Despite ongoing payer battles on sky-high price tags and challenges in managing severe side-effects, CAR-T cells have most certainly lived up to their name since their commercial arrival in 2017. Through unprecedented efficacy data promising deep and long responses in severe haematological indications, CAR-Ts have secured their place as a new hope for patients and oncologists around the globe, but manufacturers are facing multiple challenges trying to expand access and secure a long-promised ROI.

Current treatment administration heavily relies on in-patient procedures at key academic centres within specialized bone marrow transplant (BMT) and immunotherapy programs. However, these centres’ hospital management teams are struggling to achieve financially advantageous payer reimbursement rates, despite the release of new Medicare reimbursement MS-DRG codes for cell therapies in the US. As such, both manufacturers seeking expanded access to drive better sales and hospitals pursuing better reimbursement rates have considered offering CAR-T within the outpatient setting. A great idea at hand as product perceptions and safety concerns improve, yet a much larger industry problem in securing the necessary hospital infrastructure beyond academic centres.

Changes in adverse event occurrence and management as well as physician perceptions democratise CAR-T administration

Product safety concerns and physician perceptions, which previously limited the outpatient administration of CAR-T, now represent an – almost – distant problem of the past. New data supporting the feasibility and safety of outpatient administration continues to accumulate with manufacturers sponsoring clinical trials including outpatient cohorts, such as BMS’ TRANSCEND-NHL-001 (JCAR017) and Janssen & Legend Biotech’s CARTITUDE-2/CARTITUDE-4 (JNJ4528). However, it appears HCPs are only favouring outpatient administration for 41bb-based CAR-T constructs such as Novartis’ Kymriah (CLT019) or BMS’ Liso-cel (JCAR017) as these next-gen products have improved safety profiles over other CD28-ζ-based costimulatory CARs like Kite’s Yescarta (KTE-C19).

Additionally, physicians ability to manage the severe side effects of Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) not only improves with experience but is being expedited through studies promoting early use of steroids or monoclonal antibodies such as tocalizumab or lenzilumab (Kite’s ZUMA-19, KTE-C19). As such, the historic limiting factors to outpatient administration are chipping away, setting the stage for the next challenge: ensuring hospital infrastructure is fit-for-purpose.

Community centres must secure top-of-class outpatient infrastructure

As highlighted by Dr. Joseph Mikhael in the second Diamond Insights Miniseries video, outpatient CAR-T administration requires the establishment of adequate hospital infrastructure and rigorous processes. Yet, most community centres currently do not boast such facilities, nor hold the required JACIE (EU) or FACT (US) accreditation necessary for delivering cell therapies; meaning they lack resources to even provide in-patient treatments. Additionally, without designated beds, patient residences are required near outpatient infusion sites and this is particularly challenging for most community centres, with some turning to hotels or patient assistance groups (PAG)-owned appartements near treatment centres.

These residences must also be located nearby intensive care units (ICUs) during the two-week post-infusion period to manage the likely onset of CRS/ICANS. Adverse event onset requires rapid re-admission of patients to ICUs or hospital wards, and so brings light into another problem regarding bedspace management. Patients experiencing grade >3 CRS/ICANS cannot wait to receive treatment, yet most ICUs currently operate at maximum capacity with some US physicians mentioning lead-times of up to 14 hours to secure emergency bedspace. Key ICU triage procedures will need to be defined to solve this problem alongside new payer agreements to limit hospital losses linked to holding reserved premium bedspace.

Hospitals will also need to secure new staff such as specialised nurses, a scarce resource given the COVID pandemic. These nurses will need to offer 24/7 patient care and will require extensive CAR-T training to achieve Risk Evaluations and Mitigation Strategies (REMS) compliance. Moreover, key standard operating procedures (SOPs) and streamlined communication channels between the multitude of stakeholders within CAR-T process will also need to be developed on an hospital-by-hospital basis to align with existing workflows. This is a large and timely task for both manufacturers and providers, which will be difficult to standardize on a global scale. Key processes to cover will also include ensuring an efficient chain of custody, characterising short and long-term patient follow-ups, as well as developing clinical procedures for deciding at what point CRS/ICANS patients should be referred to ICU and hospital wards. All these must then legally comply with FDA standards and match the quality of care currently delivered within the in-patient.

Hybrid models: fully outpatient CAR-T programs are unlikely to become mainstream

In essence, prior barriers to outpatient administration regarding product safety and physician perceptions have slowly chipped away, only to expose a wider issue regarding hospital infrastructure requirements, which will need to be addressed as access widens to community centres and treatment moves towards earlier lines and new indications. As such, manufacturers can seek to leverage digital tools in remote patient monitoring to alleviate part of this problem: BMS has tested this already, providing HCPs with wearable patches tied to a smartphone app to ensure adequate patient temperature tracking and detection of early CRS onset.

Seeing the current premises, it seems unlikely autologous CAR-Ts will fully be administered in the outpatient setting, while the next years could see a shift towards a hybrid model. Manufacturers and providers alike should focus on moving the less complicated aspects of CAR-T (such as lymphodepletion and apheresis) in the outpatient, whilst maintaining the more complex steps within the in-patient setting. While a fully outpatient CAR-T program will most likely be limited to large excellence centres in specific patient populations with high fitness indices and lower tumour burden, the long-term benefits of outpatient administration are clear: increase access and provide hospitals with improved reimbursement rates. Yet, its implementation remains challenging and pushes all stakeholders to look back in time and draw learnings from therapies such as hematopoietic stem cell transplantation (HSCT), which have journeyed through a similar transition within the 21st century.