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).
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).
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).
Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Rosenbaum, L. Tragedy, perseverance, and chance — the story of CAR-T therapy. N. Engl. J. Med. 377, 1313–1315 (2017).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
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).
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).
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).
Maude, S. L. et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N. Engl. J. Med. 378, 439–448 (2018).
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).
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).
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).
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).
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).
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).
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).
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).
Stroncek, D. F. et al. Elutriated lymphocytes for manufacturing chimeric antigen receptor T cells. J. Transl Med. 15, 59 (2017).
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).
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).
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).
Zhang, H. et al. Fibrocytes represent a novel MDSC subset circulating in patients with metastatic cancer. Blood 122, 1105–1113 (2013).
De Veirman, K. et al. Myeloid-derived suppressor cells as therapeutic target in hematological malignancies. Front. Oncol. 4, 349 (2014).
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).
Wang, X. & Riviere, I. Clinical manufacturing of CAR T cells: foundation of a promising therapy. Mol. Ther. Oncolyt. 3, 16015 (2016).
Tumaini, B. et al. Simplified process for the production of anti-CD19-CAR-engineered T cells. Cytotherapy 15, 1406–1415 (2013).
Kochenderfer, J. N. et al. Construction and preclinical evaluation of an anti-CD19 chimeric antigen receptor. J. Immunother. 32, 689–702 (2009).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Vormittag, P., Gunn, R., Ghorashian, S. & Veraitch, F. S. A guide to manufacturing CAR T cell therapies. Curr. Opin. Biotechnol. 53, 164–181 (2018).
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).
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).
June, C. H. & Sadelain, M. Chimeric antigen receptor therapy. N. Engl. J. Med. 379, 64–73 (2018).
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).
Cornetta, K. et al. Absence of replication-competent lentivirus in the clinic: analysis of infused T cell products. Mol. Ther. 26, 280–288 (2018).
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).
Qin, D. Y. et al. Paralleled comparison of vectors for the generation of CAR-T cells. Anticancer Drugs 27, 711–722 (2016).
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).
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).
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).
Monjezi, R. et al. Enhanced CAR T cell engineering using non-viral Sleeping Beauty transposition from minicircle vectors. Leukemia 31, 186–194 (2017).
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).
Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (2016).
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).
Xu, J., Melenhorst, J. J. & Fraietta, J. A. Toward precision manufacturing of immunogene T cell therapies. Cytotherapy 20, 623–638 (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).
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).
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).
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).
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).
Georgiadis, C. et al. Long terminal repeat CRISPR-CAR-coupled “universal” T cells mediate potent anti-leukemic effects. Mol. Ther. 26, 1215–1227 (2018).
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).
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).
Daher, M. & Rezvani, K. Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. Curr. Opin. Immunol. 51, 146–153 (2018).
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).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT03579927 (2019).
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).
Hofer, E. & Koehl, U. Natural killer cell-based cancer immunotherapies: from immune evasion to promising targeted cellular therapies. Front. Immunol. 8, 745 (2017).
US Food & Drug Administration. Package insert — Kymriah. FDA https://www.fda.gov/downloads/UCM573941.pdf (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).
Lowe, K. L. et al. Fludarabine and neurotoxicity in engineered T cell therapy. Gene Ther. 25, 176–191 (2018).
Novartis. Kymriah treatment center locator. Kymriah https://www.us.kymriah.com/treatment-center-locator/ (2018).
Kite Pharma. Where can Yescarta be received? Yescarta https://www.yescarta.com/treatment-centers (2018).
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).
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).
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).
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).
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).
Bach, P. B. National coverage analysis of CAR-T therapies — policy, evidence, and payment. N. Engl. J. Med. 379, 1396–1398 (2018).
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).
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).
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).
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).
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).
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).
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).
Feucht, J. et al. Calibration of CAR activation potential directs alternative T cell fates and therapeutic potency. Nat. Med. 25, 82–88 (2018).
Sadelain, M., Brentjens, R. & Riviere, I. The basic principles of chimeric antigen receptor design. Cancer Discov. 3, 388–398 (2013).
Maus, M. V. & June, C. H. Making better chimeric antigen receptors for adoptive T cell therapy. Clin. Cancer Res. 22, 1875–1884 (2016).
Fraietta, J. A. et al. Disruption of TET2 promotes the therapeutic efficacy of CD19-targeted T cells. Nature 558, 307–312 (2018).
Eyquem, J. et al. Targeting a CAR to the TRAC locus with CRISPR/Cas9 enhances tumour rejection. Nature 543, 113–117 (2017).
Jung, I. Y. & Lee, J. Unleashing the therapeutic potential of CAR-T cell therapy using gene-editing technologies. Mol. Cells 41, 717–723 (2018).
Maus, M. V. Immunology: T cell tweaks to target tumours. Nature 543, 48–49 (2017).
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).
Turtle, C. J. & Riddell, S. R. Artificial antigen-presenting cells for use in adoptive immunotherapy. Cancer J. 16, 374–381 (2010).
Butler, M. O. & Hirano, N. Human cell-based artificial antigen-presenting cells for cancer immunotherapy. Immunol. Rev. 257, 191–209 (2014).
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).
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).
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).
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).
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).
Kantarjian, H. M. et al. Inotuzumab ozogamicin versus standard therapy for acute lymphoblastic leukemia. N. Engl. J. Med. 375, 740–753 (2016).
Gokbuget, N. et al. Blinatumomab for minimal residual disease in adults with B cell precursor acute lymphoblastic leukemia. Blood 131, 1522–1531 (2018).
Kantarjian, H. et al. Blinatumomab versus chemotherapy for advanced acute lymphoblastic leukemia. N. Engl. J. Med. 376, 836–847 (2017).
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).
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).
Shalabi, H. et al. Intensification of lymphodepletion optimizes CAR re-treatment efficacy. Blood 130 (Suppl. 1), 3889 (2017).
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).
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).
Mejstrikova, E. et al. CD19-negative relapse of pediatric B cell precursor acute lymphoblastic leukemia following blinatumomab treatment. Blood Cancer J. 7, 659 (2017).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
Brown, C. E. et al. Regression of glioblastoma after chimeric antigen receptor T-cell therapy. N. Engl. J. Med. 375, 2561–2569 (2016).
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).
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).
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).
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).
Shah, N. N. et al. Characterization of CD22 expression in acute lymphoblastic leukemia. Pediatr. Blood Cancer 62, 964–969 (2015).
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).
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).
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).
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).
Ruella, M. et al. Dual CD19 and CD123 targeting prevents antigen-loss relapses after CD19-directed immunotherapies. J. Clin. Invest. 126, 3814–3826 (2016).
Qin, H. et al. Preclinical development of bivalent chimeric antigen receptors targeting both CD19 and CD22. Mol. Ther. Oncolyt. 11, 127–137 (2018).
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).
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).
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).
Neelapu, S. S. et al. Chimeric antigen receptor T cell therapy — assessment and management of toxicities. Nat. Rev. Clin. Oncol. 15, 47–62 (2018).
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).
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).
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).
Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).
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).
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).
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).
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).
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).
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).
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).
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).
Schmidts, A. & Maus, M. V. Making CAR T cells a solid option for solid tumors. Front. Immunol. 9, 2593 (2018).
Morgan, M. A. & Schambach, A. Engineering CAR-T cells for improved function against solid tumors. Front. Immunol. 9, 2493 (2018).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).
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).