Optimizing Commercial Manufacturing of Tisagenlecleucel for Patients in the US: A 4-Year Experiential Journey

Background: Tisagenlecleucel (Kymriah) is an autologous CD19-directed CAR-T-cell therapy, approved in Aug-2017 for treating children and young adults with relapsed/refractory (r/r) acute lymphoblastic leukemia and in May-2018 for treating adults with r/r diffuse large B-cell lymphoma. Post-approval, a key goal has been to upscale and continuously improve manufacturing success and turnaround time in the commercial settings to meet the needs of a global patient population. Here we report accrued experience from our 4-year journey of optimizing the commercial tisagenlecleucel manufacturing process at the US site (Morris Plains, NJ), for faster and successful delivery to patients in the US. Methods: As reported previously, the tisagenlecleucel manufacturing process includes leukapheresis of the patient's peripheral blood mononuclear cells, enrichment and activation of T cells, transduction of the lentiviral vector containing the anti-CD19 CAR transgene, activation with anti-CD3/CD28 antibody-coated beads, expansion in cell culture, washing, and formulation of the viable cells into a cryoformulation medium. The final product is then cryopreserved, shipped back to the treatment center and infused to patients (Tyagarajan, 2020). Use of cryopreserved leukapheresis material as the starting point in commercial manufacturing is unique to tisagenlecleucel; this allows flexibility in terms of scheduling leukapheresis when a patient's health is optimal to provide T cells, and also helps offset logistical challenges (Tyagarajan, 2019). Results: As of Jun-2021, tisagenlecleucel has been manufactured for >5000 patients worldwide, enabled by Novartis's significantly increased global manufacturing footprint at six sites strategically located across six countries (US, France, Switzerland, Germany, Japan and Australia) and a global treatment network of >340 certified centers, including 127 centers in the US. Specifically for the US manufacturing site, between Dec-2020 and Jun-2021, 376 patients in the US had starting material available for manufacturing. Overall, the manufactured product was available for shipment for 98% of patients (shipping success rate [SSR]). The commercial manufacturing success rate (MSR) was 96%, with an out-of-specification (OOS) rate of <3% and no OOS for viability. All ten OOS batches were released for infusion as benefit:risk assessment was positive. Manufacturing was cancelled for two patients upon physician's request. Immediate manufacturing capability without waiting time was available on receipt of all apheresis starting materials. The median time from start of manufacturing to shipping was 20 days. As is evident, the COVID-19 pandemic did not appear to have significantly affected the success rate or manufacturing turnaround time. These latest success metrics, reflecting significant improvements from 2018 to 2021 in MSR (69% to 96%), SSR (93% to 98%), and overall OOS rate (26% to 2%) including viability OOS rate (from 25% to 0%), are a result of upscaling the manufacturing capabilities, enhancements with hospitals focusing on optimizing apheresis collection and cryopreservation procedures, and continuous evaluation and improvement of the manufacturing process since tisagenlecleucel was first launched (Figure). Two key process and analytical improvements that were considered to have improved robustness of manufacturing and testing processes, reduced OOS rates, and minimized variability in turnaround time were introduced towards the end of 2020. Firstly, a simplified sample preparation procedure for final product cell count and viability measurement, which is more reflective of final product at infusion. Secondly, an alternate serum source (5% plasma-derived human AB serum [PD hABs]) which further improves process robustness with a trend towards improved growth and higher peak cell counts. Conclusions: Tisagenlecleucel's current global commercial manufacturing footprint and treatment network are well-positioned to meet anticipated future increase in demand for CAR-T therapies. Recent process improvements have significantly increased the MSR (to 96%) and SSR (to 98%), and immediate product availability for patients in need of CAR-T cells. Ongoing and upcoming process improvements are anticipated to further reduce the throughput time, thus allowing more patients faster access to CAR-T therapy. Figure 1 Figure 1. Disclosures Rodrigues: Novartis: Current Employment. Duran: Novartis: Current Employment. Eschgfaeller: Novartis: Current Employment. Kuzan: Novartis: Current Employment. Habucky: Novartis: Current Employment.

Caregiver strain among North American parents of children from the Autism Treatment Network Registry Call-Back Study

Elevated caregiver strain is common and linked to poor health in parents of children with autism. Yet, little research has examined caregiver strain longitudinally and in geographically diverse samples of parents whose children have autism. This study aimed to (1) examine change in caregiver strain and (2) determine correlates of improved caregiver strain in North American parents of children with autism. This was a secondary analysis of data from the Autism Treatment Network Registry Call-Back Study, conducted from 2015 to 2017 on a random sample of children with autism spectrum disorder at 12 clinical sites in the United States or Canada. Child assessments and parent-reported questionnaires were completed at two time points 1 year apart. Caregiver strain was assessed with the Caregiver Strain Questionnaire. In total, 368 children had caregiver strain data at both times. Mean caregiver strain in parents did not significantly change between Times 1 and 2 (mean difference = 0.05, t(360) = 0.1, p = 0.92). Improved caregiver strain between Times 1 and 2 was associated with improved child adaptive functioning and externalizing problem behaviors. Caregiver strain was persistent and multi-factorial. Parent training to manage challenging child behaviors and adaptively cope may benefit this vulnerable parent population. Lay abstract Caregiver strain is the adverse impact that parents of children with emotional and behavioral issues including autism often experience (e.g. negative consequences of caregiving such as financial strain and social isolation; negative feelings that are internal to the caregiver such as worry and guilt; and negative feelings directed toward the child such as anger or resentment). This study showed that on average caregiver strain did not significantly change in North American parents of children with autism during a 2-year period. Improved caregiver strain was linked to improved child functioning and behavior. Routine assessment of caregiver strain and referral to evidence-based programming and supports may help alleviate some of the burden that families of children with autism commonly experience.

Building a Country-Wide Fistula Treatment Network in Kenya: Results From the First Six Years (2014-2020)

It is estimated that one million women worldwide live with untreated fistula, a devastating injury primarily caused by prolonged obstructed labor when women do not have access to timely emergency obstetric care. Women with fistula are incontinent of urine and/or feces and often suffer severe social and psychological consequences such as profound stigma and depression. Obstetric fistula affects economically vulnerable women and garners little attention on the global health stage. Exact figures on fistula incidence and prevalence are not known. In Kenya, results from a population-based survey suggest that approximately 120,000 reproductive-aged women have experienced fistula-like symptoms.In 2013, Fistula Foundation designed a program to significantly increase country-wide fistula treatment capacity in Kenya by addressing key barriers that limit women’s ability to receive treatment. Launched as Action on Fistula, and later becoming the Fistula Treatment Network, this model created a network of hospitals, a training center for surgeons and healthcare providers, and robust community outreach and reintegration activities. The Fistula Treatment Network was implemented by Fistula Foundation in collaboration with the Ministry of Health and Kenyan non-governmental and community-based organizations. Fistula Foundation and its donors provided the program’s funding, with seed funding, representing about 30% of the program budget, provided by Astellas Pharma EMEA.Over a six-year period, 2014-2020, the network supported 6,223 surgeries at seven hospitals, established a fistula training center and trained eleven surgeons, trained 424 Community Health Volunteers, conducted extensive outreach to all 47 counties in Kenya, and contributed to the National Strategic Framework to End Female Genital Fistula. At 12 months post fistula repair, 96% of women in a community setting reported that they were dry and not experiencing any incontinence and the proportion of women reporting normal functioning increased from 18% at baseline to 85% at twelve-months. The Fistula Foundation’s Fistula Treatment Network model increased access to fistula care services, strengthened the healthcare workforce, improved understanding of fistula and reduced stigma in a community setting. This integrated approach is an effective and replicable model for building capacity to deliver comprehensive fistula care services in other countries where the burden of fistula is high.

The Impact of COVID-19 Pandemic on the Castile and Leon Addiction Treatment Network: A Real-Word Experience

Background: Patients suffering from addiction are a vulnerable group in the midst of COVID-19, so their healthcare is considered essential. In this paper, the measures and responses of the Drug Addiction Assistance Network of Castile and Leon (DAACYL) in Spain during the first 6 weeks of the COVID-19 pandemic are explained. The aim is that this experience could be useful in places where this problem will continue and could help future interventions.Methods: A telephone survey was carried out as the main methodology, to collect information for the subsequent organization and repercussion on professionals and patients. This was carried out by the heads of the 18 DAACYL units. Among the interventions applied, the following stand out: implantation of telemedicine techniques, restriction of daily methadone dispensing, suspension of urine controls and initiation of care programs for the homeless.Results: As a result of these interventions, the professionals observed that patients are less demanding and mostly stable, with a low percentage of relapses. An increase in the consumption of alcohol and benzodiazepines have been reported as more common among people who relapse. Furthermore, the prevalence of COVID-19 infection in the sample is minimal; therefore, different hypotheses should be considered as an explanation (infra-diagnosis, immune system used to aggression, possible anti-inflammatory effect of some psychotropic drugs and a greater perception of danger against infection than the general population).Conclusions: The rapid adaptation and successful implementation of DAACYL have had satisfactory results. On the other hand, the prevention of the possible increase in the development of behavioral addictions and the use of homemade drugs should be considered.