By Dr. Aung Myo, Founder & Principal Consultant, Innovicto
2nd November,2024
T cell therapy has revolutionized anti-cancer treatment, with the U.S. FDA approving six autologous CAR-T cell therapies and recently in 2024 afami-cel (Tecelra), a T-cell receptor (TCR) therapy, and lifileucel (Amtagvi), the Tumor-Infiltrating Lymphocyte (TIL) therapy. These successes, however, did not come without significant hurdles. Conducting CAR-T cell clinical trials involves navigating a complex and lengthy process filled with significant challenges. From manufacturing complexity to long-term monitoring of patients’ safety, it is very critical to have substantial experience in clinical development of CAR-T cell therapies to successfully overcome these obstacles.
In this article, I will explore from clinical development aspect the key challenges of running the clinical trials with CAR-T cell therapy and provide strategic insights on how to address them, ensuring that more life-saving treatments can reach patients in need.
Here is a summary of the key challenges and solutions involved when conducting a clinical trial with CAR-T cell therapy (especially with autologous CAR-T cells).
1.Predicting Clinical Outcomes
Challenge:
Predicting clinical outcomes remains challenging due to variability in CAR-T cell expansion and persistence, both of which are crucial for treatment efficacy. Clinical studies consistently indicates that successful expansion and sustained persistence of CAR-T cells are crucial in impacting clinical results such as response rates, duration of response, and survival (progression-free survival [PFS] and overall survival [OS]). This connection is demonstrated in many studies including the Zuma-1 trial with Yescarta 1 and the ALPHA study with Allo 501A 2. Some early-phase trials have also reported lower success rates in clinical outcomes, often due to inadequate CAR-T cell expansion and persistence.
Strategies to overcome the challenge:
- Modification of CAR-T Constructs: Over time, there have been advancements in CAR-T constructs. The approved CAR-T cell therapies are second generation CAR-T cells, which feature co-stimulatory molecules such as CD28 or 41BB. Third-generation CAR-T cells incorporate both co-stimulatory molecules, while fourth-generation CAR-T cells (TRUCK CAR-T) include cytokine-releasing genes such as IL7, IL15, and CCR4 3,4.
- Lymphodepleting Chemotherapy: Research by Ramos et al. (2018) showed that incorporating lymphodepleting (LD) chemotherapy prior to CAR-T cell infusion enhances CAR-T cell expansion, compared to CAR-T cell treatment without LD chemotherapy 5. Today, pre-CAR-T lymphodepletion chemotherapy is the standard practice, although specific chemotherapy regimens may vary.
- Equal CD4-CD8 Ratio: The TRANSCEND-NHL 001 trial with Liso-cel, which uses an equal CD4:CD8 ratio, demonstrated optimal CAR-T cell expansion, persistence, and favorable clinical outcomes. Liso-cel was subsequently approved for the treatment of non-Hodgin Lymphoma (NHL) 6.
- T Cell Subsets: Researchers are investigating specific T cell subsets, such as less differentiated T cells (Tn, Tcm, Tsm), which exhibit higher proliferative potential and sustained in vivo persistence, leading to long-term remission. These subsets are preferred over more differentiated T cell subsets (Tem, Teff) 3.
2.CAR-T Toxicity
Challenge:
CAR-T therapy is associated with various toxicities, including acute toxicities such as Cytokine Release Syndrome (CRS) and Neurotoxicity (ICANS), subacute toxicities such as prolonged cytopenia, and long-term toxicities such as secondary malignancies. Recently, there have been reports of rare cases of CAR-T-related secondary malignancies, such as T-cell lymphoma 7. In January 2024, the U.S. FDA issued a warning regarding the risk of secondary cancers associated with CAR-T therapies used to treat cancer. The U.S. FDA required manufacturers of these CAR-T therapies to update their products “boxed warning” labels in the prescribing information to highlight the serious risk of T cell malignancies. Effective management of these adverse effects is essential for ensuring patient safety and optimizing treatment outcomes.
Strategies to overcome the challenge:
- Close Monitoring and Management: A multidisciplinary team at site level, along with sponsor’s safety team and study team is crucial for early detection and managing acute and subacute toxicities that may arise from CAR-T cell therapy. In early phase trials, a safety management committee should be established, while an Independent Data Monitoring Committee (IDMC) will be necessary in pivotal trials to ensure thorough assessment. The management guidelines for CAR-T-related toxicities have been established.
- Long-term Follow-up visits: Regular follow-ups, including testing for replication-competent retrovirus (RCR) and monitoring for second malignancies, are necessary to manage potential long-term toxicities. Establishing a robust mechanism for follow-up and RCR testing is crucial.
- Switchable CAR-T: Researchers have developed CAR-T cells with safety switches to control their activity. Examples include:
- Surface antigen safety switch strategy with truncated EGFR.
- iCaspase9 safety switch strategy for inducing apoptosis.
- HSV-TK safety switch strategy to disrupt DNA replication 4.
3.Manufacturing Challenges
Challenge:
Manufacturing CAR-T cells, particularly autologous CAR-T, is a critical yet time-consuming process, typically taking 4-6 weeks. This extended timeframe presents a significant risk to cancer patients, as disease progression or death may occur during this period. Additionally, manufacturing failures may occur in 10-20% of cases, preventing some patients from receiving the therapy. This failure-to-treat population is a growing concern for regulatory agencies. In cases of manufacturing failure, CAR-T cells may be remanufactured, but prolonged stimulation can lead to T cell exhaustion. In addition, scheduling the CAR-T infusion also poses operational challenges, influenced by product availability, patient readiness, and the timing of lymphodepleting chemotherapy.
Strategies to overcome the challenge:
- Reducing Manufacturing Time and Failures: Some companies are focused to reduce CAR-T cell manufacturing time and improve process development. Bridging therapy is often used to manage the waiting period. Some reports indicate that manufacturing time can be reduced to 2-3 weeks. Additionally, some companies are investigating allogeneic approaches to offer ‘off-the-shelf’ CAR-T cell products for immediate patient use. Others are exploring in vivo CAR-T cell therapies, which bypass the need for ex vivo manufacturing. The in vivo CAR T cells are progressing into clinical trial 8.
- Meticulous Operational Planning: Establishing a dedicated team involving the sponsor, clinical trial site and contract research organization (CRO) is essential for meticulous planning and execution of the clinical, manufacturing, and logistics aspects of the of CAR-T infusions.
4.Long-term Follow-up
Challenge:
Long-term follow-up in CAR-T trials is challenging, as current guidelines recommend monitoring patients for up to 15 years to ensure long-term safety, which is particularly important for assessing risks such as second malignancies and detecting the presence of RCR.
Strategies to overcome the challenge:
A decentralized approach using telemedicine, combined with remote monitoring and sample management, can effectively facilitate long-term follow-up in CAR-T trials. This approach allows for continuous patient monitoring without requiring frequent in-person visits. It is also important to establish mechanisms for testing RCR. Discussions with regulatory authorities can be considered when an individual patient has a negative RCR result for 12 months.
These are the key challenges and strategic solutions involved in conducting clinical trials for CAR-T cell therapy. By addressing these issues, we can improve the efficiency and success of CAR-T trials, ultimately bringing these transformative therapies to more patients in need.
Stay tuned for the upcoming articles, where I will explore the allogeneic approach and specific challenges and solutions related to CAR-T cell development in solid tumours.
Thank you for taking the time to read this. Feel free to share your thoughts in the comments section below.
References
1. Neelapu SS, Locke FL, Bartlett NL, et al. Axicabtagene Ciloleucel CAR T-Cell Therapy in Refractory Large B-Cell Lymphoma. N Engl J Med 2017;377(26):2531-2544. DOI: 10.1056/NEJMoa1707447.
2. Neelapu SS, Munoz J, Locke FL, et al. First-in-human data of ALLO-501 and ALLO-647 in relapsed/refractory large B-cell or follicular lymphoma (R/R LBCL/FL): ALPHA study. J Clin Oncol 2020;38:15_suppl:8002.
3. Lopez-Cantillo G, Uruena C, Camacho BA, Ramirez-Segura C. CAR-T Cell Performance: How to Improve Their Persistence? Front Immunol 2022;13:878209. DOI: 10.3389/fimmu.2022.878209.
4. Tomasik J, Jasinski M, Basak GW. Next generations of CAR-T cells – new therapeutic opportunities in hematology? Front Immunol 2022;13:1034707. DOI: 10.3389/fimmu.2022.1034707.
5. Ramos CA, Ballard B, Zhang H, et al. Clinical and immunological responses after CD30-specific chimeric antigen receptor-redirected lymphocytes. J Clin Invest 2017;127(9):3462-3471. DOI: 10.1172/JCI94306.
6. Abramson JS, Palomba ML, Gordon LI, et al. Lisocabtagene maraleucel for patients with relapsed or refractory large B-cell lymphomas (TRANSCEND NHL 001): a multicentre seamless design study. Lancet 2020;396(10254):839-852. DOI: 10.1016/S0140-6736(20)31366-0.
7. Hamilton MP, Sugio T, Noordenbos T, et al. Risk of Second Tumors and T-Cell Lymphoma after CAR T-Cell Therapy. N Engl J Med 2024;390(22):2047-2060. DOI: 10.1056/NEJMoa2401361.
8. Mullard A. In vivo CAR T cells move into clinical trials. Nat Rev Drug Discov 2024;23(10):727-730. DOI: 10.1038/d41573-024-00150-z.