Removing made engineered T cells more persistent, less exhausted, and more cytotoxic in preclinical cancer models.
Evidence
The study combined murine models, tumor xenograft experiments, clinical specimens, single-cell transcriptomics, and TCR repertoire analysis of CD5-deficient engineered T cells.
Caveat
The antitumor evidence comes from preclinical models and patient-derived cell analyses, not from clinical efficacy testing in treated patients.
Simplified
BACKGROUND: While chimeric antigen receptor (CAR)-T cell therapy has transformed the treatment landscape for certain hematologic malignancies, therapeutic resistance and disease relapse highlight the critical need to improve the durability of clinical responses. The limited in vivo persistence and antitumor efficacy of CAR-T cells remain major barriers to achieving sustained therapeutic outcomes. Although has been extensively studied as a therapeutic target in cancers, particularly T-cell malignancies, its role as an immunomodulatory molecule in T cell-based immunotherapy remains poorly understood. Here, we developed a CD5-deficient T cell-based immunotherapy using the CRISPR-Cas9 system to address these limitations and enhance antitumor potency.
METHODS: Employing green fluorescent protein knock-in murine models alongside clinical specimens, we examined the in vivo persistence of CD5-deficient T cells and their influence on T-cell receptor (TCR) clonality diversity. The antitumor efficacy of CD5-deficient engineered T cells was assessed in tumor cell line-derived xenograft murine models. To elucidate underlying mechanisms, we performed a comprehensive evaluation of the activation, expansion and infiltration of CD5-deficient engineered T cells in response to antigen stimulation, as well as their exhaustion dynamics under conditions of repeated antigen exposure.
RESULTS: Our study identifies CD5 as a bona fide inhibitory immunomodulatory molecule. CD5 ablation significantly enhances T cell functionality by enhancing the activation level, mitigating exhaustion, promoting CD8T cell expansion, and improving in vivo persistence. Single-cell transcriptomic profiling of patient-derived CD5-deficient T cells revealed distinct effector subsets with elevated cytotoxicity markers and cell cycle regulators, such as STMN1, which correlate with enhanced expansion while preserving clonal diversity, as evidenced by TCR repertoire analysis. +
CONCLUSIONS: These collective findings establish CD5 ablation as a viable strategy to circumvent the intrinsic limitations of current T cell-based therapies, providing a mechanistic rationale for clinical translation.
Key numbers
85.59%
Increase in -deficient cell frequency
Frequency of -deficient on day 26 post-infusion.
≥94%
Indel frequency at gene locus
Measured in patient-derived post-manufacturing.
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