Mechanisms of resistance to CAR T cell therapy

Abstract

The successes with chimeric antigen receptor (CAR) T cell therapy in early clinical trials involving patients with pre-B cell acute lymphoblastic leukaemia (ALL) or B cell lymphomas have revolutionized anticancer therapy, providing a potentially curative option for patients who are refractory to standard treatments. These trials resulted in rapid FDA approvals of anti-CD19 CAR T cell products for both ALL and certain types of B cell lymphoma — the first approved gene therapies in the USA. However, growing experience with these agents has revealed that remissions will be brief in a substantial number of patients owing to poor CAR T cell persistence and/or cancer cell resistance resulting from antigen loss or modulation. Furthermore, the initial experience with CAR T cells has highlighted challenges associated with manufacturing a patient-specific therapy. Understanding the limitations of CAR T cell therapy will be critical to realizing the full potential of this novel treatment approach. Herein, we discuss the factors that can preclude durable remissions following CAR T cell therapy, with a primary focus on the resistance mechanisms that underlie disease relapse. We also provide an overview of potential strategies to overcome these obstacles in an effort to more effectively incorporate this unique therapeutic strategy into standard treatment paradigms.

Key points

  • Chimeric antigen receptor (CAR) T cell immunotherapy is a highly effective form of adoptive cell therapy, as demonstrated by the remission rates in patients with B cell acute lymphoblastic leukaemia or large B cell lymphoma, which have supported FDA approvals.

  • A complete understanding of the limitations of CAR T cell therapy will help to identify crucial areas requiring further research to improve patient outcomes.

  • Factors that can preclude durable remissions following CAR T cell therapy include CAR T cell manufacturing issues, limited CAR T cell expansion and/or persistence, various resistance mechanisms and toxicities.

  • Various intuitive strategies to overcome these obstacles are being investigated in order to optimize this unique therapeutic strategy and expand the indications for treatment.

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Fig. 1: Limitations to durable remissions after CAR T cell therapy.

References

  1. 1.

    Kalos, M. et al. T cells with chimeric antigen receptors have potent antitumor effects and can establish memory in patients with advanced leukemia. Sci. Transl Med. 3, 95ra73 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    Porter, D. L., Levine, B. L., Kalos, M., Bagg, A. & June, C. H. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N. Engl. J. Med. 365, 725–733 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  3. 3.

    Kochenderfer, J. N. et al. Eradication of B-lineage cells and regression of lymphoma in a patient treated with autologous T cells genetically engineered to recognize CD19. Blood 116, 4099–4102 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  5. 5.

    Rosenbaum, L. Tragedy, perseverance, and chance — the story of CAR-T therapy. N. Engl. J. Med. 377, 1313–1315 (2017).

    PubMed  Article  PubMed Central  Google Scholar 

  6. 6.

    Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  7. 7.

    Lee, D. W. et al. T cells expressing CD19 chimeric antigen receptors for acute lymphoblastic leukaemia in children and young adults: a phase 1 dose-escalation trial. Lancet 385, 517–528 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  8. 8.

    Gardner, R. A. et al. Intent-to-treat leukemia remission by CD19 CAR T cells of defined formulation and dose in children and young adults. Blood 129, 3322–3331 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    Park, J. H. et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic leukemia. N. Engl. J. Med. 378, 449–459 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  10. 10.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  11. 11.

    US Food & Drug Administration. FDA approves CAR-T cell therapy to treat adults with certain types of large B cell lymphoma. FDA https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm581216.htm (2017).

  12. 12.

    US Food & Drug Administration. FDA approval brings first gene therapy to the United States. FDA https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm574058.htm (2017).

  13. 13.

    US Food & Drug Administration. FDA approves tisagenlecleucel for adults with relapsed or refractory large B cell lymphoma. FDA https://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm606540.htm (2018).

  14. 14.

    Tang, J., Hubbard-Lucey, V. M., Pearce, L., O’Donnell-Tormey, J. & Shalabi, A. The global landscape of cancer cell therapy. Nat. Rev. Drug Discov. 17, 465–466 (2018).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    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).

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Jacoby, E. et al. CD19 CAR immune pressure induces B-precursor acute lymphoblastic leukaemia lineage switch exposing inherent leukaemic plasticity. Nat. Commun. 7, 12320 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Gardner, R. et al. Acquisition of a CD19-negative myeloid phenotype allows immune escape of MLL-rearranged B-ALL from CD19 CAR-T cell therapy. Blood 127, 2406–2410 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Mueller, K. T. et al. Cellular kinetics of CTL019 in relapsed/refractory B cell acute lymphoblastic leukemia and chronic lymphocytic leukemia. Blood 130, 2317–2325 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Stroncek, D. F. et al. Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells. J. Transl Med. 15, 59 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  20. 20.

    Ceppi, F. et al. Lymphocyte apheresis for chimeric antigen receptor T cell manufacturing in children and young adults with leukemia and neuroblastoma. Transfusion 58, 1414–1420 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Das, R. K., Storm, J. & Barrett, D. M. T cell dysfunction in pediatric cancer patients at diagnosis and after chemotherapy can limit chimeric antigen receptor potential. Cancer Res. 78 (Suppl), 1631 (2018).

    Google Scholar 

  22. 22.

    Singh, N., Perazzelli, J., Grupp, S. A. & Barrett, D. M. Early memory phenotypes drive T cell proliferation in patients with pediatric malignancies. Sci. Transl Med. 8, 320ra3 (2016).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  23. 23.

    Zhang, H. et al. Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122, 1105–1113 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    De Veirman, K. et al. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front. Oncol. 4, 349 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  25. 25.

    Levine, B. L., Miskin, J., Wonnacott, K. & Keir, C. Global manufacturing of CAR T cell therapy. Mol. Ther. Methods Clin. Dev. 4, 92–101 (2017).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Wang, X. & Riviere, I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol. Ther. Oncolyt. 3, 16015 (2016).

    CAS  Article  Google Scholar 

  27. 27.

    Tumaini, B. et al. Simplified process for the production of anti-CD19-CAR-engineered T cells. Cytotherapy 15, 1406–1415 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Kochenderfer, J. N. et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J. Immunother. 32, 689–702 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. 29.

    Gargett, T. & Brown, M. P. Different cytokine and stimulation conditions influence the expansion and immune phenotype of third-generation chimeric antigen receptor T cells specific for tumor antigen GD2. Cytotherapy 17, 487–495 (2015).

    CAS  PubMed  Article  Google Scholar 

  30. 30.

    Sommermeyer, D. et al. Chimeric antigen receptor-modified T cells derived from defined CD8 + and CD4 + subsets confer superior antitumor reactivity in vivo. Leukemia 30, 492–500 (2016).

    CAS  PubMed  Article  Google Scholar 

  31. 31.

    Turtle, C. J. et al. CD19 CAR-T cells of defined CD4 + :CD8 + composition in adult B cell ALL patients. J. Clin. Invest. 126, 2123–2138 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  32. 32.

    Zhang, W., Jordan, K. R., Schulte, B. & Purev, E. Characterization of clinical grade CD19 chimeric antigen receptor T cells produced using automated CliniMACS Prodigy system. Drug Des. Devel Ther. 12, 3343–3356 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  33. 33.

    Zhu, F. et al. Closed-system manufacturing of CD19 and dual-targeted CD20/19 chimeric antigen receptor T cells using the CliniMACS Prodigy device at an academic medical center. Cytotherapy 20, 394–406 (2018).

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Sabatino, M. et al. Generation of clinical-grade CD19-specific CAR-modified CD8 + memory stem cells for the treatment of human B cell malignancies. Blood 128, 519–528 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Blaeschke, F. et al. Induction of a central memory and stem cell memory phenotype in functionally active CD4( + ) and CD8( + ) CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19( + ) acute lymphoblastic leukemia. Cancer Immunol. Immunother. 67, 1053–1066 (2018).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Stroncek, D. F. et al. Myeloid cells in peripheral blood mononuclear cell concentrates inhibit the expansion of chimeric antigen receptor T cells. Cytotherapy 18, 893–901 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  38. 38.

    Ruella, M. et al. Induction of resistance to chimeric antigen receptor T cell therapy by transduction of a single leukemic B cell. Nat. Med. 24, 1499–1503 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  39. 39.

    Fesnak, A., Lin, C., Siegel, D. L. & Maus, M. V. CAR-T cell therapies from the transfusion medicine perspective. Transfus. Med. Rev. 30, 139–145 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Shah, N. N. et al. CD4/CD8 T-cell selection enhances CD22 CAR-T cell transduction and in-vivo CAR-T expansion: updated results on phase I anti-CD22 CAR dose expansion cohort. Blood 130, 809 (2017).

    Article  CAS  Google Scholar 

  41. 41.

    Vormittag, P., Gunn, R., Ghorashian, S. & Veraitch, F. S. A guide to manufacturing CAR T cell therapies. Curr. Opin. Biotechnol. 53, 164–181 (2018).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Perica, K., Curran, K. J., Brentjens, R. J. & Giralt, S. A. Building a CAR garage: preparing for the delivery of commercial CAR T cell products at Memorial Sloan Kettering Cancer Center. Biol. Blood Marrow Transplant. 24, 1135–1141 (2018).

    PubMed  Article  Google Scholar 

  43. 43.

    Kawalekar, O. U. et al. Distinct signaling of coreceptors regulates specific metabolism pathways and impacts memory development in CAR T cells. Immunity 44, 380–390 (2016).

    CAS  PubMed  Article  Google Scholar 

  44. 44.

    June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).

    CAS  PubMed  Article  Google Scholar 

  45. 45.

    van der Stegen, S. J., Hamieh, M. & Sadelain, M. The pharmacology of second-generation chimeric antigen receptors. Nat. Rev. Drug Discov. 14, 499–509 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  46. 46.

    Cornetta, K. et al. Absence of replication-competent lentivirus in the clinic: analysis of infused T cell products. Mol. Ther. 26, 280–288 (2018).

    CAS  PubMed  Article  Google Scholar 

  47. 47.

    Cornetta, K. et al. Screening clinical cell products for replication competent retrovirus: the National Gene Vector Biorepository experience. Mol. Ther. Methods Clin. Dev. 10, 371–378 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Qin, D. Y. et al. Paralleled comparison of vectors for the generation of CAR-T cells. Anticancer Drugs 27, 711–722 (2016).

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Golumba-Nagy, V., Kuehle, J. & Abken, H. Genetic modification of T cells with chimeric antigen receptors: a laboratory manual. Hum. Gene Ther. Methods 28, 302–309 (2017).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Riet, T. et al. Nonviral RNA transfection to transiently modify T cells with chimeric antigen receptors for adoptive therapy. Methods Mol. Biol. 969, 187–201 (2013).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Panjwani, M. K. et al. Feasibility and safety of RNA-transfected CD20-specific chimeric antigen receptor T cells in dogs with spontaneous B cell lymphoma. Mol. Ther. 24, 1602–1614 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Monjezi, R. et al. Enhanced CAR T cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia 31, 186–194 (2017).

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Singh, H., Huls, H., Kebriaei, P. & Cooper, L. J. A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol. Rev. 257, 181–190 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  54. 54.

    Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  55. 55.

    de Wolf, C., van de Bovenkamp, M. & Hoefnagel, M. Regulatory perspective on in vitro potency assays for human T cells used in anti-tumor immunotherapy. Cytotherapy 20, 601–622 (2018).

    PubMed  Article  CAS  Google Scholar 

  56. 56.

    Xu, J., Melenhorst, J. J. & Fraietta, J. A. Toward precision manufacturing of immunogene T cell therapies. Cytotherapy 20, 623–638 (2018).

    CAS  PubMed  Article  Google Scholar 

  57. 57.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Ghosh, A. et al. Donor CD19 CAR T cells exert potent graft-versus-lymphoma activity with diminished graft-versus-host activity. Nat. Med. 23, 242–249 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Brudno, J. N. et al. Allogeneic T cells that express an anti-CD19 chimeric antigen receptor induce remissions of B-cell malignancies that progress after allogeneic hematopoietic stem-cell transplantation without causing graft-versus-host disease. J. Clin. Oncol. 34, 1112–1121 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  60. 60.

    Chen, Y. et al. Donor-derived CD19-targeted T cell infusion induces minimal residual disease-negative remission in relapsed B cell acute lymphoblastic leukaemia with no response to donor lymphocyte infusions after haploidentical haematopoietic stem cell transplantation. Br. J. Haematol. 179, 598–605 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Kochenderfer, J. N. et al. Donor-derived CD19-targeted T cells cause regression of malignancy persisting after allogeneic hematopoietic stem cell transplantation. Blood 122, 4129–4139 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Georgiadis, C. et al. Long terminal repeat CRISPR-CAR-coupled “universal” T cells mediate potent anti-leukemic effects. Mol. Ther. 26, 1215–1227 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    Poirot, L. et al. Multiplex genome-edited T cell manufacturing platform for “off-the-shelf” adoptive T cell immunotherapies. Cancer Res. 75, 3853–3864 (2015).

    CAS  PubMed  Article  Google Scholar 

  64. 64.

    Cooper, M. L. et al. An “off-the-shelf” fratricide-resistant CAR-T for the treatment of T cell hematologic malignancies. Leukemia 32, 1970–1983 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  65. 65.

    Daher, M. & Rezvani, K. Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr. Opin. Immunol. 51, 146–153 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  66. 66.

    Tang, X. et al. First-in-man clinical trial of CAR NK-92 cells: safety test of CD33-CAR NK-92 cells in patients with relapsed and refractory acute myeloid leukemia. Am. J. Cancer Res. 8, 1083–1089 (2018).

    PubMed  PubMed Central  Google Scholar 

  67. 67.

    US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03579927 (2019).

  68. 68.

    Quintarelli, C. et al. CD19 redirected CAR NK cells are equally effective but less toxic than CAR T cells. Blood 132 (Suppl. 1), 3491 (2018).

    Google Scholar 

  69. 69.

    Hofer, E. & Koehl, U. Natural killer cell-based cancer immunotherapies: from immune evasion to promising targeted cellular therapies. Front. Immunol. 8, 745 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  70. 70.

    US Food & Drug Administration. Package insert — Kymriah. FDA https://www.fda.gov/downloads/UCM573941.pdf (2018).

  71. 71.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    Lowe, K. L. et al. Fludarabine and neurotoxicity in engineered T cell therapy. Gene Ther. 25, 176–191 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  73. 73.

    Novartis. Kymriah treatment center locator. Kymriah https://www.us.kymriah.com/treatment-center-locator/ (2018).

  74. 74.

    Kite Pharma. Where can Yescarta be received? Yescarta https://www.yescarta.com/treatment-centers (2018).

  75. 75.

    European Medicines Agency. First two CAR-T cell medicines recommended for approval in the European Union. EMA https://www.ema.europa.eu/en/news/first-two-car-t-cell-medicines-recommended-approval-european-union (2018).

  76. 76.

    Novartis Pharmaceuticals Canada Inc. Novartis receives Health Canada approval of its CAR-T cell therapy, Kymriah™ (tisagenlecleucel)i. Newswire https://www.newswire.ca/news-releases/novartis-receives-health-canada-approval-of-its-car-t-cell-therapy-kymriah-tisagenlecleuceli-692581041.html (2018).

  77. 77.

    June, C. H., O’Connor, R. S., Kawalekar, O. U., Ghassemi, S. & Milone, M. C. CAR T cell immunotherapy for human cancer. Science 359, 1361–1365 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  78. 78.

    Shah, G. L., Majhail, N., Khera, N. & Giralt, S. Value-based care in hematopoietic cell transplantation and cellular therapy: challenges and opportunities. Curr. Hematol. Malig. Rep. 13, 125–134 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  79. 79.

    Caffrey, M. With approval of CAR T-cell therapy comes the next challenge: payer coverage. Am. J. Manag. Care https://www.ajmc.com/journals/evidence-based-oncology/2018/february-2018/with-approval-of-car-tcell-therapy-comes-the-next-challenge-payer-coverage (2018).

  80. 80.

    Bach, P. B. National coverage analysis of CAR-T therapies — policy, evidence, and payment. N. Engl. J. Med. 379, 1396–1398 (2018).

    PubMed  Article  Google Scholar 

  81. 81.

    Kotani, H. et al. Aged CAR T cells exhibit enhanced cytotoxicity and effector function but shorter persistence and less memory-like phenotypes. Blood 132, 2047 (2018).

    Google Scholar 

  82. 82.

    Gardner, R. et al. Starting T cell and cell product phenotype are associated with durable remission of leukemia following CD19 CAR-T cell immunotherapy. Blood 132, 4022 (2018).

    Google Scholar 

  83. 83.

    Fesnak, A. D., June, C. H. & Levine, B. L. Engineered T cells: the promise and challenges of cancer immunotherapy. Nat. Rev. Cancer 16, 566–581 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Zhao, Z. et al. Structural design of engineered costimulation determines tumor rejection kinetics and persistence of CAR T cells. Cancer Cell 28, 415–428 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  85. 85.

    Kochenderfer, J. N. et al. Chemotherapy-refractory diffuse large B cell lymphoma and indolent B cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor. J. Clin. Oncol. 33, 540–549 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Davila, M. L. et al. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci. Transl Med. 6, 224ra25 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  87. 87.

    Long, A. H. et al. 4-1BB costimulation ameliorates T cell exhaustion induced by tonic signaling of chimeric antigen receptors. Nat. Med. 21, 581–590 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82–88 (2018).

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  89. 89.

    Sadelain, M., Brentjens, R. & Riviere, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  90. 90.

    Maus, M. V. & June, C. H. Making better chimeric antigen receptors for adoptive T cell therapy. Clin. Cancer Res. 22, 1875–1884 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Jung, I. Y. & Lee, J. Unleashing the therapeutic potential of CAR-T cell therapy using gene-editing technologies. Mol. Cells 41, 717–723 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Maus, M. V. Immunology: T cell tweaks to target tumours. Nature 543, 48–49 (2017).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Hasan, A. N., Selvakumar, A. & O’Reilly, R. J. Artificial antigen presenting cells: an off the shelf approach for generation of desirable T-cell populations for broad application of adoptive immunotherapy. Adv. Genet. Eng. 4, 130 (2015).

    PubMed  PubMed Central  Google Scholar 

  96. 96.

    Turtle, C. J. & Riddell, S. R. Artificial antigen-presenting cells for use in adoptive immunotherapy. Cancer J. 16, 374–381 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. 97.

    Butler, M. O. & Hirano, N. Human cell-based artificial antigen-presenting cells for cancer immunotherapy. Immunol. Rev. 257, 191–209 (2014).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Yoon, D. H., Osborn, M. J., Tolar, J. & Kim, C. J. Incorporation of immune checkpoint blockade into chimeric antigen receptor T cells (CAR-Ts): combination or built-in CAR-T. Int. J. Mol. Sci. 19, E340 (2018).

    PubMed  Article  CAS  Google Scholar 

  99. 99.

    Cherkassky, L. et al. Human CAR T cells with cell-intrinsic PD-1 checkpoint blockade resist tumor-mediated inhibition. J. Clin. Invest. 126, 3130–3144 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Gargett, T. et al. GD2-specific CAR T cells undergo potent activation and deletion following antigen encounter but can be protected from activation-induced cell death by PD-1 blockade. Mol. Ther. 24, 1135–1149 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. 101.

    Li, A. M. et al. Checkpoint inhibitors augment CD19-directed chimeric antigen receptor (CAR) T cell therapy in relapsed B-cell acute lymphoblastic leukemia. Blood 132 (Suppl. 1), 556 (2018).

    Google Scholar 

  102. 102.

    Schuster, S. J. et al. Primary analysis of Juliet: a global, pivotal, phase 2 trial of CTL019 in adult patients with relapsed or refractory diffuse large B-cell lymphoma. Blood 130, 577 (2017).

    Google Scholar 

  103. 103.

    Kantarjian, H. M. et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N. Engl. J. Med. 375, 740–753 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  104. 104.

    Gokbuget, N. et al. Blinatumomab for minimal residual disease in adults with B cell precursor acute lymphoblastic leukemia. Blood 131, 1522–1531 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  105. 105.

    Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. 106.

    Martinelli, G. et al. Complete hematologic and molecular response in adult patients with relapsed/refractory philadelphia chromosome-positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. J. Clin. Oncol. 35, 1795–1802 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  107. 107.

    Turtle, C. J. et al. Immunotherapy of non-Hodgkin’s lymphoma with a defined ratio of CD8 + and CD4 + CD19-specific chimeric antigen receptor-modified T cells. Sci. Transl Med. 8, 355ra116 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  108. 108.

    Shalabi, H. et al. Intensification of lymphodepletion optimizes CAR re-treatment efficacy. Blood 130 (Suppl. 1), 3889 (2017).

    Google Scholar 

  109. 109.

    Maude, S. L. et al. Efficacy of humanized CD19-targeted chimeric antigen receptor (CAR)-modified T cells in children and young adults with relapsed/refractory acute lymphoblastic leukemia. Blood 128, 217 (2016).

    Article  CAS  Google Scholar 

  110. 110.

    Zoghbi, A., Zur Stadt, U., Winkler, B., Muller, I. & Escherich, G. Lineage switch under blinatumomab treatment of relapsed common acute lymphoblastic leukemia without MLL rearrangement. Pediatr. Blood Cancer 64, e26594 (2017).

    Article  CAS  Google Scholar 

  111. 111.

    Mejstrikova, E. et al. CD19-negative relapse of pediatric B cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J. 7, 659 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  112. 112.

    Jabbour, E. et al. Outcome of patients with relapsed/refractory acute lymphoblastic leukemia after blinatumomab failure: no change in the level of CD19 expression. Am. J. Hematol. 93, 371–374 (2018).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  113. 113.

    Bhojwani, D. et al. Inotuzumab ozogamicin in pediatric patients with relapsed/refractory acute lymphoblastic leukemia. Leukemia https://doi.org/10.1038/s41375-018-0265-z (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  114. 114.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  115. 115.

    Fischer, J. et al. CD19 isoforms enabling resistance to CART-19 immunotherapy are expressed in B-ALL patients at initial diagnosis. J. Immunother. 40, 187–195 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  116. 116.

    Braig, F. et al. Resistance to anti-CD19/CD3 BiTE in acute lymphoblastic leukemia may be mediated by disrupted CD19 membrane trafficking. Blood 129, 100–104 (2017).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  117. 117.

    Watanabe, K. et al. Target antigen density governs the efficacy of anti-CD20-CD28-CD3 zeta chimeric antigen receptor-modified effector CD8 + T cells. J. Immunol. 194, 911–920 (2015).

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  118. 118.

    Walker, A. J. et al. Tumor antigen and receptor densities regulate efficacy of a chimeric antigen receptor targeting anaplastic lymphoma kinase. Mol. Ther. 25, 2189–2201 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    Caruso, H. G. et al. Tuning sensitivity of CAR to EGFR density limits recognition of normal tissue while maintaining potent antitumor activity. Cancer Res. 75, 3505–3518 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  120. 120.

    Shalabi, H. et al. Sequential loss of tumor surface antigens following chimeric antigen receptor T cell therapies in diffuse large B cell lymphoma. Haematologica 103, e215–e218 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  121. 121.

    Krenciute, G. et al. Transgenic expression of IL15 improves antiglioma activity of IL13Ralpha2-CAR T cells but results in antigen loss variants. Cancer Immunol. Res. 5, 571–581 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  123. 123.

    O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl Med. 9, eaaa0984 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  124. 124.

    Piccaluga, P. P. et al. Surface antigens analysis reveals significant expression of candidate targets for immunotherapy in adult acute lymphoid leukemia. Leuk. Lymphoma 52, 325–327 (2011).

    PubMed  Article  Google Scholar 

  125. 125.

    Nagel, I. et al. Hematopoietic stem cell involvement in BCR-ABL1-positive ALL as a potential mechanism of resistance to blinatumomab therapy. Blood 130, 2027–2031 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  126. 126.

    Raponi, S. et al. Flow cytometric study of potential target antigens (CD19, CD20, CD22, CD33) for antibody-based immunotherapy in acute lymphoblastic leukemia: analysis of 552 cases. Leuk. Lymphoma 52, 1098–1107 (2011).

    CAS  PubMed  Article  Google Scholar 

  127. 127.

    Shah, N. N. et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr. Blood Cancer 62, 964–969 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Chevallier, P. et al. Simultaneous study of five candidate target antigens (CD20, CD22, CD33, CD52, HER2) for antibody-based immunotherapy in B-ALL: a monocentric study of 44 cases. Leukemia 23, 806–807 (2009).

    CAS  PubMed  Article  Google Scholar 

  129. 129.

    Mitterbauer-Hohendanner, G. & Mannhalter, C. The biological and clinical significance of MLL abnormalities in haematological malignancies. Eur. J. Clin. Invest. 34 (Suppl. 2), 12–24 (2004).

    CAS  PubMed  Article  Google Scholar 

  130. 130.

    Chien, C. D. et al. FLT3 chimeric antigen receptor T cell therapy induces B to T cell lineage switch in infant acute lymphoblastic leukemia. Cancer Res. 78 (Suppl), 1630 (2018).

    Google Scholar 

  131. 131.

    Schneider, D. et al. A tandem CD19/CD20 CAR lentiviral vector drives on-target and off-target antigen modulation in leukemia cell lines. J. Immunother. Cancer 5, 42 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Ruella, M. et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest. 126, 3814–3826 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Qin, H. et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol. Ther. Oncolyt. 11, 127–137 (2018).

    CAS  Article  Google Scholar 

  134. 134.

    Shalabi, H. et al. Chimeric antigen receptor T-cell (CAR-T) therapy can render patients with ALL into PCR-negative remission and can be an effective bridge to transplant (HCT). Biol. Blood Marrow Transplant. 24, S25–S26 (2018).

    Article  Google Scholar 

  135. 135.

    Summers, C. et al. Long term follow-up after SCRI-CAR19v1 reveals late recurrences as well as a survival advantage to consolidation with HCT after CAR T cell induced remission. Blood 132, 967 (2018).

    Google Scholar 

  136. 136.

    Hay, K. A. et al. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T cell therapy. Blood 130, 2295–2306 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  137. 137.

    Neelapu, S. S. et al. Chimeric antigen receptor T cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).

    CAS  PubMed  Article  Google Scholar 

  138. 138.

    Teachey, D. T. et al. Identification of predictive biomarkers for cytokine release syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Cancer Discov. 6, 664–679 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  139. 139.

    Porter, D., Frey, N., Wood, P. A., Weng, Y. & Grupp, S. A. Grading of cytokine release syndrome associated with the CAR T cell therapy tisagenlecleucel. J. Hematol. Oncol. 11, 35 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  140. 140.

    Gust, J. et al. Endothelial activation and blood-brain barrier disruption in neurotoxicity after adoptive immunotherapy with CD19 CAR-T cells. Cancer Discov. 7, 1404–1419 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  141. 141.

    Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Mahadeo, K. M. et al. Management guidelines for paediatric patients receiving chimeric antigen receptor T cell therapy. Nat. Rev. Clin. Oncol. 16, 45–63 (2018).

    Article  CAS  Google Scholar 

  143. 143.

    Lee, D. W. et al. ASBMT Consensus Grading for cytokine release syndrome and neurological toxicity associated with immune effector cells. Biol. Blood Marrow Transplant. https://doi.org/10.1016/j.bbmt.2018.12.758 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  144. 144.

    Gardner, R. et al. Decreased rates of severe CRS seen with early intervention strategies for CD19 CAR-T cell toxicity management. Blood 128, 586 (2016).

    Article  CAS  Google Scholar 

  145. 145.

    Perales, M. A., Kebriaei, P., Kean, L. S. & Sadelain, M. Reprint of: building a safer and faster CAR: seatbelts, airbags, and CRISPR. Biol. Blood Marrow Transplant. 24, S15–S19 (2018).

    PubMed  Article  PubMed Central  Google Scholar 

  146. 146.

    Yu, H. et al. Repeated loss of target surface antigen after immunotherapy in primary mediastinal large B cell lymphoma. Am. J. Hematol. 92, E11–E13 (2017).

    CAS  PubMed  Article  Google Scholar 

  147. 147.

    Kochenderfer, J. N. et al. Long-duration complete remissions of diffuse large B cell lymphoma after anti-CD19 chimeric antigen receptor T cell therapy. Mol. Ther. 25, 2245–2253 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  148. 148.

    Budde, L. et al. Remissions of acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm following treatment with CD123-specific CAR T cells: a first-in-human clinical trial. Blood 130 (Suppl), 811 (2017).

    Google Scholar 

  149. 149.

    Yang, L. et al. Preclinical efficacy of CD33 chimeric antigen receptor T cell immunotherapy in childhood acute myeloid leukemia. Pediatr. Blood Cancer 65 (Suppl.), O-100 (2018).

    Google Scholar 

  150. 150.

    Schmidts, A. & Maus, M. V. Making CAR T cells a solid option for solid tumors. Front. Immunol. 9, 2593 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  151. 151.

    Morgan, M. A. & Schambach, A. Engineering CAR-T cells for improved function against solid tumors. Front. Immunol. 9, 2493 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  152. 152.

    Watanabe, K., Kuramitsu, S., Posey, A. D. Jr & June, C. H. Expanding the therapeutic window for CAR T cell therapy in solid tumors: the knowns and unknowns of CAR T cell biology. Front. Immunol. 9, 2486 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  153. 153.

    DeRenzo, C., Krenciute, G. & Gottschalk, S. The landscape of CAR T cells beyond acute lymphoblastic leukemia for pediatric solid tumors. Am. Soc. Clin. Oncol. Educ. Book 38, 830–837 (2018).

    PubMed  Article  Google Scholar 

  154. 154.

    Kachala, S. S. et al. Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clin. Cancer Res. 20, 1020–1028 (2014).

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Heinmoller, P. et al. HER2 status in non-small cell lung cancer: results from patient screening for enrollment to a phase II study of herceptin. Clin. Cancer Res. 9, 5238–5243 (2003).

    PubMed  Google Scholar 

  156. 156.

    Situ, D. et al. Expression and prognostic relevance of MUC1 in stage IB non-small cell lung cancer. Med. Oncol. 28 (Suppl. 1), 596–604 (2011).

    CAS  Article  Google Scholar 

  157. 157.

    Louis, C. U. et al. Antitumor activity and long-term fate of chimeric antigen receptor-positive T cells in patients with neuroblastoma. Blood 118, 6050–6056 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  158. 158.

    Long, A. H. et al. Reduction of MDSCs with all-trans retinoic acid improves CAR therapy efficacy for sarcomas. Cancer Immunol. Res. 4, 869–880 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Yeku, O. O., Purdon, T. J., Koneru, M., Spriggs, D. & Brentjens, R. J. Armored CAR T cells enhance antitumor efficacy and overcome the tumor microenvironment. Sci. Rep. 7, 10541 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  160. 160.

    Avanzi, M. P. et al. Engineered tumor-targeted T cells mediate enhanced anti-tumor efficacy both directly and through activation of the endogenous immune system. Cell Rep. 23, 2130–2141 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    Brown, C. E. et al. Optimization of IL13Ralpha2-targeted chimeric antigen receptor T cells for improved anti-tumor efficacy against glioblastoma. Mol. Ther. 26, 31–44 (2018).

    CAS  PubMed  Article  Google Scholar 

  162. 162.

    Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M( + ) diffuse midline gliomas. Nat. Med. 24, 572–579 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    Nellan, A. et al. Durable regression of medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. J. Immunother. Cancer 6, 30 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  164. 164.

    Ahmed, N. et al. HER2-specific chimeric antigen receptor-modified virus-specific T cells for progressive glioblastoma: a phase 1 dose-escalation trial. JAMA Oncol. 3, 1094–1101 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

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Acknowledgements

The work of the authors is supported in part by the Intramural Research Program, the National Cancer Institute and the NIH Clinical Center.

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Nature Reviews Clinical Oncology thanks S. Grupp and other anonymous reviewer(s) for their contribution to the peer review of this work.

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Shah, N.N., Fry, T.J. Mechanisms of resistance to CAR T cell therapy. Nat Rev Clin Oncol 16, 372–385 (2019). https://doi.org/10.1038/s41571-019-0184-6

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