Discrete Event Simulation to Incorporate Infusion Wait-Time When Assessing Cost-Effectiveness of a Chimeric-Antigen Receptor T Cell Therapy.

OBJECTIVES: The main objective was to use discrete event simulation to model the impact of wait-time, defined as the time between leukapheresis and chimeric antigen receptor (CAR-T) infusion, when assessing the cost-effectiveness of tisagenlecleucel in young patients with relapsed/refractory acute lymphoblastic leukemia. METHODS: The movement of patients through the model was determined by parametric time-to-event distributions, with the competing risk of an event determining the costs and quality-adjusted life-years (QALYs) assigned. Cost-effectiveness was expressed using the incremental cost-effectiveness ratio (ICER) for tisagenlecleucel compared with chemotherapy over the lifetime. RESULTS: The base case generated a total of 5.79 QALYs and $622 872 for tisagenlecleucel and 1.19 QALYs and $181 219 for blinatumomab, resulting in an ICER of $96 074 per QALY. An increase in mean CAR-T wait-time to 6.20 months reduced the benefit and costs of tisagenlecleucel to 2.78 QALYs and $294 478 because of fewer patients proceeding to infusion, reducing the ICER to $71 112 per QALY. Alternatively, when the cost of tisagenlecleucel was assigned pre-infusion in sensitivity analysis, the ICER increased with increasing wait-time. CONCLUSIONS: Under a payment arrangement where CAR-T cost is incurred post-infusion, the loss of benefit to patients is not reflected in the ICER. This may be misguiding to decision makers, where cost-effectiveness ratios are used to guide resource allocation. discrete event simulation is an important tool for economic modeling of CAR-T as it is amenable to capturing the impact of wait-time, facilitating better understanding of factors affecting service delivery and consequently informed decision making to deliver faster access to CAR-T for patients.

Norwegian health service should offer stem cell therapy for multiple sclerosis. / Norsk helsevesen bør tilby stamcellebehandling mot multippel sklerose.

Many Norwegian patients with multiple sclerosis choose to travel abroad for stem cell therapy at their own expense and risk. Based on the current knowledge base, selected patients should now be offered this therapy in Norway.

Remuneration of donors for cell and gene therapies: an update on the principles and perspective of the World Marrow Donor Association.

The cell and gene therapy (CGT) sector has witnessed significant advancement over the past decade, the inception of advanced therapy medicinal products (ATMPs) being one of the most transformational. ATMPs treat serious medical conditions, in some cases providing curative therapy for seriously ill patients. There is interest in pivoting the ATMP development from autologous based treatments to allogenic, to offer faster and greater patient access that should ultimately reduce treatment costs. Consequently, starting material from allogenic donors is required, igniting ethical issues associated with financial gains and donor remuneration within CGT. The World Marrow Donor Association (WMDA) established the Cellular Therapy Committee to identify the role WMDA can play in safeguarding donors and patients in the CGT field. Here we review key ethical principles in relation to donating cellular material for the CGT field. We present the updated statement from WMDA on donor remuneration, which supports non-remuneration as the best way to ensure the safety and well-being of donors and patients alike. This is in line with the fundamental objective of the WMDA to maintain the health and safety of volunteer donors while ensuring high-quality stem cell products are available for all patients. We acknowledge that the CGT field is evolving at a rapid pace and there will be a need to review this position as new practices and applications come to pass.

2023 White Paper on Recent Issues in Bioanalysis: ISR for ADA Assays, the Rise of dPCR vs qPCR, International Reference Standards for Vaccine Assays, Anti-AAV TAb Post-Dose Assessment, NanoString Validation, ELISpot as Gold Standard (Part 3 - Recommendations on Gene Therapy, Cell Therapy, Vaccines Immunogenicity & Technologies; Biotherapeutics Immunogenicity & Risk Assessment; ADA/NAb Assay/Reporting Harmonization).

The 17th Workshop on Recent Issues in Bioanalysis (17th WRIB) took place in Orlando, FL, USA on June 19-23, 2023. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 17th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week to allow an exhaustive and thorough coverage of all major issues in bioanalysis of biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on "EU IVDR 2017/746 Implementation and impact for the Global Biomarker Community: How to Comply with these NEW Regulations" and on "US FDA/OSIS Remote Regulatory Assessments (RRAs)" were the special features of the 17th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2023 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2023 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity. Part 1A (Mass Spectrometry Assays and Regulated Bioanalysis/BMV), P1B (Regulatory Inputs) and Part 2 (Biomarkers, IVD/CDx, LBA and Cell-Based Assays) are published in volume 16 of Bioanalysis, issues 8 and 9 (2024), respectively.

Emerging Biomarkers for Monitoring Chimeric Antigen Receptor T-Cell Therapy.

BACKGROUND: Chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment of hematologic malignancies and holds promise for solid tumors. While responses to CAR T-cell therapy have surpassed other available options for patients with refractory malignancies, not all patients respond the same way. The reason for this variability is not currently understood. Therefore, there is a strong need to identify characteristics of patients as well as cellular products that lead to an effective response to CAR T-cell therapy. CONTENT: In this review, we discuss potential biomarkers that may predict clinical outcomes of CAR T-cell therapy. Based on correlative findings from clinical trials of both commercially available and early-phase products, we classify biomarkers into categories of pre- and post-infusion as well as patient and product-related markers. Among the biomarkers that have been explored, measures of disease burden both pre- and post-infusion, as well as CAR T-cell persistence post-infusion, are repeatedly identified as predictors of disease response. Higher proportions of early memory T cells at infusion appear to be favorable, and tracking T-cell subsets throughout treatment will likely be critical. SUMMARY: There are a growing number of promising biomarkers of CAR T-cell efficacy described in the research setting, however, none of these have been validated for clinical use. Some potentially important predictors of response may be difficult to obtain routinely under the current CAR T-cell therapy workflow. A collaborative approach is needed to select biomarkers that can be validated in large cohorts and incorporated into clinical practice.

Experiences and perspectives on chimeric antigen receptor (CAR) T-cell therapy among recipients, carers and referrers (RE-TELL): a qualitative study to inform CAR T-cell service design.

OBJECTIVES: RE-TELL is a qualitative study, which aims to understand patient, support person, clinician and coordinator experiences and perspectives of chimeric antigen receptor (CAR) T-cell therapy, to inform design of a clinical CAR T-cell service in Aotearoa New Zealand. DESIGN: Semistructured qualitative interviews focused on domains of: experience through treatment, elements that work well and those that could be improved on. Interviews used thematic analysis to identify key themes. A workshop was held to obtain participants' reflections on interim analysis and proposed improvements. PARTICIPANTS: New Zealanders with experience of CAR T-cell therapy, including recipients, support persons, clinicians and coordinators. RESULTS: We interviewed 19 participants comprising 5 CAR T-cell recipients, 3 support persons, 6 clinicians and 5 coordinators. Four participants identified as Maori. Thematic analysis identified three global themes. The first, 'sociocultural factors impact CAR T access', identified potential sources of inequity including geographic, financial and informed consent barriers. The second, 'varying emotions, roles and enablers', identified an easier treatment experience compared with alternatives; an underwhelming cell administration process; frustration with inpatient monitoring; burden on support persons and importance of 'bridge' organisations such as charities and patient support groups. Lastly, 'golden opportunities: reimagining CAR T service delivery', suggested: improved geographical access to CAR T-cell therapy, while retaining consolidated clinician experience; a 'dashboard' with information on CAR T-cell treatment, time frames and manufacture; a health navigator to co-ordinate non-medical aspects of treatment and signpost care; embedding of indigenous data sovereignty and ownership of cells; a cell infusion ceremony, incorporating family involvement and Maori cultural elements and outpatient administration and monitoring where possible. CONCLUSION: This study documented the current experience of New Zealanders receiving CAR T-cell therapy and identified opportunities for future service development. These insights are relevant to service design within Aotearoa New Zealand, and other countries developing equitable CAR T-cell services.

Healthcare cost and utilization for chimeric antigen receptor (CAR) T-cell therapy in the treatment of pediatric acute lymphoblastic leukemia: A commercial insurance claims database analysis.

BACKGROUND: B-lineage acute lymphoblastic leukemia (B-ALL) is the most common malignancy of childhood. With the introduction of novel cellular therapies, cost of care is a critical component and the financial burden experienced by patients and society requires evaluation. AIMS: This study aims to assess the utilization and cost of care for chimeric antigen receptor T-cell (CAR-T) therapy for pediatric ALL patients with commercial insurance coverage in the United States. METHODS AND RESULTS: Using de-identified commercial insurance data from the OptumLabs® Data Warehouse, a cohort of 37 patients, aged 1-25 years, with B-ALL treated with CAR-T therapy between Oct 2016 and Dec 2021 in the United States was identified. Cost was evaluated for a 90 day period encompassing CAR-T infusion and by administration and complication characteristics. Among the 37 identified B-ALL patients that received a CAR-T product infusion, 14 patients were female, median age at administration was 13 years. The median 90-day total cost was $620,500 (Mean: $589,108). Inpatient cost accounted for approximately 71% of the total cost with an average of 28 inpatient days per patient. Although inpatient cost was slightly higher in the older age group (aged 10-25 years) and in patients with a code for cytokine release syndrome (CRS), these differences were not statistically significant. CONCLUSION: This real-world cost analysis shows for the first time the encompassing cost of CAR-T therapy for pediatric B-ALL patients in the US with commercial insurance. This study provides a valuable benchmark that can be used to analyze the financial implications of CAR-T therapy for pediatric B-ALL therapy on health systems.

Access to CAR T-cell therapy: Focus on diversity, equity and inclusion.

Chimeric antigen receptor T-cell (CAR T-cell) therapy has revolutionized the treatment of hematologic malignancies in patients with relapsed or refractory disease without other treatment options. However, only a very small proportion of patients with an indication for CAR T-cell can access the treatment. The imbalance between supply and demand is magnified in minority and vulnerable populations. Limited access is multifactorial and in part a result of factors directly related to the cellular product such as cost, complex logistics and manufacturing limitations. On the other hand, the impact of diversity, equity, and inclusion (DEI) and their social and structural context are also key to understanding access barriers in cellular therapy and health care in general. CAR T-cell therapy provides us with a new opportunity to better understand and prioritize this gap, a key step towards proactively and strategically addressing access. The aim of this review is to provide an analysis of the current state of access to CAR T therapy with a focus on the influence of DEI. We will cover aspects related to the cellular product and the inseparable context of social and structural determinants. Identifying and addressing barriers is necessary to ensure equitable access to this and all future novel therapies.

Cost-Effectiveness of Anti-BCMA Chimeric Antigen Receptor T Cell Therapy in Relapsed/Refractory Multiple Myeloma.

Despite its promising outcomes, anti-BCMA chimeric antigen receptor T cell therapy (CAR-T) is the most expensive myeloma treatment developed to date, and its cost-effectiveness is an important issue. This study aimed to assess the cost-effectiveness of anti-BCMA CAR-T compared to standard antimyeloma therapy in patients with relapsed/refractory multiple myeloma. The model included myeloma patients in Japan and the United States who have received ≥3 prior lines of antimyeloma therapy, including immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. A Markov model was constructed to compare the CAR-T strategy, in which patients receive either idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) followed by 3 lines of multiagent chemotherapy after relapse, and the no CAR-T strategy, in which patients receive only chemotherapy. Data from the LocoMMotion, KarMMa, and CARTITUDE-1 trials were extracted. Several assumptions were made regarding long-term progression-free survival (PFS) with CAR-T. Extensive scenario analyses were made regarding regimens for no CAR-T strategies. The outcome was an incremental cost-effectiveness ratio (ICER) with willingness-to-pay thresholds of ¥7,500,000 in Japan and $150,000 in the United States. When a 5-year PFS of 40% with cilta-cel was assumed, the ICER of the CAR-T strategy versus the no CAR-T strategy was ¥7,603,823 per QALY in Japan and $112,191 per QALY in the United States over a 10-year time horizon. When a 5-year PFS of 15% with ide-cel was assumed, the ICER was ¥20,388,711 per QALY in Japan and $261,678 per QALY in the United States over a 10-year time horizon. The results were highly dependent on the PFS assumption with CAR-T and were robust to changes in most other parameters and scenarios. Although anti-BCMA CAR-T can be cost-effective even under current pricing, a high long-term PFS is necessary.

Histological Assessment of Synovial Sarcoma Before and After TCR-T Cell Therapy and Cryoablation: A Case Report.

BACKGROUND/AIM: Cancer/testis antigens (CTAs) are well-known molecular targets with expression restricted to testicular germ cells and malignant tumors. T-cell receptor (TCR)-engineered T-cell (TCR-T) therapy against CTAs in patients with sarcoma has shown substantial progress, but resistance to TCR-T therapy remains a critical problem. In this report, we present a case of synovial sarcoma treated with TCR-T therapy targeting the New York-esophageal squamous cell carcinoma (NY-ESO)-1 protein. Histological findings were compared before and after TCR-T therapy and before and immediately after cryoablation. CASE REPORT: A 68-year-old man received additional wide resection for synovial sarcoma in the left leg. Due to multiple metastases, he was enrolled in a clinical trial of TCR-T therapy for NY-ESO-1. The tumor demonstrated a 34.9% reduction in diameter. However, disease progression occurred by day 84 after TCR-T therapy. Six months after disease progression, cryoablation was performed for right posterior rib lesion and tumor specimens were obtained by needle biopsy both before and immediately after cryoablation. Ten months after the diagnosis of disease progression, the patient died. Expression levels of NY-ESO-1, human leukocyte antigen, and immune checkpoint proteins remained unchanged before and after TCR-T therapy. Beta catenin was up-regulated in recurrent tumor tissues after TCR-T therapy compared to levels observed before TCR-T therapy. Immediately after cryoablation, immunoreactivity for NY-ESO-1 showed a slightly reduction. CONCLUSION: Up-regulation of beta-catenin in synovial sarcoma with recurrence after TCR-T therapy may be involved in T-cell exclusion and resistance to TCR-T therapy. Needle biopsy after cryoablation can be performed with sufficient pathological diagnostic accuracy including immunostaining.

Assessment of Motor Unit Potentials Duration as the Biomarker of DT-DEC01 Cell Therapy Efficacy in Duchenne Muscular Dystrophy Patients up to 12 Months After Systemic-Intraosseous Administration.

Duchenne muscular dystrophy (DMD) is a lethal X-linked disease caused by mutations in the dystrophin gene, leading to muscle degeneration and wasting. Electromyography (EMG) is an objective electrophysiological biomarker of muscle fiber function in muscular dystrophies. A novel, DT-DEC01 therapy, consisting of Dystrophin Expressing Chimeric (DEC) cells created by fusing allogeneic myoblasts from normal donors with autologous myoblasts from DMD-affected patients, was assessed for safety and preliminary efficacy in boys of age 6-15 years old (n = 3). Assessments included EMG testing of selected muscles of upper (deltoideus, biceps brachii) and lower (rectus femoris and gastrocnemius) extremities at the screening visit and at 3, 6, and 12 months following systemic-intraosseous administration of a single low dose of DT-DEC01 therapy (Bioethics Committee approval no. 46/2019). No immunosuppression was administered. Safety of DT-DEC01 was confirmed by the lack of therapy-related Adverse Events or Serious Adverse Events up to 22 months following DT-DEC01 administration. EMG of selected muscles of both, ambulatory and non-ambulatory patients confirmed preliminary efficacy of DT-DEC01 therapy by an increase in motor unit potentials (MUP) duration, amplitudes, and polyphasic MUPs at 12 months. This study confirmed EMG as a reliable and objective biomarker of functional assessment in DMD patients after intraosseous administration of the novel DT-DEC01 therapy.

The future of affordable cancer immunotherapy.

The treatment of cancer was revolutionized within the last two decades by utilizing the mechanism of the immune system against malignant tissue in so-called cancer immunotherapy. Two main developments boosted cancer immunotherapy: 1) the use of checkpoint inhibitors, which are characterized by a relatively high response rate mainly in solid tumors; however, at the cost of serious side effects, and 2) the use of chimeric antigen receptor (CAR)-T cells, which were shown to be very efficient in the treatment of hematologic malignancies, but failed to show high clinical effectiveness in solid tumors until now. In addition, active immunization against individual tumors is emerging, and the first products have reached clinical approval. These new treatment options are very cost-intensive and are not financially compensated by health insurance in many countries. Hence, strategies must be developed to make cancer immunotherapy affordable and to improve the cost-benefit ratio. In this review, we discuss the following strategies: 1) to leverage the antigenicity of "cold tumors" with affordable reagents, 2) to use microbiome-based products as markers or therapeutics, 3) to apply measures that make adoptive cell therapy (ACT) cheaper, e.g., the use of off-the-shelf products, 4) to use immunotherapies that offer cheaper platforms, such as RNA- or peptide-based vaccines and vaccines that use shared or common antigens instead of highly personal antigens, 5) to use a small set of predictive biomarkers instead of the "sequence everything" approach, and 6) to explore affordable immunohistochemistry markers that may direct individual therapies.

2022 White Paper on Recent Issues in Bioanalysis: FDA Draft Guidance on Immunogenicity Information in Prescription Drug Labeling, LNP & Viral Vectors Therapeutics/Vaccines Immunogenicity, Prolongation Effect, ADA Affinity, Risk-based Approaches, NGS, qPCR, ddPCR Assays (Part 3 - Recommendations on Gene Therapy, Cell Therapy, Vaccines Immunogenicity & Technologies; Immunogenicity & Risk Assessment of Biotherapeutics and Novel Modalities; NAb Assays Integrated Approach).

The 2022 16th Workshop on Recent Issues in Bioanalysis (WRIB) took place in Atlanta, GA, USA on September 26-30, 2022. Over 1000 professionals representing pharma/biotech companies, CROs, and multiple regulatory agencies convened to actively discuss the most current topics of interest in bioanalysis. The 16th WRIB included 3 Main Workshops and 7 Specialized Workshops that together spanned 1 week in order to allow exhaustive and thorough coverage of all major issues in bioanalysis, biomarkers, immunogenicity, gene therapy, cell therapy and vaccines. Moreover, in-depth workshops on ICH M10 BMV final guideline (focused on this guideline training, interpretation, adoption and transition); mass spectrometry innovation (focused on novel technologies, novel modalities, and novel challenges); and flow cytometry bioanalysis (rising of the 3rd most common/important technology in bioanalytical labs) were the special features of the 16th edition. As in previous years, WRIB continued to gather a wide diversity of international, industry opinion leaders and regulatory authority experts working on both small and large molecules as well as gene, cell therapies and vaccines to facilitate sharing and discussions focused on improving quality, increasing regulatory compliance, and achieving scientific excellence on bioanalytical issues. This 2022 White Paper encompasses recommendations emerging from the extensive discussions held during the workshop and is aimed to provide the bioanalytical community with key information and practical solutions on topics and issues addressed, in an effort to enable advances in scientific excellence, improved quality and better regulatory compliance. Due to its length, the 2022 edition of this comprehensive White Paper has been divided into three parts for editorial reasons. This publication (Part 3) covers the recommendations on Gene Therapy, Cell therapy, Vaccines and Biotherapeutics Immunogenicity. Part 1 (Mass Spectrometry and ICH M10) and Part 2 (LBA, Biomarkers/CDx and Cytometry) are published in volume 15 of Bioanalysis, issues 16 and 15 (2023), respectively.

The Regulation of Cell Therapy and Gene Therapy Products in Switzerland.

This chapter describes the regulation of cell and gene therapy products (CGTPs) in Switzerland and its legal basis. The Swiss Agency for Therapeutic Products, Swissmedic, is the lead Regulatory Authority and its ATMP Division is responsible for the regulation of these products at the level of clinical trials and marketing authorization. CGTPs are regulated similarly to medicinal products. The legal basis is set by the Therapeutic Product Act, the Transplantation Act, the Human Research Act, and associated ordinances. The ATMP Division is involved in processes such as scientific advice meetings, presubmission advice meetings, pharmacovigilance, market surveillance, import/export approvals, manufacturing license approval, and inspections. In Switzerland, guidance documents relevant for cell and gene therapy provided by PIC/S, OECD, ICH, Ph.Eur., EMA, or FDA are considered. In order to harmonize requirements for CGTPs, the ATMP Division is in constant exchange of information with foreign Regulatory Authorities and part of working groups of ICH, IPRP, and Ph.Eur. As CGTPs are biologically and technically complex, a risk-based approach is applied on a case-by-case basis for the evaluation of clinical trial and marketing applications. A substantial part of this chapter will provide requirements with respect to the manufacturing and quality, nonclinical and clinical evaluation of CGTPs. Furthermore, information will be provided regarding the use of real-world evidence in evaluation of clinical long-term efficacy and safety in case of rare diseases where the numbers of patients are too small for statistically meaningful analysis during clinical trials. Finally, the chapter will provide information on a health technology assessment (HTA) program that was launched in 2015 in Switzerland by the federal authorities.

Implementation of a gene therapy education initiative by the ASGCT and Muhimbili University of Health and Allied Sciences.

There has been rapid growth in gene therapy development with an expanding list of approved clinical products. Several therapies are particularly relevant to patients in low- and middle-income countries. Moreover, investing in research and manufacturing presents an opportunity for economic development. To increase awareness of gene therapy, the American Society of Gene and Cell Therapy partnered with the Muhimbili University of Health and Allied Sciences, Tanzania, to create a certificate-bearing course. The goal was to provide faculty teaching in graduate and medical schools with the tools needed to add gene therapy to the university curriculum. The first virtual course was held in October of 2022, and 45 individuals from 9 countries in Africa completed the training. The content was new to approximately two-thirds of participants, with the remaining third indicating that the course increased their knowledge base. The program was well received and will be adapted for other under-resourced regions.

Assessing Medicaid Coverage for Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T Cell Therapy: A Project from the American Society for Transplantation and Cellular Therapy and the National Marrow Donor Program ACCESS Initiative.

The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) to ensure equal access and outcomes for all patients in need. The 3 committees, addressing awareness, poverty, and racial and ethnic inequity, defined pilot projects focusing on addressing relevant barriers to HCT/CT. Because many socioeconomically disadvantaged HCT/CT recipients receive care through state Medicaid programs, the Poverty Committee conducted a Medicaid scan of all 50 US states with the following objectives: to define beneficiary coverage for allogeneic and autologous HCT and chimeric antigen receptor (CAR) T cell therapy; to define support for travel, temporary lodging, and meals for both beneficiaries and caregivers; and to determine search and cell acquisition payment procedures. Here we summarize the results of the Medicaid scan and highlight significant variations and gaps in coverage for HCT/CT recipients. We also provide an initial roadmap for addressing gaps in Medicaid support for HCT and CAR-T therapy recipients.