: CD19-directed chimeric antigen receptor T (CAR-T) cell therapy has shown great promise for cure of relapsed or refractory B cell non-Hodgkin lymphoma (r/r B-NHL). Previous studies reported that 4-1BB-based CD19 CAR-T was more beneficial for the clinical outcomes than CD28-based CAR-T, especially lower rates of severe adverse events. However, the median progression-free survival (mPFS) of 4-1BB-based product Kymriah was shorter than that of the CD28-based Yescarta (2.9 v.s. 5.9 months), suggesting that the long-term effectiveness of Kymriah was limited. Thus, a safe and durable 4-1BB-based CD19 CAR-T needs to be developed.
Here we presented a CD19 CAR-T (named IM19) with FMC63 scFv, 4-1BB and CD3ζ intracellular domain, which was manufactured into a memory T-enriched formulation and launched a clinical trial for treatemt of r/r B-NHL. The clinical outcomes of IM19 were evaluated in 22 r/r B-NHL patients in a Phase I/II trial with dose-escalation investigation (5×105, 1×106 and 3×106/kg).
All patients received a single infusion of IM19 after 3-day conditional regimen. Cytokine release syndrome (CRS) occurred in 13 patients (59%), with 54.5% of grade 1–2 and 4.5% of grade 3, whereas Kymriah led to 22% of > grade 3 CRS. Only one patient showed > grade 3 immune effector cell-associated neurotoxicity syndrome (ICANS). At 6 months, the overall response rate was 47.62%, and the complete response rate was 42.86%. The mPFS of IM19 achieved 9 months and the 1-year overall survival rate was 78%.
These results demonstrated the safety and durable efficacy of IM19 with FMC63 scFv, 4-1BB and CD3ζ intracellular domain, that is promising for further development and clinical investigation.
: The registration date of the clinical trial is May 17, 2018(17/05/2018) and the trial registration numbers is NCT03528421.