With the six foundational Chimeric Antigen T-cell (CAR T) therapies achieving remarkably effective results and continued evolution of the technology, CAR T clinical programs in other indications are a rapidly growing space. As these innovative therapies begin clinical trials in new patient communities, it’s essential to understand how to successfully adapt lessons and processes from oncology CAR T therapies into these studies.
To address these concerns in CAR T therapy trials, Worldwide’s Dr. Simran Padam, Dr. Amy Raymond, and Nathan Chadwick discussed with Dr. Chris Jenkins of Sabai Global and Dr. Tahseen Mozaffar of UC Irvine in an on-demand webinar, Expanding CAR T Beyond Oncology: Medical, Operational & Practical Considerations.
Current CAR T Landscape & Growth Trends
CAR T therapies are witnessing an impressive surge of growth, with 2024 marking a record number of these studies. This growth is driven by ongoing technological innovations and a greater understanding of how CAR T can be applied to new therapeutic areas and patient communities.
While initial CAR T designs focused exclusively on oncology, with many of these molecules now moving into fourth- and fifth-generation designs, there has been a notable increase in trials targeting autoimmune diseases. In autoimmune diseases, since the patients’ own antigens are driving the disease, the treatment strategy aligns with many of the factors that inspired antibody-based B cell depletion. Achieving such depletion offers a promising pathway for developing meaningful treatments for patients, particularly for single administration options.
Some of the challenges that traditional autologous CAR T treatments have faced stem from the apheresis and leukodepletion steps required for harvesting the patient’s own T-cells and preparing the patient to have the manufactured treatment flourish once delivered. These not only restrict the pool of potential study candidates but also greatly constrain the clinical research sites that could run these trials. Moreover, these factors continue to be limiting even after marketing authorization is achieved.
Encouragingly , more than half of recently launched Phase I CAR T studies are developing allogeneic products, which involve the use of stem cells from healthy donors rather than the medically-challenged patient. Although several new programs are still autologous, which use the individual’s own cells, the increase in allogeneic trials may address current barriers to treatment and maximize commercial potential for these products.
Six Drivers of a Successful CAR T Program
Drawing on their experience over the years, as well as the questions and concerns that come up most often when working with drug developers, the panelists identified six drivers of a successful program that should be utilized when expanding CAR T beyond oncology indications.
- Site Identification: Selecting the right sites for a CAR T study is critical to its success. Although many participating clinics are new to CAR T-cell trials, risks can be mitigated by selecting sites that are already FACT/JACIE accredited and have physicians with access to the target patient population.
- Cross-Department Collaboration: Effective collaboration between different departments, such as the oncology unit and rheumatology/immunology/neurology unit, is essential for monitoring adverse events (AEs) and managing patient safety. In some instances, a centralized apheresis/lymphodepletion center could be considered.
- Site Activation: Ensure sites are well-prepared and have the necessary infrastructure, internal processes, and expertise to support study start-up timelines. Early adopters of CAR T studies outside of oncology were surprised by the multidisciplinary team needed and the number of departments that required input at every stage of site activation and study execution – early identification and engagement of the full team is key.
- Patient Recruitment & Retention: As many patients will be naïve to CAR T and, depending on the exact patient community, may have a variety of disease modifiers available to them – engaging patients and keeping them informed throughout treatment and follow-up is crucial for data integrity and trial success.
- Clinical Logistics Coordination: Managing the logistics of cell collection and shipment, third-party providers, the patient journey, regulatory needs, and other complex processes of cell therapy development programs will be key. Sponsors should consider dedicated roles and resources to be the steward of these processes to ensure operational success.
- Maximizing Data Value: Ensuring sites can make timely data entry and clinical monitors are promptly verifying these data is essential, as data collection in these studies is very front-loaded. Backlog in oversight of these data reduce the ability to interpret the safety and efficacy of these important treatments, ultimately risking BLA approval.
Medical, Operational, & Practical Challenges & Opportunities
As CAR T therapies continue to evolve, it’s natural to expect both new challenges and opportunities to arise.
Managing Adverse Effects
Medically, close monitoring and a multidisciplinary approach will continue to play an essential role in managing AEs. The most common AEs associated with CAR T treatment of any indication are cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Both CRS and ICANS can lead to complications like cytopenia and infections, requiring supportive care and potentially additional medications.
To combat these challenges, it’s necessary to have standard operating procedures in place that ensure close follow-up care and open communication. This process may involve daily calls with the sites and physicians, particularly during the post-infusion period, to guarantee continuous and real-time patient monitoring. Depending on the technology being developed and/or the site’s processes, there may be a need for the patient to remain under the care of the hem-oncology team until the risk of these is sufficiently reduced or for them to remain accessible to the principal investigator for regular patient review.
Logistical & Budgetary Considerations
Conducting CAR T trials involves significant logistical and budgetary challenges. Early planning is critical to ensure all needs and timelines are met regarding site selection, complex site activation, patient/sample flow, and other elements are on track. Consistent budget review calls can further expedite timelines to ensure both sponsor and CRO are aligned throughout the study.
One critically important way specialized CROs such as Worldwide mitigate these challenges is to implement 360-degree comprehensive training for all members of the study team, which encompasses training on the CAR T modality, thorough protocol training, anticipated patient pathways, identification of potential AEs, and more. This approach, combined with our flexible monitoring operational strategy, ensures sponsors have robust and interpretable data.
Patient & Provider Education
To reduce patient dropout and maximize patient data, expectation setting and clear communication are vital. Using technology, such as websites and video patient testimonials, can help build understanding and confidence among site personnel, which in turn can enhance patient engagement and commitment.
As CAR T therapies move beyond life-threatening oncology indications to chronic and debilitating diseases, recruitment can become more difficult for trials with a high patient burden. However, implementing these solutions can help ensure the study’s enrollment and retention goals remain on track.
Watch Worldwide’s On-Demand Webinar
With the future of CAR T filled with advancements in allogeneic treatments and other exciting developments, these innovations will improve safety, accessibility, and overall therapeutic potential. To learn more about the medical, operational, and practical considerations for CAR T clinical trials beyond oncology, make sure to watch our on-demand webinar.
