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.

  • Year in Review
  • Published:

CANCER IMMUNOTHERAPY IN 2018

CAR T cell therapy: inroads to response and resistance

Nature Reviews Immunology volume 19, pages 73–74 (2019)Cite this article

Subjects

Here, we highlight key papers published in 2018 that advance our understanding of resistance to chimeric antigen receptor (CAR) T cell immunotherapy for leukaemia and lymphoma and in so doing reveal barriers that must be addressed to increase efficacy of this novel class of therapeutics for B cell malignancies and expand their reach to solid tumours.

Key advances

  • CD19-targeted chimeric antigen receptor (CAR) T cells induce high complete response rates in paediatric B cell acute lymphoblastic leukaemia (B-ALL) cases, but many of these patients will relapse, most often with CD19-negative leukaemia.

  • CD22-directed CAR T cells induce high response rates in CD19-naive or CD19-resistant B-ALL, but often relapse with CD22lo leukaemia.

  • Intrinsic gene programmes of memory versus exhaustion correlate with T cell fitness and determine response to CD19-targeted CAR T cells in chronic lymphocytic leukaemia (CLL).

  • Loss of Tet methylcytosine dioxygenase 2 (TET2), an epigenetic modulator, prevented terminal T cell differentiation and enabled the progeny of a single CD8+ CAR T cell clone to mediate complete remission in a patient with CLL.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Fig. 1: Major mechanisms of acquired resistance to CAR T cells.

References

  1. Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).

    Article  CAS  Google Scholar 

  2. Sotillo, E. et al. Convergence of acquired mutations and alternative splicing of CD19 enables resistance to CART-19 immunotherapy. Cancer Discov. 5, 1282–1295 (2015).

    Article  CAS  Google Scholar 

  3. Bagashev, A. et al. CD19 alterations emerging after CD19-directed immunotherapy cause retention of the misfolded protein in the endoplasmic reticulum. Mol. Cell Biol. https://doi.org/10.1128/MCB.00383-18 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  4. Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).

    Article  Google Scholar 

  5. Neelapu, S. S. et al. Axicabtagene ciloleucel CAR T-cell therapy in refractory large B-cell lymphoma. N. Engl. J. Med. 377, 2531–2544 (2017).

    Article  CAS  Google Scholar 

  6. Fry, T. J. et al. CD22-targeted CAR T cells induce remission in B-ALL that is naive or resistant to CD19-targeted CAR immunotherapy. Nat. Med. 24, 20–28 (2018).

    Article  CAS  Google Scholar 

  7. Brudno, J. N. et al. T cells genetically modified to express an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of poor-prognosis relapsed multiple myeloma. J. Clin. Oncol. 36, 2267–2280 (2018).

    Article  Google Scholar 

  8. Fraietta, J. A. et al. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat. Med. 24, 563–571 (2018).

    Article  CAS  Google Scholar 

  9. Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).

    Article  CAS  Google Scholar 

  10. Rossi, J. et al. Preinfusion polyfunctional anti-CD19 chimeric antigen receptor T cells are associated with clinical outcomes in NHL. Blood 132, 804–814 (2018).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

C.L.M. and C.B. are members of the Parker Institute for Cancer Immunotherapy, which supports the Stanford University and City of Hope Cancer Immunotherapy Program.

Author information

Authors and Affiliations

  1. Heritage Provider Network Professor in Immunotherapy, City of Hope, Duarte, CA, USA

    Christine E. Brown

  2. Ernest and Amelia Gallo Family Professor of Pediatrics and Medicine, Stanford University, Stanford, CA, USA

    Crystal L. Mackall

Authors
  1. Christine E. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Crystal L. Mackall
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Crystal L. Mackall.

Ethics declarations

Competing interests

C.L.M. is a member of the Scientific Advisory board and/or has provided consulting services for Adaptimmune LLC, Allogene, Apricity Health, GlaxoSmithKline Cell and Gene Therapy, Lyell Immunopharma, Nektar, PACT Pharma, Pfizer, Roche, TPG, Unum Therapeutics and Vor Pharmaceuticals. C.L.M. owns equity in Apricity Health, Lyell Immunopharma, PACT Pharma, Unum Therapeutics and Vor Pharmaceuticals and has received research funding from Bluebird Bio and Obsidian Therapeutics. C.B. declares no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Brown, C.E., Mackall, C.L. CAR T cell therapy: inroads to response and resistance. Nat Rev Immunol 19, 73–74 (2019). https://doi.org/10.1038/s41577-018-0119-y

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41577-018-0119-y

This article is cited by

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