Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity

Gene Therapy volume 22, pages 675–684 (2015)Cite this article

Subjects

Abstract

Chimeric antigen receptor (CAR) T-cell therapies have demonstrated durable and potentially curative therapeutic efficacy against B-cell leukemia in clinical trials. A CAR strategy can target any tumor surface antigens as long as an antigen-binding receptor can be generated. New CARs that target solid tumors and have the potential to target multiple tumor types are needed. In this study, B7H6, a ligand for the NK cell activating receptor NKp30, was targeted to create a CAR that targets multiple tumor types. B7H6 is expressed on various primary human tumors, including leukemia, lymphoma and gastrointestinal stromal tumors, but it is not constitutively expressed on normal tissues. B7H6-specific CAR T cells have robust cellular cytotoxicity and interferon-γ secretion when co-cultured with B7H6+ tumor cells, and they exhibit little self-reactivity to immature dendritic cells or pro-inflammatory monocytes. In vivo, B7H6-specific CAR T cells greatly enhanced the survival of RMA/B7H6 lymphoma-bearing mice. The long-term survivor mice were protected against a B7H6-deficient tumor re-challenge. This CAR therapy also decreased tumor burden in a murine ovarian cancer model. In conclusion, B7H6-specific CARs have the potential to treat B7H6+ hematologic and solid tumors.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

References

  1. Porter DL, Levine BL, Kalos M, Bagg A, June CH . Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med 2011; 365: 725–733.

    Article  CAS  Google Scholar 

  2. Kalos M, Levine BL, Porter DL, Katz S, Grupp SA, Bagg A et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci Transl Med 2011; 3: 95ra73.

    Article  CAS  Google Scholar 

  3. Grupp SA, Kalos M, Barrett D, Aplenc R, Porter DL, Rheingold SR et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N Engl J Med 2013; 368: 1509–1518.

    Article  CAS  Google Scholar 

  4. Brentjens RJ, Davila ML, Riviere I, Park J, Wang X, Cowell LG et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci Transl Med 2013; 5: 177ra38.

    Article  Google Scholar 

  5. Sadelain M, Brentjens R, Riviere I . The basic principles of chimeric antigen receptor design. Cancer Discov 2013; 3: 388–398.

    Article  CAS  Google Scholar 

  6. Zhang T, Lemoi BA, Sentman CL . Chimeric NK-receptor-bearing T cells mediate antitumor immunotherapy. Blood 2005; 106: 1544–1551.

    Article  CAS  Google Scholar 

  7. Barber A, Zhang T, DeMars LR, Conejo-Garcia J, Roby KF, Sentman CL . Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer. Cancer Res 2007; 67: 5003–5008.

    Article  CAS  Google Scholar 

  8. Zhang T, Wu MR, Sentman CL . An NKp30-based chimeric antigen receptor promotes T cell effector functions and antitumor efficacy in vivo. J Immunol 2012; 189: 2290–2299.

    Article  CAS  Google Scholar 

  9. Lanier LL . NK cell recognition. Annu Rev Immunol 2005; 23: 225–274.

    Article  CAS  Google Scholar 

  10. Pende D, Parolini S, Pessino A, Sivori S, Augugliaro R, Morelli L et al. Identification and molecular characterization of NKp30, a novel triggering receptor involved in natural cytotoxicity mediated by human natural killer cells. J Exp Med 1999; 190: 1505–1516.

    Article  CAS  Google Scholar 

  11. Brandt CS, Baratin M, Yi EC, Kennedy J, Gao Z, Fox B et al. The B7 family member B7-H6 is a tumor cell ligand for the activating natural killer cell receptor NKp30 in humans. J Exp Med 2009; 206: 1495–1503.

    Article  CAS  Google Scholar 

  12. Delahaye NF, Rusakiewicz S, Martins I, Menard C, Roux S, Lyonnet L et al. Alternatively spliced NKp30 isoforms affect the prognosis of gastrointestinal stromal tumors. Nat Med 2011; 17: 700–707.

    Article  CAS  Google Scholar 

  13. Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D et al. Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood 2007; 109: 323–330.

    Article  CAS  Google Scholar 

  14. Ferlazzo G, Tsang ML, Moretta L, Melioli G, Steinman RM, Munz C . Human dendritic cells activate resting natural killer (NK) cells and are recognized via the NKp30 receptor by activated NK cells. J Exp Med 2002; 195: 343–351.

    Article  CAS  Google Scholar 

  15. Simhadri VR, Reiners KS, Hansen HP, Topolar D, Simhadri VL, Nohroudi K et al. Dendritic cells release HLA-B-associated transcript-3 positive exosomes to regulate natural killer function. PLoS One 2008; 3: e3377.

    Article  Google Scholar 

  16. Barth RJ Jr, Mule JJ, Spiess PJ, Rosenberg SA . Interferon gamma and tumor necrosis factor have a role in tumor regressions mediated by murine CD8+ tumor-infiltrating lymphocytes. J Exp Med 1991; 173: 647–658.

    Article  CAS  Google Scholar 

  17. Qin Z, Blankenstein T . CD4+ T cell—mediated tumor rejection involves inhibition of angiogenesis that is dependent on IFN gamma receptor expression by nonhematopoietic cells. Immunity 2000; 12: 677–686.

    Article  CAS  Google Scholar 

  18. Zhang T, Barber A, Sentman CL . Chimeric NKG2D modified T cells inhibit systemic T-cell lymphoma growth in a manner involving multiple cytokines and cytotoxic pathways. Cancer Res 2007; 67: 11029–11036.

    Article  CAS  Google Scholar 

  19. Matta J, Baratin M, Chiche L, Forel JM, Cognet C, Thomas G et al. Induction of B7-H6, a ligand for the natural killer cell-activating receptor NKp30, in inflammatory conditions. Blood 2013; 122: 394–404.

    Article  CAS  Google Scholar 

  20. Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D et al. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 2004; 6: 1–6.

    Article  CAS  Google Scholar 

  21. Zhang J, Grubor V, Love CL, Banerjee A, Richards KL, Mieczkowski PA et al. Genetic heterogeneity of diffuse large B-cell lymphoma. Proc Natl Acad Sci USA 2013; 110: 1398–1403.

    Article  CAS  Google Scholar 

  22. Schaner ME, Ross DT, Ciaravino G, Sorlie T, Troyanskaya O, Diehn M et al. Gene expression patterns in ovarian carcinomas. Mol Biol Cell 2003; 14: 4376–4386.

    Article  CAS  Google Scholar 

  23. Nielsen TO, West RB, Linn SC, Alter O, Knowling MA, O'Connell JX et al. Molecular characterisation of soft tissue tumours: a gene expression study. Lancet 2002; 359: 1301–1307.

    Article  CAS  Google Scholar 

  24. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA et al. Molecular portraits of human breast tumours. Nature 2000; 406: 747–752.

    Article  CAS  Google Scholar 

  25. Morgan RA, Yang JC, Kitano M, Dudley ME, Laurencot CM, Rosenberg SA . Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol Ther 2010; 18: 843–851.

    Article  CAS  Google Scholar 

  26. Morton LM, Wang SS, Devesa SS, Hartge P, Weisenburger DD, Linet MS . Lymphoma incidence patterns by WHO subtype in the United States, 1992-2001. Blood 2006; 107: 265–276.

    Article  CAS  Google Scholar 

  27. Connolly EM, Gaffney E, Reynolds JV . Gastrointestinal stromal tumours. Br J Surg 2003; 90: 1178–1186.

    Article  CAS  Google Scholar 

  28. Barber A, Zhang T, Sentman CL . Immunotherapy with chimeric NKG2D receptors leads to long-term tumor-free survival and development of host antitumor immunity in murine ovarian cancer. J Immunol 2008; 180: 72–78.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank the National Cancer Institute Biological Resource Branch for providing recombinant human IL-2 and the staff of the Center for Comparative Medicine and Research in Dartmouth College for providing animal care. This work was supported by a grant from the NIH CA130911 and funds from the Center for Synthetic Immunity.

Author information

Authors and Affiliations

  1. The Center for Synthetic Immunity and the Department of Microbiology and Immunology, The Geisel School of Medicine at Dartmouth, Lebanon, NH, USA

    M-R Wu, T Zhang & C L Sentman

  2. Department of Obstetrics and Gynecology, Dartmouth-Hitchcock Medical Center, Lebanon, NH, USA

    L R DeMars

Authors
  1. M-R Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. L R DeMars
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C L Sentman
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C L Sentman.

Ethics declarations

Competing interests

Tong Zhang and Charles Sentman are inventors on a patent application covering the B7H6 CAR described in this study. This technology has been licensed by Cardio3 Biosciences. This work is managed in compliance with the policies of Dartmouth College. Ming-Ru Wu and Leslie DeMars declare no potential conflict of interest.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Wu, MR., Zhang, T., DeMars, L. et al. B7H6-specific chimeric antigen receptors lead to tumor elimination and host antitumor immunity. Gene Ther 22, 675–684 (2015). https://doi.org/10.1038/gt.2015.29

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/gt.2015.29

This article is cited by

Search

Advanced search

Quick links