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Nat Med. 2015 May;21(5):524-9. doi: 10.1038/nm.3833. Epub 2015 Apr 13.

Heparanase promotes tumor infiltration and antitumor activity of CAR-redirected T lymphocytes.

Author information

1
Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA.
2
1] Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA. [2] Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
3
Biostatistics Shared Resource, Baylor College of Medicine, Houston, Texas, USA.
4
Department of Surgery, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas, USA.
5
1] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. [2] Interdepartmental Program in Translational Biology and Molecular Medicine, Baylor College of Medicine, Houston, Texas, USA. [3] Michael E. DeBakey Department of Veterans Affairs Medical Center, Dan L. Duncan Cancer Center, Houston, Texas, USA.
6
Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA.
7
1] Center for Cell and Gene Therapy, Baylor College of Medicine and Houston Methodist Hospital, Houston, Texas, USA. [2] Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas, USA. [3] Department of Medicine, Baylor College of Medicine, Houston, Texas, USA.

Abstract

Adoptive transfer of chimeric antigen receptor (CAR)-redirected T lymphocytes (CAR-T cells) has had less striking therapeutic effects in solid tumors than in lymphoid malignancies. Although active tumor-mediated immunosuppression may have a role in limiting the efficacy of CAR-T cells, functional changes in T lymphocytes after their ex vivo manipulation may also account for the reduced ability of cultured CAR-T cells to penetrate stroma-rich solid tumors compared with lymphoid tissues. We therefore studied the capacity of human in vitro-cultured CAR-T cells to degrade components of the extracellular matrix (ECM). In contrast to freshly isolated T lymphocytes, we found that in vitro-cultured T lymphocytes lack expression of the enzyme heparanase (HPSE), which degrades heparan sulfate proteoglycans, the main components of ECM. We found that HPSE mRNA is downregulated in in vitro-expanded T cells, which may be a consequence of p53 (officially known as TP53, encoding tumor protein 53) binding to the HPSE gene promoter. We therefore engineered CAR-T cells to express HPSE and showed their improved capacity to degrade the ECM, which promoted tumor T cell infiltration and antitumor activity. The use of this strategy may enhance the activity of CAR-T cells in individuals with stroma-rich solid tumors.

PMID:
25849134
PMCID:
PMC4425589
DOI:
10.1038/nm.3833
[Indexed for MEDLINE]
Free PMC Article

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