Abstract 298P
Background
The CAR-T cell therapy has achieved great success in hematological malignancies and is gradually being used in solid tumors. Autologous CAR-T cell therapy targeting B7-H3 (CD276) has been studied and achieved preliminary results. However, autologous products are expensive and time-consuming to manufacture, and significant variability in patient T cells characteristics. We are developing the allogeneic universal CAR-T cells targeting B7-H3 (B7-H3 UCAR-T) for the treatment of advanced glioma, an off-the-shelf product candidate manufactured from serial healthy donor material and avoids many disadvantages of autologous CAR-T products.
Methods
The B7-H3 UCAR-T is produced using two key platform technologies: the lentiviral expression system and the gene editing system.The modified B7-H3 CAR is transduced into T cells via lentivirus vector, the gene encoding T cell receptor α chain (TRAC) and HLA-A molecules highly associated with rejection (retaining other HLA-I molecules), are knocked out by CRISPR/Cas9 technology. The resulting product not only eliminates GVHD and reduces rejection, but also prolongs the survival time of CAR-T in vivo.
Results
We have completed the generation of seven batches of clinical samples for the investigator initiated trial (IIT). The manufacturing success rate was 100%. Efficiencies of Double KO＞90%,with final product always demonstrating >99% TCR-KO. T cell expansion varied from70-300 fold. At clinical production scale, this means that up to 1,000 doses of CAR-T per manufacturing run at a dose of 3e7 CAR-T cells/patient/time. B7-H3 UCAR-T demonstrated a high percentage of TCM cells (CD45RO+ CD62L+). Furthermore, B7-H3 UCAR-T generated from multiple donors demonstrated potent efficacy in the U251 xenograft model in NSG mice. Moreover,our product had observed a longer half-life in different animal models, comparing with the TRAC/CD52 knockout strategy from Cellectis or the TRAC/B2M knockout strategy from CRISPR therapeutics.
Conclusions
In summary,these data demonstrate a stable,controllable,and scalable manufacturing process. In addition,this production process can be expanded to treat other targets in solid tumors and hematological malignancies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Jiangsu T-Maximum Biotech Co., Ltd.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.