Surveying Local CAR-T Manufacturing Processes to Promote Standardization of Protocols

Background: The availability of CAR-T (Chimeric Antigen Receptor T-cell) therapies is a pivotal advancement in cancer treatment. Local, or point-of-care, manufacturing addresses logistical and accessibility challenges but can lead to inconsistencies in product quality and therapeutic outcomes. This study surveys local CAR-T manufacturing processes to promote protocol standardization, ensuring consistent and high-quality CAR-T products across institutions.

Methods: We conducted a cross-sectional web-based survey to academic institutions with current Good Manufacturing Practice (GMP) facilities involved in CAR-T cell production in the United States (US) and internationally. The survey questions were guided by semi-structured interviews with academic experts in CAR-T manufacturing. Survey items assessed aspects of the manufacturing processes and protocols. Data were collected and managed using REDCap electronic data capture tools. Descriptive statistics were used to report the data.

Results: As of August 1, 2024, 23 institutions responded (15 US-based, 8 international). Key findings were: 52% of institutions currently manufacture CAR-T cell therapies, while the other 48% plan to start within 2 years. Institutions planning to produce and/or not currently manufacturing CAR-T therapies often refer patients to other institutions (83%), use commercially available products (70%), and participate in clinical trials run by other institutions or companies (65%). The top reasons cited for not currently manufacturing CAR-T cells included cost constraints (76%), lack of infrastructure (65%), and regulatory complexities (57%). Institutions indicated that access to appropriate manufacturing facilities (78%), availability of turnkey manufacturing solutions (67%), and increased patient demand (61%) were critical factors that will significantly influence future manufacturing. The biggest anticipated challenges included equipment costs (73%), facility requirements (65%), and training personnel (55%). Challenges for current manufacturers included maintaining consistent quality control across batches (41%) and integrating new technologies into existing workflows (34%). There was considerable variability in usage of automated devices. Common automated or semi-automated platforms used included Miltenyl CliniMACS Prodigy (71%), Lonza Cocoon (48%), and Gibco CTS Rotea (43%). Some institutions partnered with these companies to use customized solutions tailored to their specific needs. Significant variability was observed in culture conditions and expansion protocols (70% static culture, 30% dynamic bioreactors), and product characteristics and quality control measures (100% viability testing, 90% potency assays, 85% sterility testing). Primary regulatory challenges in US institutions included FDA requirements (57%), navigating frequent updates in guidelines (52%), and managing comprehensive documentation (48%). Solutions cited included hiring regulatory experts (43%) and attending regulatory workshops (39%). Key regulatory challenges in international institutions were complex international regulations (72%) and limited local regulatory guidance (67%). Solutions included forming international regulatory alliances (52%) and participating in global compliance forums (47%). US institutions versus international institutions reported: higher concerns about training personnel (61% vs 40%, respectfully), favored static culture conditions (75% vs 30%), less usage of dynamic bioreactors (25% vs 70%), differences in performing viability testing (100% vs 70%), and differences in potency assays (95% vs 80%).

Conclusion: The survey highlights significant variability in local CAR-T manufacturing processes both within institutions in the US and between US and international institutions. The findings underscore the need for standardizing protocols, which are essential to mitigate variability, enhance quality control/release testing, improve the consistency of therapeutic outcomes, and encourage more institutions towards local manufacturing. Addressing these disparities through sharing best practices, creating tailored solutions, and promoting international cooperation will be crucial for the advancement of CAR-T manufacturing and improving patient access and outcomes.

No relevant conflicts of interest to declare.