Brexucabtagene autoleucel, a CD19-directed genetically modified autologous T-cell immunotherapy, binds to CD19 expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19 expressing target cells, the CD28 co-stimulatory domain and CD3-zeta signalling domain activate downstream signalling cascades that lead to T-cell activation, proliferation, acquisition of effector functions and secretion of inflammatory cytokines and chemokines. This sequence of events leads to killing of CD19-expressing cells.
In both ZUMA-2 and ZUMA-3, after brexucabtagene autoleucel infusion, pharmacodynamic responses were evaluated over a 4-week interval by measuring transient elevation of cytokines, chemokines, and other molecules in blood. Levels of cytokines and chemokines such as IL-6, IL-8, IL-10, IL-15, TNF-α, interferon-gamma (IFN-γ) and IL-2 receptor alpha were analysed. Peak elevation was generally observed within the first 8 days after infusion and levels generally returned to baseline within 28 days.
Due to the on target, off-tumour effect of brexucabtagene autoleucel a period of B-cell aplasia may occur following treatment.
Translational analyses performed to identify associations between cytokine levels and incidence of CRS or neurologic events showed that higher levels (peak and AUC at 1 month) of multiple serum analytes, including IL-6, IL-10 and TNF-α, were associated with Grade 3 or higher neurologic adverse reactions and Grade 3 or higher CRS.
Following infusion of 2 × 106 anti-CD19 CAR T cells/kg of brexucabtagene autoleucel in ZUMA-2, anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 3 months. Peak levels of anti-CD19 CAR T cells occurred within the first 7 to 15 days after the infusion.
Among patients with MCL, the number of anti-CD19 CAR T cells in blood was associated with objective response (CR or PR) (Table 1).
Table 1. Summary of brexucabtagene autoleucel pharmacokinetics in ZUMA-2:
| Number of anti-CD19 CAR T cell | Responding patients (CR or PR) (N=63) | Non-responding patients (N=5) | P-Value |
|---|---|---|---|
| Peak (cells/μL) Median [min; max], n | 97.52 [0.24, 2 589.47], 62 | 0.39 [0.16, 22.02], 5 | 0.0020 |
| AUC0–28 (cells/μL·day) Median [min; max], n | 1 386.28 [3.83 to 2.77 × 104], 62 | 5.51 [1.81, 293.86], 5 | 0.0013 |
P-value is calculated by Wilcoxon test.
Median peak anti-CD19 CAR T-cell values were 74.08 cells/μL in MCL patients ≥65 years of age (n=39) and 112.45 cells/μL in MCL patients <65 years of age (n=28). Median anti-CD19 CAR T-cell AUC values were 876.48 cells/μL∙day in MCL patients ≥65 years of age and 1 640.21 cells/μL∙day in MCL patients <65 years of age.
Following infusion of a target dose of 1 × 106 anti-CD19 CAR T cells/kg of brexucabtagene autoleucel in ZUMA-3 (Phase 2), anti-CD19 CAR T cells exhibited an initial rapid expansion followed by a decline to near baseline levels by 3 months. Median time to peak levels of anti-CD19 CAR T cells was within the first 15 days after brexucabtagene autoleucel infusion.
A summary of the brexucabtagene autoleucel pharmacokinetics over time, based on central assessment by overall response, is provided in Table 2.
Table 2. Summary of brexucabtagene autoleucel pharmacokinetics in ZUMA-3 Phase 2:
| Number of anti-CD19 CAR T cell | Patients with overall complete remission (CR/CRi) (N=39) | Patients with non- complete remissiona (N=16) | P-Value |
|---|---|---|---|
| Peak (cells/μL) Median [min; max], n | 38.35 [1.31, 1 533.4], 36b | 0.49 [0.00, 183.50], 14b | 0.0001c |
| AUC0–28 (cells/μL·day) Median [min; max], n | 424.03 [14.12 to 19 390.42], 36b | 4.12 [0.00, 642.25], 14b | 0.0001c |
a Three of 39 subjects who achieved CR or CRi and 2 of 16 subjects who were non-CR/CRi had no anti-CD19 CAR Tcell data at any postinfusion visit.
b Noncomplete remission includes all non-CR/CRi subjects whose response is classified incomplete remission response with partial hematologic recovery, blast-free hypoplastic or aplastic bone marrow (N=4), partial response (N=0), no response (N=9), or not evaluable (N=3).
c P-value is calculated by Wilcoxon test.
Median peak anti-CD19 CAR T-cell values were 34.8 cells/μL in ALL patients ≥65 years of age (n=8) and 17.4 cells/μL in ALL patients <65 years of age (n=47). Median anti-CD19 CAR T-cell AUC values were 425.0 cells/μL∙day in ALL patients ≥65 years of age and 137.7 cells/μL∙day in ALL patients <65 years of age.
In MCL and ALL patients, gender had no significant impact on AUCDay 0–28 and Cmax of brexucabtagene autoleucel.
Studies of brexucabtagene autoleucel in patients with hepatic and renal impairment were not conducted.
Brexucabtagene autoleucel comprises engineered human T cells; therefore, there are no representative in vitro assays, ex vivo models, or in vivo models that can accurately address the toxicological characteristics of the human product. Hence, traditional toxicology studies used for medicinal product development were not performed.
No carcinogenicity or genotoxicity studies have been conducted.
No studies have been conducted to evaluate the effects of this treatment on fertility, reproduction, and development.
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