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DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma

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Abstract

Chimeric antigen receptor (CAR) T cell therapies hold great potential for treating cancers, and new CARs that can target multiple tumor types and have the potential to target non-hematological malignancies are needed. In this study, the tumor recognition ability of a natural killer cell-activating receptor, DNAM-1 was harnessed to design CARs that target multiple tumor types. DNAM-1 ligands, PVR and nectin-2, are expressed on primary human leukemia, myeloma, ovarian cancer, melanoma, neuroblastoma, and Ewing sarcoma. DNAM-1 CARs exhibit high tumor cell cytotoxicity but low IFN-γ secretion in vitro. In contrast to other CAR designs, co-stimulatory domains did not improve the expression and function of DNAM-1 CARs. A DNAM-1/CD3zeta CAR reduced tumor burden in a murine melanoma model in vivo. In conclusion, DNAM-1-based CARs may have the potential to treat PVR and nectin-2 expressing hematological and solid tumors.

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Abbreviations

B6:

C57BL/6

CAR:

Chimeric antigen receptor

51Cr:

51Chromium

CYP:

Cytoplasmic

DC:

Dendritic cell

DNAM-1:

DNAX accessory molecule-1

EC:

Extracellular

MFI:

Mean fluorescent intensity

NK:

Natural killer

PI-3 kinase:

Phosphoinositide-3 kinase

PIP2:

Phosphatidylinositol-4,5-bisphosphate

scFv:

Single-chain variable fragment

TM:

Transmembrane

TME:

Tumor microenvironment

UnTd:

Untransduced

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Acknowledgments

The authors thank the National Cancer Institute Biological Resource Branch for providing recombinant human IL-2, Dartmouth College Molecular biology Core for technical support, and the Center for Comparative Medicine and Research for providing animal care. This work was supported by a National Institute of Health grant CA130911.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, One Medical Center Drive, Lebanon, NH, 03756, USA

    Ming-Ru Wu, Tong Zhang, Andre Alcon & Charles L. Sentman

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  1. Ming-Ru Wu
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  2. Tong Zhang
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  3. Andre Alcon
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  4. Charles L. Sentman
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Correspondence to Charles L. Sentman.

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Wu, MR., Zhang, T., Alcon, A. et al. DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma. Cancer Immunol Immunother 64, 409–418 (2015). https://doi.org/10.1007/s00262-014-1648-2

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  • DOI: https://doi.org/10.1007/s00262-014-1648-2

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