The development of chimeric antigen receptor (CAR) T-cell therapy has been an exciting advancement in pharmaceutical research and oncology. It has revolutionized cancer care by expanding treatment options beyond traditional therapies such as chemotherapy. It is used to treat various malignancies, including leukemias, lymphomas, and multiple myeloma, with broader indications under investigation. CAR T-cell therapy shows a promising future as a highly targeted treatment from which many patients with cancer may benefit, shaping a new paradigm in cancer care.1,2
Obecabtagene autoleucel (obe-cel, Aucatzyl; Autolus Therapeutics plc) is the latest CAR T-cell therapy to enter the rapidly advancing field of oncology therapeutics. It was approved by the FDA on November 8, 2024, for adults with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL).3 Obe-cel’s advantageous mechanism of action yields favorable efficacy and safety profiles compared with other available CAR T-cell therapies and has the potential for outpatient administration, allowing for a more comfortable patient experience.4
CAR T-cell therapy leverages the patient’s immune system to treat cancer. After the patient’s blood is collected, the T cells are separated and modified by the addition of a transgene, typically with a viral vector, to express CARs that recognize and bind to cancer cells. The CAR T cells are then multiplied and infused back into the patient. Once infused, they utilize their extracellular single-chain variable fragment (scFv) to bind their target antigen expressed by the tumor cell. The CAR T cell’s intracellular domains, such as 41BB.ζ, then activate a cascade of T-cell proliferation and activation, eliciting cytokine-mediated apoptosis of the tumor cell. The target antigen determines the type of malignancy the CAR T-cell therapy will treat. Some targets include CD19 for ALL and B-cell maturation antigen for multiple myeloma.5
Obe-cel is an autologous 41BB.ζ anti-CD19 CAR T-cell therapy. Its intermediate-affinity scFv for recognizing CD19 distinguishes it from previously approved therapies such as tisagenlecleucel (Kymriah; Novartis) and brexucabtagene autoleucel (Tecartus; Kite), which utilize high-affinity scFvs. This allows obe-cel to elicit improved CAR T-cell engraftment and persistence while reducing toxicity.4
Comparative Analysis of CAR T-Cell Therapies for ALL
Obe-cel’s FDA approval marks a significant advancement in CAR T-cell therapy by offering a therapeutic option with improved efficacy and, importantly, reduced toxicity compared with its counterparts. As a result, this regimen is preferred by the National Comprehensive Cancer Network for R/R B-cell ALL.6 One of the greatest concerns with CAR T-cell therapy, however, is the risk of cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), cytopenias, and infections. CRS is a common but potentially serious adverse effect (AE) caused by the release of inflammatory proteins by immune cells, resulting in an aggressive immune response characterized by symptoms such as fever, hypotension, and hypoxia. ICANS is another common AE, causing symptoms including headache, dizziness, language disturbances, and neuropsychiatric or motor impairment.7
Tisagenlecleucel is a CAR T-cell therapy indicated for patients 25 years or younger with B-cell ALL that is refractory or in second or later relapse, and it is also a preferred regimen for R/R B-cell ALL.6,8 The ELIANA trial (NCT02435849), a phase 2 study of tisagenlecleucel in pediatric and young adult patients with CD19+ R/R B-cell ALL, found an overall remission rate (ORR) within 3 months of 81%. The 6-month and 12-month event-free survival (EFS) rates were 73% and 50%, respectively, and the overall survival (OS) rate was 76% at 12 months. Grade 3 or 4 AEs occurred in 73% of patients, and CRS occurred in 77% of patients, with 47% developing grade 3 or 4 CRS. Neurologic events were observed in 40% of patients, with grade 3 or higher events in 13%. Febrile neutropenia occurred in 36%, and infections developed in 43%, with 24% being grade 3 or higher. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months.9
A follow-up study from ELIANA found an ORR of 82%, an estimated EFS of 44% at 36 months, and an OS rate of 63% at the same time point. No new or unexpected long-term AEs were reported, and grade 3 or 4 infections did not increase beyond 1 year after infusion.10
Brexucabtagene autoleucel, evaluated in the phase 1/2 ZUMA-3 trial (NCT02614066), demonstrated a remission rate of 71%, with 56% achieving complete remission. Median duration of remission was 12.8 months, and median OS was 18.2 months. However, CRS occurred in 89% of patients, with 24% experiencing grade 3 or higher. Neurologic events occurred in 60%, with grade 3 or higher events in 25%. Grade 3 or higher cytopenias and infections occurred in 76% and 25% of patients, respectively.11
The significance of obe-cel’s development and integration as an established therapy for B-cell ALL is demonstrated in its efficacy and advantageous safety profile compared with other available CAR T-cell therapies. The FELIX trial (NCT04404660) was a phase 1b/2 study of obe-cel in adults with R/R B-cell ALL, stratified into 3 groups: Cohort A included patients with morphologic disease (≥ 5% bone marrow blasts) and matched the disease status of previously mentioned trials; cohort B consisted of patients with measurable residual disease (< 5% bone marrow blasts); and cohort C comprised patients with isolated extramedullary disease at enrollment. Compared with tisagenlecleucel and brexucabtagene autoleucel, rates of AEs such as CRS and ICANS occurred less frequently in patients treated with obe-cel. These findings underscore obe-cel’s potential to improve tolerability and safety while maintaining efficacy, solidifying its role as a transformative treatment option for B-cell ALL.4
Key Differentiators
Obe-cel is redefining the paradigm of CAR T-cell therapy with its innovative design and clinical impact. As highlighted in the FELIX trial, this next-generation therapy demonstrated impressive outcomes for adults with R/R B-cell ALL, showcasing its potential to improve efficacy and safety compared with earlier CAR T-cell therapies.4
Obe-cel is a CD19-directed, genetically modified autologous T-cell therapy composed of patient-derived T cells transduced with a lentiviral vector. The CAR construct includes a CAT19 fast off-rate binder, enabling rapid disengagement from target cells and mimicking physiologic T-cell interactions. Traditional CAR T cells often bind to targets for extended periods (eg, 21 minutes for tisagenlecleucel), leading to excessive cytokine release and T-cell exhaustion. In contrast, obe-cel’s fast off-rate of 9.8 seconds allows it to rapidly disengage from multiple targets, promoting serial killing while minimizing cytokine release and T-cell exhaustion.12,13 Additionally, the inclusion of a 41BB.ζ costimulatory domain enhances T-cell expansion and persistence while reducing exhaustion, compared with CARs using CD28 costimulatory domains. The CD3ζ activation domain drives T-cell activation and cytotoxicity, whereas the CD8-derived hinge/transmembrane domain provides structural stability and durability for enhanced performance. These features deliver improved potency, reduced toxicity, and superior engraftment, ensuring robust expansion and persistence while mitigating risks such as CRS and ICANS. Additionally, unlike other CAR T-cell therapies, obe-cel does not require a Risk Evaluation and Mitigation Strategy program due to its lower risk of CRS and ICANS.14,15
The FELIX trial underscored obe-cel’s promise as a groundbreaking therapy for R/R B-cell ALL. Among the patients treated, 77% achieved remission, with 55% achieving complete remission, demonstrating the therapy’s robust efficacy even in a heavily pretreated population. The median OS was 15.6 months, nearly double the typical survival of approximately 8 months seen in this aggressive disease. These results reflect obe-cel’s potential to extend life while maintaining a manageable safety profile. Severe cases of CRS were rare, occurring in just 2.4% of patients, whereas grade 3 or higher neurotoxicity was observed in 7.1%. These findings highlight obe-cel as a transformative option for patients with limited treatment alternatives, offering efficacy and safety advantages over earlier CAR T-cell therapies.4
Unlike traditional single-infusion CAR T-cell therapies, obe-cel employs a split-dose regimen administered on day 1 and day 10 (± 2 days). The dose for the day 1 infusion is determined by the patient’s bone marrow blast percentage, assessed through a sample obtained within 7 days before the start of lymphodepletion.15 This personalized approach ensures optimal safety and efficacy by tailoring the treatment to the patient’s tumor burden. The day 10 infusion completes the regimen, sustaining T-cell activity and persistence while enhancing overall outcomes. This innovative split-dose strategy reduces the risk of severe CRS and provides flexibility in treating patients with varying disease states.4
Exploring Outpatient Potential
Obe-cel’s split-dose regimen offers a practical and transformative solution for outpatient administration, significantly reducing the need for prolonged inpatient stays. By tailoring doses to a patient’s tumor burden and mitigating severe toxicities such as CRS and ICANS, obe-cel provides a safer and more flexible alternative to traditional CAR T-cell treatments.3,15 Insights from the FELIX trial highlight this potential, demonstrating that patients with intermediate bone marrow burden (5%-75% blasts) achieved a remission rate of 82%, whereas those with high bone marrow burden (> 75% blasts) had a remission rate of 65%. This underscores the importance of tailoring therapy to individual patient profiles and emphasizes the importance of tumor burden in correlation with predicting treatment outcomes. This efficacy, alongside its reduced toxicity profile and ability to treat patients with varying disease burdens, positions obe-cel as a promising option for outpatient care.4
About the Authors
Amir Ali, PharmD, BCOP, is a clinical pharmacist specialist at USC Norris Comprehensive Cancer Center and an adjunct assistant professor of pharmacy practice at USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles, California.
Tammy Harutunyan is a class of 2025 PharmD candidate at the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
Arman Melikyan is a class of 2026 PharmD candidate at the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences in Los Angeles.
The therapy’s efficacy and reduced toxicity profile may also help address financial barriers, especially for patients far from specialized treatment centers because of the reduced need for inpatient requirements. However, this operationally intensive dosing schedule, which differs from the single-infusion protocols used by other CAR T-cell therapies, can pose logistical challenges for treatment centers. Despite these challenges, obe-cel’s innovative approach signals a shift toward more accessible, patient-centered CAR T-cell therapy models in the future.
Conclusion
Obe-cel’s innovative design and compelling clinical data position it as a transformative option for patients with R/R B-cell ALL. By addressing key limitations of earlier CAR T-cell therapies, such as prolonged cytokine signaling and high toxicity rates, obe-cel offers renewed hope for patients and clinicians. With ongoing research and real-world implementation, it has the potential to set new standards for safety, efficacy, and patient outcomes in CAR T-cell therapy.
REFERENCES
Feins S, Kong W, Williams EF, Milone MC, Fraietta JA. An introduction to chimeric antigen receptor (CAR) T-cell immunotherapy for human cancer. Am J Hematol. 2019;94(S1):S3-S9. doi:10.1002/ajh.25418
Singh AK, McGuirk JP. CAR T cells: continuation in a revolution of immunotherapy. Lancet Oncol. 2020;21(3):e168-e178. doi:10.1016/S1470-2045(19)30823-X
FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed March 14, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute
Roddie C, Sandhu KS, Tholouli E, et al. Obecabtagene autoleucel in adults with B-cell acute lymphoblastic leukemia. N Engl J Med. 2024;391(23):2219-2230. doi:10.1056/NEJMoa2406526
Alnefaie A, Albogami S, Asiri Y, et al. Chimeric antigen receptor T-cells: an overview of concepts, applications, limitations, and proposed solutions. Front Bioeng Biotechnol. 2022;10:797440. doi:10.3389/fbioe.2022.797440
Shah B, Mattison RJ, Abboud R, et al. Acute lymphoblastic leukemia, version 2.2024, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2024;22(8):563-576. doi:10.6004/jnccn.2024.0051
NCCN. Immunotherapy side effects: CAR T-cell therapy. 2024. Accessed March 14, 2025. https://www.nccn.org/patients/guidelines/content/PDF/immunotherapy-se-car-tcell-patient.pdf
Kymriah. Prescribing information. Novartis; 2023. Accessed March 14, 2025. https://www.fda.gov/media/107296/download
Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866
Laetsch TW, Maude SL, Rives S, et al. Three-year update of tisagenlecleucel in pediatric and young adult patients with relapsed/refractory acute lymphoblastic leukemia in the ELIANA trial. J Clin Oncol. 2023;41(9):1664-1669. doi:10.1200/JCO.22.00642
Shah BD, Ghobadi A, Oluwole OO, et al. KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study. Lancet. 2021;398(10299):491-502. doi:10.1016/S0140-6736(21)01222-8
Autolus Therapeutics. Full year 2023 financial results and business updates. March 14, 2024. Accessed March 14, 2025. https://www.autolus.com/media/gs1fwk5m/240314-q4-2023-deck-vfinal2.pdf
Ghorashian S, Kramer AM, Onuoha S, et al. Enhanced CAR T cell expansion and prolonged persistence in pediatric patients with ALL treated with a low-affinity CD19 CAR. Nat Med. 2019;25(9):1408-1414. doi:10.1038/s41591-019-0549-5
Aucatzyl. Autolus Therapeutics. Accessed March 14, 2025. https://www.aucatzylhcp.com/about-aucatzyl/moa/
Aucatzyl. Prescribing information. Autolus Therapeutics; 2024. Accessed March 14, 2025. https://www.fda.gov/media/183463/download
