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.

CANCER IMMUNOTHERAPY

Splitting signals drives CARs further

Nature Cancer volume 2, pages 873–875 (2021)Cite this article

Subjects

CAR T cell therapies have made great strides in the clinic; however, multiple hurdles limit the efficacy of this approach for solid tumors. A new study has developed an optimized, dual-targeting CAR T cell that overcomes several of these challenges by enhancing T cell persistence and reducing therapy escape due to antigen loss.

Hirabayashi et al. bicistronically encoded two CARs into a single retroviral vector, with one scFv targeting GD2 and the other targeting B7-H3; GD2 and B7-H3 were selected as clinically relevant targets expressed by human neuroblastoma (NB)6. This ‘split-signaling’ CAR approach was first developed by Kloss et al. with a proof-of-concept first-generation CAR (e.g., directed against CD19ζ (‘anti-CD19ζ’)) and a dual-co-stimulatory (CD28 and 4-1BB) CAR (e.g., anti-PSMA.28.BB)7. Here, Hirabayashi et al. demonstrated that a B7-H3-directed CAR bearing 4-1BB co-stimulation and lacking CD3ζ (B7-H3.BB) was able to enhance the anti-tumor activity of T cells expressing a CAR targeting GD2, with CD28 co-stimulation and a CD3ζ domain (GD2.28ζ CAR T cells)6. This approach seemed to provide optimal co-stimulatory signaling from CD28 and 4-1BB while constraining the T cell activation signal of CD3ζ to the GD2.28ζ CAR molecule. In addition, dual targeting of tumor antigens is an attractive approach to limiting antigen loss and the escape of tumors from recognition by CAR T cells, exemplified by pre-clinical and clinical studies evaluating bi-specific anti-CD19–anti-CD20 CAR T cells8,9, among other dual targets.

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

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

Buy

All prices are NET prices.

Fig. 1: Dual CAR expression with split co-stimulation and a shared CD3ζ domain enhances CAR activity.

BioRender.com

References

  1. Carpenito, C. et al. Proc. Natl Acad. Sci. USA 106, 3360–3365 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Milone, M. C. et al. Mol. Ther. 17, 1453–1464 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Annu. Rev. Immunol. 31, 259–283 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. O’Sullivan, D. et al. Immunity 41, 75–88 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kawalekar, O. U. et al. Immunity 44, 380–390 (2016).

    Article  CAS  PubMed  Google Scholar 

  6. Hirabayashi, K. et al. Nat. Cancer https://doi.org/10.1038//s43018-021-00244-2 (2021).

  7. Kloss, C. C., Condomines, M., Cartellieri, M., Bachmann, M. & Sadelain, M. Nat. Biotechnol. 31, 71–75 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Shah, N. N. et al. Nat. Med. 26, 1569–1575 (2020).

    Article  CAS  PubMed  Google Scholar 

  9. Zah, E., Lin, M. Y., Silva-Benedict, A., Jensen, M. C. & Chen, Y. Y. Cancer Immunol. Res. 4, 498–508 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Heczey, A. et al. Mol. Ther. 25, 2214–2224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Feucht, J. et al. Nat. Med. 25, 82–88 (2019).

    Article  CAS  PubMed  Google Scholar 

  12. Wherry, E. J. & Kurachi, M. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Guedan, S. et al. J. Clin. Invest. 130, 3087–3097 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Boucher, J. C. et al. Cancer Immunol. Res. 9, 62–74 (2021).

    Article  CAS  PubMed  Google Scholar 

  15. Kofler, D. M. et al. Mol. Ther. 19, 760–767 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Systems Pharmacology and Translational Therapeutics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Tiffany R. King-Peoples & Avery D. Posey Jr.

  2. Corporal Michael J Crescenz VA Medical Center, Philadelphia, PA, USA

    Avery D. Posey Jr.

Authors
  1. Tiffany R. King-Peoples
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Avery D. Posey Jr.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Avery D. Posey Jr..

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

King-Peoples, T.R., Posey, A.D. Splitting signals drives CARs further. Nat Cancer 2, 873–875 (2021). https://doi.org/10.1038/s43018-021-00257-x

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s43018-021-00257-x

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing