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Fast Facts: CAR T-Cell Therapy
Insight into current and future applications
R.J. Buka, A.J. Kansagra
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eBook - ePub
Fast Facts: CAR T-Cell Therapy
Insight into current and future applications
R.J. Buka, A.J. Kansagra
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About This Book
Chimeric antigen receptor (CAR) T cells are genetically engineered immune cells that can seek out and destroy cancer cells. The results from their use in cancer immunotherapy have been very promising, but treatment is often associated with frequent, serious short-term toxicities. 'Fast Facts: CAR-T Therapy' explains what CAR T cells are and how they were developed, discusses the results of clinical trials and the management of toxicities, and outlines future improvements and applications. It is ideal reading for any healthcare professional wanting to know more about this exciting therapeutic field. Table of Contents: • CAR T cells • Clinical application • Practical aspects • Future directions
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2 | Clinical application |
Approved CAR T-cell products
By 2010, there were over 70 CAR T-cell constructs under investigation targeting over 30 antigens, with seven in Phase I trials. At the time of publication, three CD19-targeted CAR T-cell products had been approved for use in clinical practice: tisagenlecleucel (Kymriah; Novartis), axicabtagene ciloleucel (Yescarta; Kite [Gilead]) and brexucabtagene autoleucel (Tecartus; Kite [Gilead]).
The first to gain approval by the Food and Drug Administration (FDA) in the USA was tisagenlecleucel in August 2017, for use in precursor B-cell acute lymphoblastic leukemia (B-ALL). Axicabtagene ciloleucel gained FDA approval in October 2017 for use in relapsed and refractory diffuse large B-cell lymphoma (DLBCL), and tisagenlecleucel was also approved for a similar indication shortly afterward. Although axicabtagene ciloleucel was the second CAR T-cell product to be licensed, it was the first to be administered to a patient with DLBCL (Table 2.1).1 Regulatory approval for these products was then granted in Europe, Canada, Australia and Japan. Brexucabtagene autoleucel was granted accelerated FDA approval for the treatment of relapsed or refractory mantle cell lymphoma in July 2020 based on the results of the Phase II open-label single-arm multicenter ZUMA-2 trial.2
Feature | Tisagenlecleucel | Axicabtagene ciloleucel |
Trade name | Kymriah | Yescarta |
Company | Novartis | Kite (Gilead) |
Construct | FMC63 Co-stimulation: 4-1BB Vector: lentivirus | FMC63 Co-stimulation: CD28 Vector: retrovirus |
FDA approval and indication | 30 August 2017 Patients ≤ 25 years with refractory or second-relapse B-ALL 01 May 2018 Adults with relapsed or refractory DLBCL after ≥ 2 lines of therapy | 18 October 2017 Adults with relapsed or refractory DLBCL after ≥ 2 lines of therapy |
Cost | $475 000 for B-ALL $373 000 for DLBCL | $373 000 |
Sales 2018 | $78 million | $264 million |
Manufacturing time | 22 days | 17 days |
Persistence/activity | 1–7 years | ~ 6 weeks but more co-stimulated, more rapid mode of action |
Structural and manufacturing differences. All three approved CAR T therapies carry the same single-chain Fv gene that recognizes CD19, but they differ in their co-stimulation. Tisagenlecleucel carries the co-stimulation molecule 4-1BB, while axicabtagene ciloleucel and brexucabtagene autoleucel use CD28 (Figure 2.1). The products are also manufactured slightly differently – tisagenlecleucel makes use of a lentiviral vector while axicabtagene ciloleucel and brexucabtagene autoleucel use a retrovirus.
Pharmacokinetic differences. The main effect of these differences appears to be in the cells’ expansion kinetics: for example axicabtagene ciloleucel reaches a higher peak number of cells than tisagenlecleucel.3 However, tisagenlecleucel persists in the body for much longer, with cells detectable up to 7 years after infusion.
Efficacy. The clinical effect of the differences described above is unclear as there are no head-to-head comparisons. However, tisagenlecleucel and axicabtagene ciloleucel have shown largely similar efficacies in the JULIET and ZUMA-1 trials, respectively.4,5 The results from these trials are encouraging, given the usually poor prognosis of patients with relapsed DLBCL and relapsed/refractory B-ALL (Table 2.2).
Trial | Indication | Outcomes | Toxicity |
SCHOLAR-1 (n = 636) Pooled analysis of 3 trials and 2 observational studies6 | Relapsed or refractory DLBCL: ≤ 12 months after autograft | OR: 26% CR: 7% Median OS: 6.3 months 6-month OS: 50% 1-year OS: 28% 2-year OS: 20% | Not reported |
Phase II trial of clofarabine (n = 61) Of 61 patients, 9 went on to transplant. Trial excluded relapsed patients < 3 months after transplant7 | Children and young adults with refractory or relapsed ALL (79% B cell... |