Axicabtagene 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.
After axicabtagene ciloleucel infusion, pharmacodynamic responses were evaluated by measuring transient elevation of cytokines, chemokines, and other molecules in blood over a 4-week interval. 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.
Analyses performed to identify associations between cytokine levels and incidence of CRS or neurologic events showed that higher post-infusion levels (peak and AUC at 1 month) of multiple immune-modulatory and pro-inflammatory analytes were associated with Grade 3 or higher neurologic adverse reactions and Grade 3 or higher CRS in ZUMA-1, ZUMA-7 and ZUMA-5.
Due to the on-target, off-tumour effect of axicabtagene ciloleucel, a period of B-cell aplasia is expected following treatment.
Among 73 patients in ZUMA-1 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. Among 141 patients in ZUMA-7 with evaluable samples at baseline, 57% had detectable B-cells. Following axicabtagene ciloleucel treatment, the proportion of patients with detectable B-cells decreased: 38% had detectable B-cells at Month 3, and 41% had detectable B-cells at Month 6. The initiation of B-cell recovery was apparent at Month 9, when 58% 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 84% of patients had detectable B-cells at Month 24. Among 113 FL patients with evaluable samples at baseline in ZUMA-5, 75% of patients had detectable B-cells. Following axicabtagene ciloleucel treatment, the proportion of patients with detectable B-cells decreased: 40% of patients had detectable B-cells at Month 3. B-cell recovery was observed over time, with 61% of patients having 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.
Axicabtagene ciloleucel comprises human autologous T cells. The anticipated residual 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.
Following infusion of axicabtagene ciloleucel 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 14 days after the day of axicabtagene ciloleucel infusion. Age (range: 21 to 80 years) and sex had no significant impact on AUC and peak levels of axicabtagene ciloleucel.
Among patients in ZUMA-1, the median peak level of anti-CD19 CAR T cells in the blood 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. Among patients in ZUMA-7 the median peak level of anti-CD19 CAR T cells in the blood was 25.84 cells/μL (range: 0.04 to 1173.25 cells/μL), which decreased towards baseline in evaluable patients by 3 months (0.35 cells/μL; range: 0.00 to 28.44 cells/μL), but were still detectable in 12 out of 30 evaluable patients until 24 months post-treatment.
Among patients in ZUMA-5 with FL, the median peak level of anti-CD19 CAR T cells in the blood was 37.6 cells/μL (range: 0.5 to 1415.4 cells/μL). The median time to peak of anti-CD19 CAR T cells in the blood was 8 days after infusion (range: 8 to 371 days). By 3 months, anti-CD19 CAR T cell levels decreased to near baseline levels to a median of 0.3 cells/μL (range: 0 to 15.8 cells/μL).
Among patients in ZUMA-1, 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 peak 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 AUC0-28 in responding patients (N=71) was 253% of the corresponding level in nonresponders (N=25) (562 days × cells/μL versus 222 days × cells/μL).
Among patients in ZUMA-7 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 peak levels in responders (n=142) were about 275% higher compared to the corresponding level in nonresponders (n=20) (28.9 cells/μL versus 10.5 cells/μL). Median AUC0-28 in responding patients (n=142) was about 417% higher compared to the corresponding level in nonresponders (n=20) (292.9 days × cells/μL versus 70.1 days × cells/μL).
Among patients with FL in ZUMA-5, the median peak anti-CD19 CAR T-cell levels in responders (n=112) versus nonresponders (n=5) were 38.0 cells/μL and 31.3 cells/μL, respectively. The median AUC0-28 in responders versus nonresponders were 454.8 cells/μL•days and 247.1 cells/μL•days, respectively.
Studies of axicabtagene ciloleucel in patients with hepatic and renal impairment were not conducted.
Axicabtagene 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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