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.
-
Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications
Signal Transduction and Targeted Therapy Open Access 26 April 2024
-
Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer
Military Medical Research Open Access 08 November 2023
-
Characteristics of premanufacture CD8+ T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma
Signal Transduction and Targeted Therapy Open Access 25 October 2023
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
References
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
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).
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).
Orlando, E. J. et al. Genetic mechanisms of target antigen loss in CAR19 therapy of acute lymphoblastic leukemia. Nat. Med. 24, 1504–1506 (2018).
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).
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).
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).
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).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
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).
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
Corresponding author
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
About this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41577-018-0119-y
This article is cited by
-
Induced pluripotent stem cells (iPSCs): molecular mechanisms of induction and applications
Signal Transduction and Targeted Therapy (2024)
-
Insights gained from single-cell analysis of chimeric antigen receptor T-cell immunotherapy in cancer
Military Medical Research (2023)
-
Development of a cGMP-compliant process to manufacture donor-derived, CD45RA-depleted memory CD19-CAR T cells
Gene Therapy (2023)
-
Characteristics of premanufacture CD8+ T cells determine CAR-T efficacy in patients with diffuse large B-cell lymphoma
Signal Transduction and Targeted Therapy (2023)
-
Dominant-negative transforming growth factor-β receptor-armoured mesothelin-targeted chimeric antigen receptor T cells slow tumour growth in a mouse model of ovarian cancer
Cancer Immunology, Immunotherapy (2023)