Obecabtagene autoleucel is an autologous immunotherapy consisting of the patient's own T cells engineered to express a CAR that recognises CD19 on-target cells via the murine CAT13.1E10 hybridoma (CAT) binding domain. Engagement of anti-CD19 (CAT) CAR-positive T cells with CD19-expressed on-target cells, such as cancer cells and normal B cells, leads to activation of the anti-CD19 (CAT) CAR-positive T cells and downstream signalling through the CD3-zeta domain. Proliferation and persistence by the anti-CD19 (CAT) CAR-positive T cells following activation are enhanced by the presence of the 4-1BB co-stimulatory domain. This binding to CD19 results in anti-tumour activity and killing of CD19-expressing target cells.
Studies demonstrate obecabtagene autoleucel has a fast off-rate of 3.1 × 10-3s-1 of its CD19 binding domain.
Serum levels of cytokines such as IL-2, IL-5, IL-6, IL-7, IL-8, IL-10, IL-15, TNF-α, IFN-γ, and granulocyte macrophage colony-stimulating factors were evaluated pre- and up to 3 months post-obecabtagene autoleucel infusion. Peak elevation of plasma cytokines was observed at day 28 of obecabtagene autoleucel infusion and levels returned to baseline by month 3.
Due to the on-target effect of obecabtagene autoleucel, a period of B cell aplasia is expected.
The pharmacokinetics (PK) of obecabtagene autoleucel were assessed in 94 patients with r/r CD19+ B ALL receiving a median dose of 410 × 106 CD19 CAR-positive viable T cells (range: 10-480 × 106 CD19 CAR-positive viable T cells).
A rapid expansion occurred after infusion of the first dose in the majority of the patients and continued after the second dose up to the median time of maximal expansion to peak (Tmax) at day 14 (range: 2-55 days).
Decline of CAR T concentrations started shortly after day 28 and reached a stabilised concentration from month 6; with a maximum persistency observed at 27.7 months.
A high level of expansion was generally observed regardless of response status (CR/CRi vs. non-CR/non-CRi). A total of 84.6% (22/26) of patients who had ongoing remission had ongoing CAR T persistency at the last laboratory assessment.
Summary of PK parameters in peripheral blood by BOR (Cohort IIA, infused set:
| Parameter metric | Best overall response | Overall (N=94) | |
|---|---|---|---|
| CR/CRi (N=72) | Not CR/CRi (N=22) | ||
| Cmax (copies/μg DNA) | |||
| N | 72 | 22 | 94 |
| Geometric mean (Geo-CV%) | 117 381 (206.0) | 107 465 (832.7) | 114 982 (287.6) |
| Range (min - max) | 2 120-478 000 | 129-600 000 | 129-600 000 |
| Tmax (days) | |||
| N | 72 | 22 | 94 |
| Median | 14 | 17 | 14 |
| Range (min - max) | 2-55 | 6-28 | 2-55 |
| AUC(0-28d) (copies/μg DNA*days) | |||
| N | 68 | 14 | 82 |
| Geometric mean (Geo-CV%) | 1 089 908 (236.0) | 1 404 899 (186.4) | 1 138 188 (225.6) |
| Range (min - max) | 17 900-6 730 000 | 176 000-7 230 000 | 17 900-7 230 000 |
AUC(0-28d) = area under the concentration-time curve from day 0 to day 28; BOR = best overall response; Cmax = maximum concentration; CR = complete remission; CRi = complete remission with incomplete recovery of counts; DNA = deoxyribonucleic acid; Geo-CV% = geometric coefficient of variation; PK = pharmacokinetic; Tmax = time to maximum concentration.
Patients who received a first split dose of 10 × 106 cells (>20% blast) demonstrated a higher expansion of CAR T cells (Cmax and AUC0-28d) compared with patients who received a first split dose of 100 × 106 cells (≤20% blast). In turn, patients with high expansion tended to have higher rates of CRS and ICANS. Therefore, high tumour burden is the main risk factor for onset of CRS and ICANS.
In the FELIX study, the median body weight was 75.75 kg (range: 42.6-230.6 kg). The PK profile was comparable between patients with lower (<75.75 kg) and higher (≥75.75 kg) body weight.
Gender or age (below 65 years, between 65 and 74 years, and between 75 and 84 years) did not have a significant impact on the PK of obecabtagene autoleucel (Cmax, AUC0-28d or persistency).
The data in the non-white population are too limited to draw any conclusions on the impact of race on PK parameters.
Hepatic and renal impairment studies of obecabtagene autoleucel were not conducted.
Obecabtagene 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 with obecabtagene autoleucel. No studies have been conducted to evaluate the effects of obecabtagene autoleucel on fertility, reproduction and development.
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