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Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells.
Cancer Res. 2011 Mar 15; 71(6):2066-76.CR

Abstract

T-cell immunotherapy is a promising strategy to treat cancer, but its efficacy, complexity, and costs may pose challenges. In this study, we report the results of an investigation of a new approach to selectively activate a T-cell attack against tumor cells. The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer)-activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-γ, and cytotoxicity against NKG2D ligand-positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand-positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival. Administration of scFv-NKG2D in vivo also promoted survival in a murine lymphoma model. Tumor-free mice were resistant to rechallenge with cognate tumor cells, suggesting that a host-specific immunologic memory response had been generated. Host adaptive immunity including γδ T cells was required for scFv-NKG2D-mediated therapeutic efficacy. ScFv-NKG2D also inhibited the growth of NKG2D ligand-negative B16F10 tumors, reduced the percentage of myeloid-derived suppressor cells and regulatory T cells, and increased the infiltration of T cells, suggesting that scFv-NKG2D may target these immune suppressive cells. Together, these results establish scFv-NKG2D as a promising biological fusion protein to induce effective antitumor immunity.

Authors+Show Affiliations

Department of Microbiology and Immunology, Dartmouth Medical School, Lebanon, New Hampshire 03756, USA. Tong.Zhang@dartmouth.eduNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21282338

Citation

Zhang, Tong, and Charles L. Sentman. "Cancer Immunotherapy Using a Bispecific NK Receptor Fusion Protein That Engages Both T Cells and Tumor Cells." Cancer Research, vol. 71, no. 6, 2011, pp. 2066-76.
Zhang T, Sentman CL. Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. Cancer Res. 2011;71(6):2066-76.
Zhang, T., & Sentman, C. L. (2011). Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. Cancer Research, 71(6), 2066-76. https://doi.org/10.1158/0008-5472.CAN-10-3200
Zhang T, Sentman CL. Cancer Immunotherapy Using a Bispecific NK Receptor Fusion Protein That Engages Both T Cells and Tumor Cells. Cancer Res. 2011 Mar 15;71(6):2066-76. PubMed PMID: 21282338.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Cancer immunotherapy using a bispecific NK receptor fusion protein that engages both T cells and tumor cells. AU - Zhang,Tong, AU - Sentman,Charles L, Y1 - 2011/01/31/ PY - 2011/2/2/entrez PY - 2011/2/2/pubmed PY - 2011/7/26/medline SP - 2066 EP - 76 JF - Cancer research JO - Cancer Res. VL - 71 IS - 6 N2 - T-cell immunotherapy is a promising strategy to treat cancer, but its efficacy, complexity, and costs may pose challenges. In this study, we report the results of an investigation of a new approach to selectively activate a T-cell attack against tumor cells. The immunotherapeutic approach we developed utilizes a bifunctional fusion protein that binds tumor cells through NK (natural killer)-activating receptor NKG2D and that recruits and stimulates T cells through an anti-CD3 single-chain variable fragment (scFv-NKG2D). In vitro, this scFv-NKG2D fusion protein engaged both T cells and tumor cells, stimulating T cells to produce IFN-γ, and cytotoxicity against NKG2D ligand-positive tumor cells. In vivo, expression of scFv-NKG2D by NKG2D ligand-positive tumor cells reduced tumor burden and, in some cases, led to tumor-free survival. Administration of scFv-NKG2D in vivo also promoted survival in a murine lymphoma model. Tumor-free mice were resistant to rechallenge with cognate tumor cells, suggesting that a host-specific immunologic memory response had been generated. Host adaptive immunity including γδ T cells was required for scFv-NKG2D-mediated therapeutic efficacy. ScFv-NKG2D also inhibited the growth of NKG2D ligand-negative B16F10 tumors, reduced the percentage of myeloid-derived suppressor cells and regulatory T cells, and increased the infiltration of T cells, suggesting that scFv-NKG2D may target these immune suppressive cells. Together, these results establish scFv-NKG2D as a promising biological fusion protein to induce effective antitumor immunity. SN - 1538-7445 UR - https://www.unboundmedicine.com/medline/citation/21282338/Cancer_immunotherapy_using_a_bispecific_NK_receptor_fusion_protein_that_engages_both_T_cells_and_tumor_cells_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=21282338 DB - PRIME DP - Unbound Medicine ER -