CAR T-Cell Therapy in R/R B-ALL: High Remission Rates, New Allogeneic Option, and TP53 Prognostic Impact
In R/R B-ALL, CAR T-cell therapy shows a pooled complete remission rate of 83.4%, with 4-1BB CD19-targeted constructs offering the best efficacy and safety. A phase 1 trial of non-gene-edited allogeneic ThisCAR-T showed promising activity, and TP53 alterations emerged as a strong adverse prognostic factor.
Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment landscape of relapsed/refractory B-cell precursor acute lymphoblastic leukemia (R/R B-ALL), with a pooled complete remission rate of 83.4% across 40 clinical trials, but durable responses remain a major challenge. A phase 1 study of ThisCAR-T, a non-gene-edited, CD19-directed allogeneic CAR-T cell product, demonstrated a favorable safety profile and promising antileukemic activity, while a retrospective study identified TP53 alterations as a strong adverse prognostic factor in pediatric and young adult patients treated with tisagenlecleucel.
Autologous CAR-T cell therapy is effective in R/R B-ALL, but its clinical application is restricted by manufacturing failures, high costs, and limited accessibility. Gene-edited allogeneic CAR-T cells offer an off-the-shelf alternative, yet concerns remain regarding genomic instability and graft-versus-host disease (GVHD).
In the phase 1 study, eleven patients were treated with escalating doses of ThisCAR-T at 1 × 10^6, 3 × 10^6, and 5 × 10^6 cells/kg. One patient withdrew after infusion. Among the remaining ten patients, eight developed cytokine release syndrome, including seven with grade 1–2 and one with grade 3. Immune effector cell-associated neurotoxicity syndrome occurred in two patients (grade 1 and grade 4, respectively). No GVHD was observed. At day 28, 8 of 9 evaluable patients achieved complete remission (CR) or CR with incomplete hematologic recovery (CRi). At a median follow-up of 31 months, the 1-year progression-free survival and overall survival rates were 30% and 40%, respectively.
A single-center retrospective study of 69 pediatric and young adult patients with r/r B-ALL treated with tisagenlecleucel evaluated the prognostic impact of TP53 alterations (mutations and/or deletions). Among 49 patients with available samples, 17 (34.7%) had TP53 alterations. These patients showed significantly lower remission rates (68.8% vs. 93.8%, p = 0.033) and worse event-free survival (EFS) and overall survival (OS), independent of genetic risk group. Median EFS was 3.8 months (95% CI: 1.2–NE) for those with TP53 alterations versus 50.9 months (95% CI: 23.9–NE) for TP53 wild-type. Three-year EFS and OS were 33.1% and 37.2% for TP53-altered patients, compared to 56.2% and 81.2% for TP53 wild-type (p = 0.0069 and p = 0.0010, respectively). The findings identify TP53 alterations as a strong adverse prognostic factor, and screening may guide risk-adapted strategies, including early consolidation with hematopoietic stem cell transplantation.
A systematic review and meta-analysis comparing the efficacy and safety of different CAR T-cell constructs across 40 clinical trials, including 1,540 R/R B-ALL patients, found a pooled complete remission rate of 83.4% (I2 = 49%) and a minimal residual disease-negative complete remission (MRDneg-CR/CRi) rate of 92.7% (I2 = 48%). 4-1BB co-stimulatory domain constructs showed higher MRDneg-CR/CRi rates compared with CD28 (94.0% vs. 84.4%, p = 0.048) and a lower incidence of immune effector cell-associated neurotoxicity syndrome. Additionally, CAR T-cell products targeting CD19 or CD19/CD22 presented higher MRDneg-CR/CRi rates than those targeting CD22 alone. The findings suggest that 4-1BB-based CAR T-cell therapy targeting CD19 offers the best efficacy and safety profile in R/R B-ALL.