CD19-Targeted Chimeric Antigen Receptor-Modified T Cells Induce Remission in Relapsed B-ALL After UCBT

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CD19-Targeted Chimeric Antigen Receptor-Modified T Cells Induce Remission in Patients with Relapsed Acute B Lymphoblastic Leukemia After Umbilical Cord Blood Transplantation

Umbilical cord blood transplantation (UCBT) is a critical therapeutic alternative for patients with B-cell acute lymphoblastic leukemia (ALL) lacking compatible donors. However, relapse after UCBT remains a significant challenge. Chimeric antigen receptor (CAR)-T cell therapy has emerged as a promising treatment for relapsed/refractory ALL. This study investigated the safety, efficacy, and survival outcomes of CD19-targeted CAR-T cell therapy in 10 pediatric and young adult patients with relapsed B-ALL following UCBT.

Patient Characteristics and Study Design

Between April 2018 and September 2019, 11 patients (3 females, 8 males; median age: 10 years, range: 7–22 years; median weight: 35.0 kg, range: 21.0–72.0 kg) with relapsed B-ALL post-UCBT were enrolled. One patient was excluded due to unsuccessful CAR-T cell manufacturing. The remaining 10 received a median dose of 1.245 × 10⁶ (range: 0.42–3.91 × 10⁶) CD19 CAR-T cells/kg. All patients exhibited ≥30% CD19 expression on leukemic cells at enrollment and were morphologically unresponsive or minimal residual disease (MRD)-positive after UCBT. The study endpoints included relapse, death from primary disease, or loss to follow-up.

CAR-T Cell Manufacturing and Conditioning Regimen

The CAR construct comprised an FMC63-derived anti-CD19 single-chain variable fragment (scFv) fused to a modified IgG4 hinge, CD28 costimulatory domain, and CD3ζ signaling domain. CAR-T cells were manufactured by PersonGen-Anke Cellular Therapeutics Co., Ltd. (Hefei, China). Prior to infusion, patients received conditioning chemotherapy with fludarabine (30 mg/m²/day for 3 days) and cyclophosphamide (300 mg/m²/day for 3 days). The median interval between conditioning and CAR-T infusion was 7 days (range: 4–15 days).

Treatment Outcomes

Response Rates

Nine of 10 patients (90%) achieved MRD-negative complete remission (CR) after the first CAR-T infusion. One patient (Patient 4) failed to respond and received a second infusion but died from a severe pulmonary infection. The median progression-free survival (PFS) among responders was 5.0 months (95% CI: 2.8–27.9 months), with 6-month and 1-year PFS rates of 44.4% (5/9) and 33.3% (4/9), respectively. Median overall survival (OS) was 17.1 months (95% CI: 5.8–32.7 months), with 6-month and 1-year OS rates of 77.8% (8/9) and 55.6% (6/9). Three patients (30%) sustained remission until the end of follow-up (median: 14.2 months; range: 5.8–32.7 months).

Relapse Patterns

Six patients (60%) experienced relapse, categorized as:

  1. CD19-Negative Relapse: One patient (Patient 6) showed undetectable CD19 expression at relapse but remained alive at follow-up.
  2. CD19-Positive Relapse: Five patients received a second CAR-T infusion. Only Patient 1 achieved transient bone marrow remission but developed central nervous system leukemia (CNSL) 12 days later. Others (Patients 2, 3, 8, 9) showed no response.

Survival and Secondary Interventions

Patient 7, a Philadelphia chromosome-positive case, sustained remission with daily dasatinib (100 mg). None of the patients underwent secondary transplantation due to prohibitive risks or costs.

Safety Profile

Cytokine Release Syndrome (CRS) and Neurotoxicity

CRS severity was graded per ASTCT criteria:

  • Grade 1–2: 80% (8/10; 4 grade 1, 4 grade 2).
  • Grade 3: 10% (1/10).
    Common CRS manifestations included fever (90%), hypotension (40%), pleural effusion (50%), elevated bilirubin (20%), and intestinal obstruction (10%). Neurotoxicity occurred in 10% (1/10), with Patient 11 developing grade 4 CAR-T-related encephalopathy syndrome (CRES) characterized by recurrent seizures.

Cytokine Dynamics

Inflammatory markers peaked post-infusion (Figure 1):

  • Serum Ferritin (SF): Elevated up to 45,000 ng/mL (Patient 3).
  • C-Reactive Protein (CRP): Peaked at 180 mg/L (Patient 11).
  • IL-6 and IL-10: Highest levels (320 pg/mL and 85 pg/mL, respectively) correlated with severe CRS.
  • Granzyme B: Increased transiently (peak: 250 pg/mL).

Tocilizumab was administered to 80% (8/10) for CRS management; glucocorticoids were used in 20% (2/10). All adverse events resolved with treatment.

Graft-Versus-Host Disease (GVHD)

No acute or chronic GVHD occurred during follow-up, likely due to the short persistence of CAR-T cells (median peak at 7.4 days post-infusion) and lower cell doses compared to donor lymphocyte infusions.

CAR-T Cell Expansion and Persistence

Quantitative PCR and flow cytometry revealed CAR-T cell expansion peaking at a median of 7.4 days post-infusion. By day 30, CD19+ B-cells were nearly undetectable in peripheral blood of 90% (9/10) patients.

Mechanistic Insights and Limitations

Relapse Mechanisms

  1. CD19-Negative Escape:Immune pressure or lineage switch may lead to antigen loss..
  2. CD19-Positive Relapse: Limited CAR-T persistence and transient B-cell aplasia likely contributed.

Challenges in Reinfusion

Five patients received repeated CD19 CAR-T infusions, but efficacy was poor. Combining CAR-T cells targeting alternate antigens (e.g., CD22) or optimizing CAR designs (e.g., dual-targeting) may improve outcomes.

Conclusion

CD19 CAR-T therapy demonstrated high remission rates (90% MRD-negative CR) and manageable toxicity in relapsed B-ALL post-UCBT. However, relapse remains a major hurdle, necessitating strategies like multi-target CAR-T cells or consolidation therapies. This study underscores CAR-T therapy as a viable salvage option for UCBT failures, warranting validation in larger multicenter trials.

doi.org/10.1097/CM9.0000000000001491

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