Developing a Novel Anti-Bcma CAR-T for Relapsed or Refractory Multiple Myeloma

CBMG has developed C-CAR088, a novel chimeric antigen receptor (CAR)-T cell therapy targeting BCMA, which is specifically and highly expressed on multiple myeloma cells. C-CAR088 is designed to improve efficacy through increasing the specificity and reducing immunogenicity by fusing a scFv from high-affinity human monoclonal antibody to a CD3ζ/4-1BB signaling domain.

In preclinical study, the human T cells transduced with the lentiviral vector encoding C-CAR088 exhibited specific functions in vitro including CAR-T proliferation, cytokine production, cytotoxicity to BCMA positive tumor cells. C-CAR088 cells were not activated by soluble BCMA protein and MM patient serums. However, they can eradicate BCMA positive tumor cells in vivo including BMCA positive multiple myeloma tumor model RPMI-8226. C-CAR088 is manufactured in a serum free, automated and digital, closed system which produce CAR-T cells with stable and high percentage of Tcm phenotype. C-CAR088 showed a very good dose dependent tumor inhibition effect and survival benefit in animal studies.

A Phase 1, 3+3 dose escalation trial is being conducted in patients with r/r MM (≥ 3 prior lines, having received treatment and proteasome inhibitors (PI) and IMiD or double refractory) to assess the safety and efficacy of C-CAR088 (NCT03815383). Patients are apheresed to harvest T cells. C-CAR088 is then manufactured and administered to patients as a single intravenous dose after a standard 3-day cyclophosphamide/fludarabine conditioning regimen. As of July 5, 2019 cutoff date, 3 patients have been treated with C-CAR088 at the dose of 1.0 x 10⁶ CAR-T cells/kg. Patients were heavily pre-treated (7 prior lines of therapy), and all failed IMiDs and proteasome inhibitor therapies. After C-CAR088 treatment, all three patients showed clinical improvement as early as two weeks post treatment. Furthermore, C-CAR088 proliferation & expansion in the peripheral blood correlated with the decrease of tumor burden. Two patients reached VGPR at 4 weeks and 8 weeks respectively, and the third patient reached PR as early as 2 weeks post C-CAR088 infusion. C-CAR088 treatment was well tolerated, no dose-limiting toxicities (DLTs), reversible Grade 1~2 CRS observed.

In conclusion, early clinical trial results in patients with r/r MM for C-CAR088 support preclinical findings that the drug shows promising efficacy and manageable safety profile.The very early clinical efficacy signal at low, suboptimal dose is encouraging and compares favorably to many other anti-BCMA CAR-T products at similar dose. The promising trend needs to be confirmed by the ongoing clinical trial.