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Updated: Jul 26, 2026
Generation of Human Chimeric Antigen Receptor Regulatory T Cells
Published on: January 3, 2025
Preclinical targeting of human T-cell malignancies using CD4-specific chimeric antigen receptor (CAR)-engineered T
K Pinz1, H Liu2, M Golightly2
1R and D, iCell Gene Therapeutics LLC, Long Island High Technology Incubator, Stony Brook, NY, USA.
Abstract:
Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with no effective upfront standard treatment and ineffective options in relapsed disease, resulting in poorer clinical outcomes as compared with B-cell lymphomas. The adoptive transfer of T cells engineered to express chimeric antigen receptors (CARs) is a promising new approach for treatment of hematological malignancies. However, preclinical reports of targeting T-cell lymphoma with CARs are almost non-existent. Here we have designed a CAR, CD4CAR, which redirects the antigen specificity of CD8+ cytotoxic T cells to CD4-expressing cells. CD4CAR T cells derived from human peripheral blood mononuclear cells and cord blood effectively redirected T-cell specificity against CD4+ cells in vitro. CD4CAR T cells efficiently eliminated a CD4+ leukemic cell line and primary CD4+ PTCL patient samples in co-culture assays. Notably, CD4CAR T cells maintained a central memory stem cell-like phenotype (CD8+CD45RO+CD62L+) under standard culture conditions. Furthermore, in aggressive orthotropic T-cell lymphoma models, CD4CAR T cells efficiently suppressed the growth of lymphoma cells while also significantly prolonging mouse survival. Combined, these studies demonstrate that CD4CAR-expressing CD8+ T cells are efficacious in ablating malignant CD4+ populations, with potential use as a bridge to transplant or stand-alone therapy for the treatment of PTCLs.
Insights
Chimeric antigen receptor (CAR) T cells targeting CD4+ cells show promise for treating aggressive peripheral T-cell lymphomas (PTCLs). This novel CD4CAR therapy effectively eliminated lymphoma cells in preclinical models, offering a potential new treatment avenue.
Area of Science:
- Immunology
- Oncology
- Cell Therapy
Background:
- Peripheral T-cell lymphomas (PTCLs) are aggressive cancers with limited treatment options and poor outcomes.
- Adoptive T-cell therapy using chimeric antigen receptors (CARs) is a promising strategy for hematological malignancies, but its application in PTCLs is underexplored.
Purpose of the Study:
- To design and evaluate a novel CAR, CD4CAR, for targeting CD4+ cells in the context of PTCL treatment.
- To assess the efficacy and characteristics of CD4CAR-engineered T cells against CD4+ PTCL.
Main Methods:
- Development of CD4CAR construct to redirect CD8+ T cells to recognize CD4+ targets.
- In vitro assessment of CD4CAR T cell activity against CD4+ cell lines and primary PTCL samples.
- Evaluation of CD4CAR T cell phenotype and in vivo efficacy in aggressive orthotropic T-cell lymphoma mouse models.
Main Results:
- CD4CAR T cells effectively redirected T-cell specificity to CD4+ cells and eliminated CD4+ leukemic cell lines and primary PTCLs in vitro.
- CD4CAR T cells maintained a central memory stem cell-like phenotype.
- In vivo studies demonstrated significant suppression of lymphoma growth and prolonged survival in mice.
Conclusions:
- CD4CAR-expressing CD8+ T cells are effective in targeting and eliminating malignant CD4+ populations in PTCL.
- This approach holds potential as a bridge to transplant or as a standalone therapy for PTCL treatment.
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