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Peer-reviewedCC BY 4.0Frontiers in Immunology

Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia: a perspective

  • JiLi Xu1
  • Lili Sui2
  • Wenzhe Yang3
  • Li Xu4
  • Mingliang Shan2
4 affiliations
  1. 1College of Traditional Chinese Medicine, Shandong Medical and Pharmaceutical University
  2. 2Gaomi Maternity and Child Health Hospital
  3. 3Shandong University of Traditional Chinese Medicine
  4. 4Shandong Second Medical University
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Abstract

Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable remission rates exceeding 80% in relapsed/refractory pediatric B-cell acute lymphoblastic leukemia (B-ALL), yet 40–50% of patients eventually relapse within the first year. This therapeutic ceiling is not a single failure mode but the convergence of at least four interrelated layers: loss of CAR-T persistence, antigen escape driven by CD19 splicing variants and lineage switch, CAR-T cell-intrinsic exhaustion from chronic tonic signaling, and an immunosuppressive bone marrow microenvironment that actively extinguishes effector function. Our systematic analysis of 226 pediatric-eligible CAR-T trials shows that 95.6% are Phase I–II, 3.5% (8/226) are registered as Phase III/IV, and 58 of 102 completed trials (56.9%) had no outcome recorded in the source database. In this Perspective, we synthesize the molecular mechanisms of CAR-T resistance, contextualize them within the current clinical trial landscape, and critically evaluate emerging engineering strategies—from dual-targeting and armored CAR architectures to CRISPR-edited allogeneic products and in vivo mRNA delivery. We argue that progress depends on both smarter receptor design and structural reforms in trial design, outcome transparency and global collaboration.

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Cite

BibTeXRIS
BibTeX
@article{xu2026resistance,
  title = {{Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia: a perspective}},
  author = {JiLi Xu and Lili Sui and Wenzhe Yang and Li Xu and Mingliang Shan},
  journal = {Frontiers in Immunology},
  year = {2026},
  month = oct,
  doi = {10.3389/fimmu.2026.1909384},
  url = {https://www.frontiersin.org/articles/10.3389/fimmu.2026.1909384/full},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Resistance mechanisms and translational bottlenecks in CAR-T cell therapy for pediatric acute lymphoblastic leukemia: a perspective
AU  - JiLi Xu
AU  - Lili Sui
AU  - Wenzhe Yang
AU  - Li Xu
AU  - Mingliang Shan
PY  - 2026
DA  - 2026/10/06
JO  - Frontiers in Immunology
DO  - 10.3389/fimmu.2026.1909384
UR  - https://www.frontiersin.org/articles/10.3389/fimmu.2026.1909384/full
AB  - Chimeric antigen receptor (CAR)-T cell therapy has achieved remarkable remission rates exceeding 80% in relapsed/refractory pediatric B-cell acute lymphoblastic leukemia (B-ALL), yet 40–50% of patients eventually relapse within the first year. This therapeutic ceiling is not a single failure mode but the convergence of at least four interrelated layers: loss of CAR-T persistence, antigen escape driven by CD19 splicing variants and lineage switch, CAR-T cell-intrinsic exhaustion from chronic tonic signaling, and an immunosuppressive bone marrow microenvironment that actively extinguishes effector function. Our systematic analysis of 226 pediatric-eligible CAR-T trials shows that 95.6% are Phase I–II, 3.5% (8/226) are registered as Phase III/IV, and 58 of 102 completed trials (56.9%) had no outcome recorded in the source database. In this Perspective, we synthesize the molecular mechanisms of CAR-T resistance, contextualize them within the current clinical trial landscape, and critically evaluate emerging engineering strategies—from dual-targeting and armored CAR architectures to CRISPR-edited allogeneic products and in vivo mRNA delivery. We argue that progress depends on both smarter receptor design and structural reforms in trial design, outcome transparency and global collaboration.
SN  - 1664-3224
ER  -