third-line setting, 57% (N = 32) of eligible patients have not been treated with CAR T therapy.
Based on the calculations of Lin et al. [65], this would correspond to 429 and 218 life years lost in 2021, respectively, due to limited access to CAR T cell therapies for DLBCL patients.
While further data are required for a complete diagnosis of the CAR T cell therapy access situation in Austria, this analysis supports identification of existing barriers that limit patient access to licensed CAR T cell therapies. It should be however noted that the analysis presented here and the identified access barriers represent an aggregated view. Potential differences in CAR T cell therapy access may exist between the different Austrian provinces.

Barriers for CAR T cell therapy access in Austria
Building on this analysis, first-hand expertise, and personal communication with experts, we have identified several significant barriers for DLBCL patient to access licensed CAR T cell therapies in Austria. We propose that significant access barriers are linked to restrictive patient selection, suboptimal patient identification and referral, as well as a difficult local approval process for CAR T cell therapy in Austria due to a complex center financing process.
Restrictive patient selection for CAR T cell therapy Based on our analysis, only 21% of the EMA-approved DLBCL population or 34% of the DLBCL patient population estimated to be eligible under the Austrian CAR T algorithm eventually receive licensed CAR T cell therapy. This probably reflects a particular cau- Table 2 Comparison of patient eligibility criteria for CAR T therapy based on the Austrian CAR T Algorithm [31], the ZUMA-1 study [32], the JULIET study [33], and the best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Hematology Association (EHA) [45] CAR T Network [31] ZUMA-1 [32] JULIET [33] EHA/EBMT/JACIE [45] ECOG PS 0-1 0-1 0-1 0-1 a The "major" and "minor" criteria as defined by the AT Selection Algorithm reflect patient characteristics that are very strongly or recommended (major criteria) or should be discussed thoroughly (minor) criteria prior to CAR T therapy ECOG PS Eastern Co-operative Oncology Group Performance Status; MRI magnetic resonance imaging; EF ejection fraction; ECHO echocardiography; SpO2 blood oxygen saturation level; ANC absolute neutrophil count; ALC absolute leukocyte count; ALT alanine aminotransferase; AST aspartate aminotransferase; ULN upper limit of normal; eGFR estimated glomerular filtration rate; CrCl creatinine clearance a Karnofsky index >60% or Lansky index >60% b Simple urinary tract infections, bacterial pharyngitis allowed or currently receiving IV antibiotics or have received IV antibiotics within 7 days prior to enrollment c Blood culture positive ≤ 72 h prior to infusion d Prophylaxis antibiotics, antivirals, and antifungals permitted e Such as seizure disorder, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, or any autoimmune disease with CNS involvement f Guillain-Barre syndrome or amyotrophic lateral sclerosis g Relative contraindication h confirmed by echocardiogram or multigated acquisition scan i Hemoglobin > 8.0 g/dL suggested but not inclusion/exclusion criterion tiousness and overestimation of the published side effects of CAR T cell therapy in Austria, which might have also contributed to the recommendation of a very stringent patient selection approach in the Austrian CAR T algorithm, which currently limits access for patients of the EMA-approved population that could potentially benefit from CAR T cell therapy. This may be exemplified by the slow adaptation of the CAR T algorithm towards relapsed/refractory DLBCL patients suffering from CNS involvement who are without other treatment options and may be safely treated [66][67][68]. The US CAR T consortium reported that CAR T cell therapy in lymphoma patients with secondary CNS involvement resulted in similar response rates, progression-free survival (PFS) and toxicity when compared with patients with systemic disease only [69]. Early data from the United States by the US CAR T consortium reported real-world evidence for 298 CAR T cell treated lymphoma patients of which 43% would have failed the ZUMA-1 CAR T cell therapy registrational trial criteria, including patients up to 83 years, with ECOG score 2-4, disease stages III-IV, IPI scores of 3-5 and doubleor triple-hit lymphoma [70]. Despite worse baseline characteristics, both toxicities and response rates in this patient group were like the ZUMA-1 registrational trial whose more strict inclusion criteria have influenced the Austrian CAR T Algorithm. These initial observations have since been confirmed by a larger postauthorization safety study (PASS) conducted by the Center for International Blood and Marrow Transplant Research (CIBMTR) enrolling 1500 US patients treated with axicabtagene-ciloleucel in the approved setting. While 682 patients (51%) enrolled and treated in the PASS had ECOG ≥ 2, and/or comorbidities, and/or CNS lymphoma/CNS metastasis that would 84 CAR T therapy access in Austria K position paper have made them otherwise ineligible for ZUMA-1 trial, efficacy and safety of CAR T therapy was comparable to results obtained in the pivotal trials [71]. More recently, similar data have also been presented by the French Lymphoma Academic Research Organization (LYSARC) in by their DESCAR T registry, highlighting that the same clinical outcomes can be obtained in a European setting [72]. Some of the major (e.g., cardiac or lung function) and minor (e.g., renal or liver) exclusion criteria proposed by the CAR T Algorithm address organ dysfunction and are derived from the exclusion/inclusion criteria of the early pivotal trials and are more stringent then the best practice recommendations of the European Society for Blood and Marrow Transplantation (EBMT) and the Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Hematology Association (EHA) ( [45]; Table 2). The previously mentioned PASS conducted by the CIBMTR evaluated the efficacy and safety of CAR T therapy in DLBCL patients with advanced age and specific organ dysfunction. While, as can be expected, long-term outcomes were more unfavorable for patients with ECOG ≥ 2 at infusion or severe hepatic, renal and cardiac disease, the rates of high-grade CRS or ICANS was only higher in patients exhibiting an ECOG ≥ 2 at infusion or severe hepatic dysfunction [73]. Similarly, organ dysfunctions seen as contraindications for CAR T cell therapy may result from the malignant disease state and may improve under bridging therapy in preparation for CAR T cell therapy. Patients with relapsed/ refractory DLBCL are often in a desperate situation and without further options. Expansion of treatment indications over the limits of the clinical trial inclusion criteria to a thoughtful application in real-world situations should be possible by experienced CAR T teams in the same manner as in other cancers.
Suboptimal patient identification and referral for CAR T cell therapy Centralization of DLBCL diagnosis and treatment differs significantly in Austrian provinces. For instance, in Salzburg with a very high centralization, most patients will receive continuous care with low hurdles to access CAR T cell therapy. In other provinces with less centralized diagnostic and therapeutic pathways, and particularly in those provinces without a CAR T center, the CAR T cell therapy process might be more cumbersome and critically depend on timely identification and referral of the patients. Particularly the absence of local regular lymphoma tumor boards can impede identification and selection of DLBCL patients for CAR T cell therapy.
Experience in some centers suggests that several DLBCL patients may be referred only late to CAR T centers, with multiple lines of prior therapies, which potentially limits their eligibility for licensed CAR T cell therapies and hampers their clinical outcomes. Late referral may cause a selection of patients with high tumor volume, massive cell turnover as indicated by elevated lactate dehydrogenase (LDH) levels and increased inflammation as indicated by high ferritin and CRP concentrations and a high ECOG score, all of them implicated in severe complications [48,[74][75][76][77]. In accordance with this, the CAR T Network has emphasized the need for assessing and considering individuals with high-risk DLBCL as potential candidates for CAR T cell therapy already at an early stage [30]. While the exact proportion of patients that will not receive CAR T therapy due to late referral and thus potentially deteriorating status in Austria is unknown, recent real-world data from the UK, where a centralized CAR T approval and national service for delivering CAR T therapy is likely to delay patient access, indicates that up to 31% of initially submitted patients might not receive therapy [58]. According to this consolidated UK report, progressive disease or death due to progressive disease between initial submission and infusion was the reason in 53% of patients why CAR T therapy could not be administered, highlighting the need for proper and timely referral.
Overestimation of the aggressiveness of the therapy and its side effects may also have caused reluctance for referral to CAR T cell therapy. This is supported by the fact that at least in Salzburg the follow-up time of CAR T cell therapy patients within the hospital has significantly decreased from the initial 2 weeks, and in the USA even outpatient CAR T cell therapy seems safe [47]. In fact, up to 65% of patients were treated in the outpatient setting in different CAR T cell therapy clinical trials (9% in TRANSCEND, 41% in PILOT, 65% in OUTREACH [78]) and in the routine setting by instituting a multidisciplinary team to develop an outpatient cellular therapy model [79,80]. In addition, 46% of patients treated with lisocabtagene maraleucel did not require any hospitalization and only 3% were ultimately admitted to the ICU, although these very favorable results may have been caused by a selection of patients with low tumor mass [47]. In addition, feasibility and safety of outpatient treatment may be significantly improved by digital health tools also investigated for CAR T cell therapies [81,82]. While these data should not call for an uncritical approach of applying CAR T cell therapy, they point to a very steep learning curve once CAR T cell therapy is adopted and mandate for the early introduction of new technologies by clinical trials to build expertise and confidence of all physicians involved as well as of referring hospitals.
Limitations of current center financing for CAR T cell therapy Provision of an expensive and complex treatment such as CAR T cell therapy requires adequate financial reimbursement for all patients treated. However, the Austrian funding system does not fully compensate costs of hospital treatment provided and places substantial economic and political pressure on K CAR T therapy access in Austria 85 position paper CAR T centers for accepting patients from outside their own provinces. At present, CAR T cell therapy is funded through an activity-based hospital financing mechanism "Leistungsorientierte Krankenanstaltenfinanzierung" (LKF) [83]. The LKF mechanism uses nationally standardized point scores to account for procedures provided in Austrian hospitals [84]. However, as the actual funding value given per LKF point can vary across provinces, LKF funding for CAR T cell therapy differs between CAR T centers and might not be sufficient to cover all costs associated with a single CAR T cell therapy in the center. Furthermore, as there is not a mechanism established for cost-transfer across provinces, the CAR T center will have to cover costs of CAR T cell therapy also for patients from other provinces, which can create additional financial burden for the treating center and its province.

Recommended health system solutions for CAR T cell therapy access barriers
Based on the above identified barriers, we propose the following health system focus areas and solutions to improve patient access to CAR T cell therapies in Austria. These solutions would need to be developed further in collaboration by key health system stakeholders (patients, hemato-oncologists, CAR T specialists, health authorities, and pharmaceutical manufacturers) and hold the potential to improve patient access not only for CAR T cell therapies but for cell and gene therapies in general.
Ensuring correct and timely patient identification and referral CAR T cell therapy registry for monitoring patient flow There is a clear need to increase the understanding of CAR T cell therapy access and the key barriers along the treatment sequences of a DLBCL patient. Systematic monitoring and analysis of the patient flow and the underlying causes could be facilitated through use of regular center surveys, regional cancer registries, or the creation of a national CAR T cell therapy registry. Importantly, such a national systematic registry, as proposed and planned by the CAR T Network recently [85], would support targeting improvement efforts as well as allow tracking of improvement in patient access over time.
CAR T cell therapy education and increased patient engagement Improvement in knowledge dissemination is sought by the CAR T Network via education seminars for physicians and patients. Education could be also delivered in the form of roadshow lectures held by experienced CAR T physicians at less established centers and trainings or preceptorships for referring physicians could be offered directly in CAR T centers. CAR T cell therapy knowledge could be further increased through regular updates ("news alerts") on CAR T eligibility criteria to the broader hemato-oncol-ogist team in referring centers to ensure up-to-date knowledge for CAR T eligibility decision-making. In addition to education for physicians, awareness and education about CAR T cell therapy should also be increased among patients and their relatives through patient associations. "Information milestones" along a typical treatment sequence of a DLBCL patient could be defined, specifying when physicians must inform their patients about available therapy options to enable shared decision-making by patients and their physicians. Clearly, clinical trials can facilitate building experience and familiarity of the clinical community with a new therapy. It is therefore also important that health system stakeholders and pharmaceutical manufacturers contribute to creating an environment where there is an optimal balance between patient access to clinical trials and licensed therapies.

Improved communication between centers and increased role of referring physicians
To optimize the referral process for CAR T cell therapies, communication between referring and CAR T centers should be strengthened. Particularly in provinces with lower degrees of centralization, information dissemination from CAR T centers to referral hospitals should be intensified. The knowledge exchange and communication between the centers could be, for instance, facilitated through virtual webinars [86], or through the introduction of a CAR T center hotline to discuss questions about potential candidates or CAR T treatment aspects already at first diagnosis. Moreover, the establishment and the increased frequency of regular provincial tumor board for CAR T cell therapies could foster the collaboration between the centers and support referring physicians in the eligibility decision-making process. Furthermore, increased involvement of referring physicians in the CAR T cell therapy pathway, with specified responsibilities along the treatment pathway, could help improve the coordination between the referring and CAR T centers. Referral standards or guidelines (e.g., defining time to referral) could also help optimize and harmonize the process. The introduction of referral standards could however also be seen as having a potential impact on the therapeutic freedom of referring physicians [87]. Moreover, in accordance with the CAR T Network's efforts regarding high-risk DLBCL patients [30], we would also recommend instituting early assessment of DLBCL patients with a high-risk status (e.g., as per their response to first-line chemoimmunotherapy) and immediate referral to CAR T centers through "fast track" cooperation, as these patients may likely progress quickly and eventually require urgent access to a bridging and CAR T cell therapy in third line. 86 CAR T therapy access in Austria K position paper Ensuring a sustainable funding situation for qualified CAR T centers National funding for innovative therapies To ensure equal and sustainable patient access to CAR T cell therapy in all Austrian provinces and address the current LKF funding limitations, a solution could be the establishment of a central Austrian fund for innovative, high-cost therapies such as CAR T cell therapy. Other European countries have already created dedicated national funds for innovative oncology therapies, such as the Cancer Drug Fund in England or the Fondo Farmaci Innovativi Oncologici in Italy [88,89]. The need to allocate funds for cross-provincial healthcare activities has also already been acknowledged by the Austrian government [90]. The upcoming financial reform (fiscal equalization "Finanzausgleich") of 2023 could be the right legislative frame for developing such a solution. Such a novel financing mechanism needs to ensure that sufficient financial, structural and personnel resources at the qualified CAR T centers for the management of current and future CAR T treatments would also need to be ensured.

Hospital access and funding decisions through an independent national supervisory board
In any case, approval of the financing of innovative high-priced therapies by Art. 32, fund administrators must be based on medical expertise. Medical freedom of therapy must not be restricted under any circumstances. The approval of the commission/board for funding must in any case consider the Health Technology Assessment (HTA) rules of the European Union in the coming years. This would allow for improved transparency and standardization in the assessment of such new therapies [91]. The national drug evaluation commission ("Heilmittel-Evaluierungs-Kommission", HEK) for social insurances may potentially serve as a template for such a hospital supervisory board. Importantly, the national supervisory board should be only composed of medical experts and should be obliged to take decisions exclusively based on medical evidence, and independently of other considerations.
Physicians must not be exposed to any economic pressure in their decision-making.
Monitoring systems (e.g. registries) and appropriate national whistle-blowing regulations (to protect the interests of patients) must be established to ensure the de facto freedom of medical therapy.
Ensuring stakeholder rights for transparency of information and involvement Finally, we want to emphasize the general need to create a CAR T cell therapy access environment in which all stakeholders, including patients and their caretakers, are informed and involved. Clarity and transparency on the decisions taken and the decision-making process as well as stakeholders' rights to be informed and contribute to the decision-mak-ing need to be ensured. The legal framework should thus provide clear and understandable legal entitlements (for patients, physicians, industry). In particular patients need to be comprehensively informed in a timely manner about appropriate state-of-the-art treatment options and centers of excellence.
Since many cancer patients have little time for court proceedings to enforce treatment options, legal tools for enforcement must be available very quickly. These legal tools must also be available to patients without any financial risk.

Conclusion
The Austrian health care system generally provides good access to quality care. In 2019, only 0.3% of the population reported unmet medical care needs due to cost, distance to travel, or waiting time (top 6 within EU-27 countries) and 5-year net survival rates for cancers such as lung, colon and breast were higher than the EU-23 average [92]. This report however highlights that for DLBCL patients, various health system barriers in Austria currently limit their access to CAR T cell therapies, particularly barriers related to patient identification, referral, and center financing. Future CAR T cell therapies and other cell and gene therapy products are likely to further increase today's access barriers and pressure on the CAR T centers and the overall health system. Pending EMA regulatory approval of CAR T therapies for use in patients failing first-line therapy, up to 172 DLBCL patients after frontline failure could theoretically become eligible for CAR T cell therapies every year in Austria based on this analysis. While, according to a recent estimation, less than 15% of DLBCL patients after first relapse will meet all second-line CAR T study inclusion criteria, up to 65% of patients progressing within 12 months of frontline therapy failure could be considered potentially eligible for second-line CAR T cell therapy based on adequate performance and organ status [93]. To ensure health system readiness also for future patients, it is important that stakeholders take actions now and collaboratively work towards an equal and sustainable CAR T patient access environment in Austria.