Long-Term Safety and Efficacy of CD19 Humanized Selective CAR-T Therapy in B-ALL Patients Who Have Previously Received Murine-Based CD19 CAR-T Therapy

Abstract

Murine-based CD19 CAR-T (CD19m CAR-T) therapy can lead to a relatively high CR rate when administered to B-ALL patients for the first time. However, the DOR is sub-optimal and a subset of patients even show primary resistance to CD19m CAR-T. To address these issues, we employed a humanized selective CD19CAR-T (CD19hs CAR-T) and evaluated the long-term safety and efficacy of treating 8 R/R B-ALL patients who had relapsed or failed to achieve CR following CD19m CAR-T infusion (Clinical trials' number: ChiCTR1800014761 and ChiCTR1800017439). Of the 8 patients, 7 achieved CR on Day 30 after the 1^st infusion of CD19hs CAR-T. The median CRS grade was 1 without significant neurotoxicity seen in any of the 8 patients. The median DOR was 11 months, significantly longer than the DOR following CD19mCAR-T infusions. Anti-CAR antibodies were induced in patients who had received prior CD19m CAR-T infusions but not in those following a single or repeated CD19hsCAR-T treatment, which probably had contributed to the sub-optimal DOR and/or failure of effective response in these patients. CD19hs CAR-T, in contrast, induced low immunogenicity compared with CD19m CAR-T, suggesting that a repeat dosing strategy might be feasible and efficacious for patients who have relapsed and/or show primary resistance to CD19m CAR-T therapy. In this clinical study, CD19hs CAR-T showed a significant clinical efficacy with mild side effect among patients with R/R B-ALL who had previously received CD19m CAR-T.

Clinical trial registration: https://www.chictr.org.cn/showprojen.aspx?proj=25199 (ChiCTR1800014761). https://www.chictr.org.cn/showproj.aspx?proj=29174 (ChiCTR1800017439).

Keywords: B-ALL; CAR-T; HSCT; humanized; repeated dosing; selective domain.

Figure 1

The flowchart of CD19hsCAR-T treatment.

Figure 2

Safety and efficacy of CD19hs CAR-T. (A) CRS following CD19m CAR-T and CD19hs CAR-T infusions. (B) CR rates after the 1^st and 2^nd infusions of CD19m CAR-T and CD19hs CAR-T, respectively.

Figure 3

Levels of cytokines in patient sera after the 1^st infusion of CD19m CAR-T and the 1^st infusion of CD19hs CAR-T. (A–D) Comparisons of the median concentration of sCD25 (A), IL-6 (B), IL-10 (C) and IFN-γ (D), respectively (n=8). The bars represented the range of concentrations for each cytokines within 30 days after the 1^st infusion; medians are shown as straight lines in each bar. P values were determined by T-test, and the significant levels were identified as p<= 0.05. Levels of each cytokine were repeatedly tested 7 times within 30 days after infusion. ns, Not statistically significant.

Figure 4

CD19hs CAR-T expansion after the 1^st infusion in patients. (A) Expansion of CD19hs CAR gene copy numbers (n=8) after infusions. Base line was detected on the Day 0 before CD19hsCAR-T infusion; Peak means the Maximum CAR transgene copy number after infusions. (B) The relative fold change of CAR transgene copy numbers after infusions in patients (n = 8). Median means the relative fold medians in patients after 1^st infusions; Maximum means the peak values of relative fold in each objects. The data were presented as scatter dots with median and range.

Figure 5

Median of peak values of the CAR-T percentage and cell count in PB after infusion of CD19m CAR-T and CD19hs CAR-T, respectively. (A, B) Median of peak values of CAR-T percentage and cell count after the 1^st infusions of CD19m CAR-T (n = 8) and CD19hs CAR-T (n = 8). (C, D) Median of peak values of CAR-T percentage and cell count after the 2^nd infusions of CD19m CAR-T (n = 5) and CD19hs CAR-T (n = 2). Bars represented the range of the peak values within 30 days after infusions. The median values are shown as straight lines in each bar. P values were determined by T-test, and the significant levels were identified as p < = 0.05. Levels of each cytokine were repeatedly tested 7 times within 30 days after infusions. ns, Not statistically significant.

Figure 6

Duration of response and survival rate of patients. (A) The duration of response of the 8 enrolled patients after infusions. (B) Survival rate after infusions. (C) Duration of response following the 1^st CD19mCAR-T or CD19hsCAR-T treatments. (D) Breakdown of duration of response into subgroups with or without HSCT. Data are presented as median values with range. LTFU, lost to follow-up.