JWCAR029 Is a CD19-Targeted CAR T Cell Product with Process and Quality Controls Delivered As a Flat Dose of CAR T Cell to Patients with NHL

Background:

JWCAR029 is the first IND approved CD19-targeted CAR T cell product by China National Drug Administration (CNDA) containing 4-1BB as the co-stimulatory factor with highly reproducible process and quality control that allows flat dose of CAR T cell infusion. To date, a total of 22 lots have been manufactured and 18 subjects have been infused in the ongoing multicenter, Phase 1 trial (NCT03344367 and NCT03355859) evaluating the safety and efficacy of JWCAR029 in adult relapsed or refractory B-cell Non-Hodgkin lymphoma patients. The process and quality control strategy for JWCAR029 contributes to the low variability in drug product quality attributes.

Methods:

Manufacturing of JWCAR029 begins with patient derived autologous T cells obtain via apheresis. JWCAR029 drug products were analyzed for viability, potency, subtype of T cells, copy numbers of lentiviral vector, and cell health related attributes using cellometer related bioassays, flow cytometry, and real-time quantitative polymerase chain reaction system (qPCR), respectively.

Results:

Process and quality of JWCAR029 started with an automated wash and T cell purification that results in pure CD3+ populations (median 99.56%, Inter Quartile Range [IQR] 99.22-99.86%). CD3+ T cells were transduced with lentiviral vector expressing a CD19-directed CAR with a 4-1 BB/CD3ζ endodomain. CAR+ T cells were cultured to a target cell dose and then formulated / cryopreserved for infusion. To reduce between-lot variance, the cryopreserved drug product (CDP) was packaged at fixed volume with a tight range of viable cell concentrations (CD3+: median 40.25 × 10^6 cells/mL, IQR 31.10-69.13 × 10^6 cells/mL, N=22) and CD3+CAR+ cell concentrations (median 27.25 × 10^6 cells/mL, IQR 23.57-33.10 × 10^6 cells/mL, N=22). JWCAR029 does not use a fixed ratio of CD4+CAR+ cells/CD8+CAR+ cells in the final CDP (median 1.18, IQR 0.70-1.95, N=22).

In the ongoing, multicenter, single arm, open-label and dose escalation Phase 1 trial, JWCAR029 was administered as a flat dose at dose level 1 (DL1) of 2.5 × 10^7 CAR+ T cells (6 subjects), at dose level 2 (DL2) of 5.0 × 10^7 CAR+ T cells (9 subjects), or dose level 3 (DL3) of 1.0 × 10^8 CAR+ T cells (3 subjects). After infusion, stable expansion of CD4+ and CD8+ CAR+ T cells were observed and peak value was appeared at day 11 to day 15 after administration. Low occurrence rate and manageable cytokine release syndrome (CRS) and neurotoxicity (NT) with high complete response (CR) rate were observed with emerging dose: response relationship. Detailed PK, clinical safety, and efficacy data of JWCAR029 will be presented separately.

Conclusion:

In order to employ standardized and high quality cell therapy methods in a Chinese multi-center trial, JWCAR029 was developed to provide a CD19-directed 4-1BB CAR T cell product with highly controlled manufacturing and quality processes enables administration in adult relapsed or refractory B-cell Non-Hodgkin lymphoma subjects. These control strategies in manufacturing and quality processes facilitated to the low rates of CRS and NT.