Αxicabtagene ciloleucel, an engineered autologous T-cell immunotherapy product, binds to CD19 expressing cancer cells and normal B cells. Following anti-CD19 CAR T-cell engagement with CD19 expressing target cells, the CD28 and CD3-zeta co-stimulatory domains 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 apoptosis and necrosis of CD19-expressing target cells.
In phase 2 of ZUMA-1, after axicabtagene ciloleucel 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, IFN-γ, and IL2Rα were analyzed. Peak elevation was observed within the first 14 days after infusion, and levels generally returned to baseline within 28 days.
Due to the on-target, off-tumour effect of axicabtagene ciloleucel, a period of B-cell aplasia is expected following treatment. Among 73 patients with evaluable samples at baseline, 40% had detectable B-cells; the B-cell aplasia observed in the majority of patients at baseline was attributed to prior therapies. Following axicabtagene ciloleucel treatment, the proportion of patients with detectable B-cells decreased: 20% had detectable B-cells at Month 3, and 22% had detectable B-cells at Month 6. The initiation of B-cell recovery was first noted at Month 9, when 56% of patients had detectable B-cells. This trend of B-cell recovery continued over time, as 64% of patients had detectable B-cells at Month 18, and 77% of patients had detectable B-cells at Month 24. Patients were not required to be followed after they progressed; thus, the majority of patients with evaluable samples were responders.
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 IL-15, as well as IL-6, were associated with Grade 3 or higher neurologic adverse reactions and Grade 3 or higher CRS.
Peak levels of anti-CD19 CAR T cells occurred within the first 8 to 15 days after axicabtagene ciloleucel infusion. The median peak level of anti-CD19 CAR T cells in the blood (Cmax) was 38.3 cells/μL (range: 0.8 to 1513.7 cells/μL), which decreased to a median of 2.1 cells/μL by 1 month (range: 0 to 167.4 cells/μL) and to a median of 0.4 cells/μL by 3 months (range: 0 to 28.4 cells/μL) after axicabtagene ciloleucel infusion.
Age (range: 23 to 76 years) and sex had no significant impact on AUC and Cmax of axicabtagene ciloleucel.
The number of anti-CD19 CAR T cells in the blood was positively associated with objective response (CR or PR). The median anti-CD19 CAR T cell Cmax level in responders (N=71) was 216% higher compared to the corresponding level in nonresponders (N=25) (43.6 cells/μL versus 20.2 cells/μL). Median AUCDay0-28 in responding patients (N=71) was 253% of the corresponding level in nonresponders (N=25) (562.0 days x cells/μL versus 222.0 days x cells/μL).
Αxicabtagene ciloleucel comprises human autologous T cells. The anticipated metabolic products are typical cellular degradation products resulting from normal cellular clearance mechanisms. Thus, the infused CAR T cells are expected to be cleared over time. Anti-CD19 CAR T cell levels decreased toward background levels by Month 3 after infusion. Studies of axicabtagene ciloleucel in patients with hepatic and renal impairment were not conducted.
Αxicabtagene ciloleucel 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 drug development were not performed.
No carcinogenicity or genotoxicity studies have been conducted with axicabtagene ciloleucel.
No studies have been conducted to evaluate the effects of axicabtagene ciloleucel on fertility, reproduction, and development.
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