Rosenberg, S. A. & Restifo, N. P. Adoptive cell transfer as personalized immunotherapy for human cancer. Science 348, 62–68 (2015).
June, C. H., Riddell, S. R. & Schumacher, T. N. Adoptive cellular therapy: a race to the finish line. Sci. Transl Med. 7, 280ps7 (2015).
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).
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).
Grupp, S. A. et al. Chimeric antigen receptor-modified T cells for acute lymphoid leukemia. N. Engl. J. Med. 368, 1509–1518 (2013).
Brentjens, R. J. et al. CD19-targeted T cells rapidly induce molecular remissions in adults with chemotherapy-refractory acute lymphoblastic leukemia. Sci. Transl Med. 5, 177ra138 (2013).
Cruz, C. R. et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed after allogeneic stem cell transplant: a phase 1 study. Blood 122, 2965–2973 (2013).
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).
Maude, S. L. et al. Chimeric antigen receptor T cells for sustained remissions in leukemia. N. Engl. J. Med. 371, 1507–1517 (2014).
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, 224ra225 (2014).
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).
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).
Garfall, A. L. et al. Chimeric antigen receptor T cells against CD19 for multiple myeloma. N. Engl. J. Med. 373, 1040–1047 (2015).
Fraietta, J. A. et al. Ibrutinib enhances chimeric antigen receptor T-cell engraftment and efficacy in leukemia. Blood 127, 1117–1127 (2016).
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).
Kebriaei, P. et al. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J. Clin. Invest. 126, 3363–3376 (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).
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).
Turtle, C. J. et al. Durable molecular remissions in chronic lymphocytic leukemia treated with CD19-specific chimeric antigen receptor-modified T cells after failure of ibrutinib. J. Clin. Oncol. http://dx.doi.org/10.1200/JCO.2017.72.8519 (2017).
Kochenderfer, J. N. et al. Lymphoma remissions caused by anti-CD19 Chimeric antigen receptor t cells are associated with high serum interleukin-15 levels. J. Clin. Oncol. 35, 1803–1813 (2017).
Hinrichs, C. S. & Rosenberg, S. A. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol. Rev. 257, 56–71 (2014).
Kochenderfer, J. N. et al. B-Cell depletion and remissions of malignancy along with cytokine-associated toxicity in a clinical trial of anti-CD19 chimeric-antigen-receptor-transduced T cells. Blood 119, 2709–2720 (2012).
Locke, F. L. et al. Phase 1 results of ZUMA-1: a multicenter study of KTE-C19 anti-CD19 CAR T Cell therapy in refractory aggressive lymphoma. Mol. Ther. 25, 285–295 (2017).
Neelapu, S. S. et al. KTE-C19 (anti-CD19 CAR T cells) induces complete remissions in patients with refractory diffuse large B-cell lymphoma (DLBCL): results from the pivotal phase 2 ZUMA-1 [abstract]. Blood 128, LBA-6 (2016).
Grupp, S. A. et al. Analysis of a Global registration trial of the efficacy and safety of CTL019 in pediatric and young adults with relapsed/refractory acute lymphoblastic leukemia (ALL) [abstract]. Blood 128, 221 (2016).
Schuster, S. J. et al. Global pivotal phase 2 trial of the CD19-targeted therapy CTL019 in adult patients with relapsed or refractory (R/R) diffuse large B-cell lymphoma (DLBCL) — an interim analysis [abstract]. Hematol. Oncol. 35 (Suppl. S2), 27 (2017).
Neelapu, S. S. et al. Axicabtagene ciloleucel (Axi-cel; KTE-C19) in patients with refractory aggressive non-Hodgkin lymphomas (NHL): primary results of the pivotal trial ZUMA-1 [abstract]. Hematol. Oncol. 35 (Suppl. S2), 28 (2017).
Abramson, J. et al. High CR rates in relapsed/refractory (R/R) aggressive B-NHL treated with the CD19-directed CAR T cell product JCAR017 (TRANSCEND NHL 001) [abstract]. Hematol. Oncol. 35 (Suppl. S2), 138 (2017).
Ali, S. A. et al. T cells expressing an anti-B-cell maturation antigen chimeric antigen receptor cause remissions of multiple myeloma. Blood 128, 1688–1700 (2016).
Lee, D. W. et al. Current concepts in the diagnosis and management of cytokine release syndrome. Blood 124, 188–195 (2014).
Brudno, J. N. & Kochenderfer, J. N. Toxicities of chimeric antigen receptor T cells: recognition and management. Blood 127, 3321–3330 (2016).
Maude, S. L., Barrett, D., Teachey, D. T. & Grupp, S. A. Managing cytokine release syndrome associated with novel T cell-engaging therapies. Cancer J. 20, 119–122 (2014).
Hu, Y. et al. Predominant cerebral cytokine release syndrome in CD19-directed chimeric antigen receptor-modified T cell therapy. J. Hematol. Oncol. 9, 70 (2016).
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).
Ishii, K. et al. Tocilizumab-refractory cytokine release syndrome (CRS) triggered by chimeric antigen receptor (CAR)-transduced T cells may have distinct cytokine profiles compared to typical CRS. Blood 128, 3358 (2016).
Robbins, P. F. et al. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29, 917–924 (2011).
Koestner, W. et al. PD-L1 blockade effectively restores strong graft-versus-leukemia effects without graft-versus-host disease after delayed adoptive transfer of T-cell receptor gene-engineered allogeneic CD8+ T cells. Blood 117, 1030–1041 (2011).
Romanski, A. et al. CD19-CAR engineered NK-92 cells are sufficient to overcome NK cell resistance in B-cell malignancies. J. Cell. Mol. Med. 20, 1287–1294 (2016).
Han, J. et al. CAR-engineered NK cells targeting wild-type EGFR and EGFRvIII enhance killing of glioblastoma and patient-derived glioblastoma stem cells. Sci. Rep. 5, 11483 (2015).
Bargou, R. et al. Tumor regression in cancer patients by very low doses of a T cell-engaging antibody. Science 321, 974–977 (2008).
Topp, M. S. et al. Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study. Lancet Oncol. 16, 57–66 (2015).
Teachey, D. T. et al. Cytokine release syndrome after blinatumomab treatment related to abnormal macrophage activation and ameliorated with cytokine-directed therapy. Blood 121, 5154–5157 (2013).
U.S. Department of Health & Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf (2010).
Frey, N. V. et al. Refractory cytokine release syndrome in recipients of chimeric antigen receptor (CAR) T cells. Blood 124, 2296–2296 (2014).
Rose-John, S. IL-6 trans-signaling via the soluble IL-6 receptor: importance for the pro-inflammatory activities of IL-6. Int. J. Biol. Sci. 8, 1237–1247 (2012).
Scheller, J., Chalaris, A., Schmidt-Arras, D. & Rose-John, S. The pro- and anti-inflammatory properties of the cytokine interleukin-6. Biochim. Biophys. Acta 1813, 878–888 (2011).
Chen, F. et al. Measuring IL-6 and sIL-6R in serum from patients treated with tocilizumab and/or siltuximab following CAR T cell therapy. J. Immunol. Methods 434, 1–8 (2016).
Singh, J. A., Beg, S. & Lopez-Olivo, M. A. Tocilizumab for rheumatoid arthritis. Cochrane Database of Syst. Rev. CD008331 (2010).
Deisseroth, A. et al. FDA approval: siltuximab for the treatment of patients with multicentric Castleman disease. Clin. Cancer Res. 21, 950–954 (2015).
Bonifant, C. L., Jackson, H. J., Brentjens, R. J. & Curran, K. J. Toxicity and management in CAR T-cell therapy. Mol. Ther. Oncolyt. 3, 16011 (2016).
Mihara, M. et al. Tocilizumab inhibits signal transduction mediated by both mIL-6R and sIL-6R, but not by the receptors of other members of IL-6 cytokine family. Int. Immunopharmacol. 5, 1731–1740 (2005).
Zaki, M. H., Nemeth, J. A. & Trikha, M. CNTO 328, a monoclonal antibody to IL-6, inhibits human tumor-induced cachexia in nude mice. Int. J. Cancer. 111, 592–595 (2004).
Nishimoto, N. et al. Mechanisms and pathologic significances in increase in serum interleukin-6 (IL-6) and soluble IL-6 receptor after administration of an anti-IL-6 receptor antibody, tocilizumab, in patients with rheumatoid arthritis and Castleman disease. Blood 112, 3959–3964 (2008).
Paliogianni, F., Ahuja, S. S., Balow, J. P., Balow, J. E. & Boumpas, D. T. Novel mechanism for inhibition of human T cells by glucocorticoids. Glucocorticoids inhibit signal transduction through IL-2 receptor. J. Immunol. 151, 4081–4089 (1993).
Lanza, L. et al. Prednisone increases apoptosis in in vitro activated human peripheral blood T lymphocytes. Clin. Exp. Immunol. 103, 482–490 (1996).
Franchimont, D. et al. Effects of dexamethasone on the profile of cytokine secretion in human whole blood cell cultures. Regul. Pept. 73, 59–65 (1998).
Ozdemir, E. et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood 100, 3690–3697 (2002).
Schultz, D. R. & Arnold, P. I. Properties of four acute phase proteins: C-reactive protein, serum amyloid A protein, α1-acid glycoprotein, and fibrinogen. Semin. Arthritis Rheum. 20, 129–147 (1990).
Pepys, M. B. & Hirschfield, G. M. C-Reactive protein: a critical update. J. Clin. Invest. 111, 1805–1812 (2003).
Schmidt-Arras, D. & Rose-John, S. IL-6 pathway in the liver: from physiopathology to therapy. J. Hepatol. 64, 1403–1415 (2016).
Schuster, S. J. et al. Sustained remissions following chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with relapsed or refractory CD19+ lymphomas. Blood 126, 183–183 (2015).
Santomasso, B. et al. Biomarkers associated with neurotoxicity in adult patients with relapsed or refractory B-ALL (R/R B-ALL) treated with CD19 CAR T cells [abstract]. J. Clin. Oncol. 35, (15 Suppl.), 3019 (2017).
Turtle, C. J. et al. Cytokine release syndrome (CRS) and neurotoxicity (NT) after CD19-specific chimeric antigen receptor- (CAR-) modified T cells [abstract]. J. Clin. Oncol. 35, (15 Suppl.), 3020 (2017).
Johnson, L. A. & June, C. H. Driving gene-engineered T cell immunotherapy of cancer. Cell Res. 27, 38–58 (2017).
Sutter, R., Semmlack, S. & Kaplan, P. W. Nonconvulsive status epilepticus in adults — insights into the invisible. Nat. Rev. Neurol. 12, 281–293 (2016).
Walker, M. et al. Nonconvulsive status epilepticus: Epilepsy Research Foundation workshop reports. Epileptic Disord. 7, 253–296 (2005).
Hovinga, C. A. Levetiracetam: a novel antiepileptic drug. Pharmacotherapy 21, 1375–1388 (2001).
Guenther, S. et al. Chronic valproate or levetiracetam treatment does not influence cytokine levels in humans. Seizure 23, 666–669 (2014).
Reuters. Juno ends development of high-profile leukemia drug after deaths. Reuters http://www.reuters.com/article/us-juno-leukemia-idUSKBN1685QQ (2017).
Harris, J. Kite reports cerebral edema death in ZUMA-1 CAR T-cell trial. OncLive http://www.onclive.com/web-exclusives/kite-reports-cerebral-edema-death-in-zuma1-car-tcell-trial (2017).
Henter, J. I. et al. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 48, 124–131 (2007).
Ramos-Casals, M., Brito-Zeron, P., Lopez-Guillermo, A., Khamashta, M. A. & Bosch, X. Adult haemophagocytic syndrome. Lancet 383, 1503–1516 (2014).
Jordan, M. B., Hildeman, D., Kappler, J. & Marrack, P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 104, 735–743 (2004).
Jordan, M. B., Allen, C. E., Weitzman, S., Filipovich, A. H. & McClain, K. L. How I treat hemophagocytic lymphohistiocytosis. Blood 118, 4041–4052 (2011).
Tamamyan, G. N. et al. Malignancy-associated hemophagocytic lymphohistiocytosis in adults: Relation to hemophagocytosis, characteristics, and outcomes. Cancer 122, 2857–2866 (2016).
Daver, N. & Kantarjian, H. Malignancy-associated haemophagocytic lymphohistiocytosis in adults. Lancet Oncol. 18, 169–171 (2017).
Schram, A. M. & Berliner, N. How I treat hemophagocytic lymphohistiocytosis in the adult patient. Blood 125, 2908–2914 (2015).
Jordan, M. et al. A novel targeted approach to the treatment of hemophagocytic lymphohistiocytosis (HLH) with an anti-interferon gamma (IFNγ) monoclonal antibody (mAb), NI-0501: first results from a pilot phase 2 study in children with primary HLH [abstract]. Blood 126, LBA-3 (2015).
Zhou, X. & Brenner, M. K. Improving the safety of T-Cell therapies using an inducible caspase-9 gene. Exp. Hematol. 44, 1013–1019 (2016).
Jackson, H. J., Rafiq, S. & Brentjens, R. J. Driving CAR T-cells forward. Nat. Rev. Clin. Oncol. 13, 370–383 (2016).
Di Stasi, A. et al. Inducible apoptosis as a safety switch for adoptive cell therapy. N. Engl. J. Med. 365, 1673–1683 (2011).
Serafini, M. et al. Characterization of CD20-transduced T lymphocytes as an alternative suicide gene therapy approach for the treatment of graft-versus-host disease. Hum. Gene Ther. 15, 63–76 (2004).
Wang, X. et al. A transgene-encoded cell surface polypeptide for selection. in vivo tracking, and ablation of engineered cells. Blood 118, 1255–1263 (2011).
Philip, B. et al. A highly compact epitope-based marker/suicide gene for easier and safer T-cell therapy. Blood 124, 1277–1287 (2014).
Thomis, D. C. et al. A Fas-based suicide switch in human T cells for the treatment of graft-versus-host disease. Blood 97, 1249–1257 (2001).
Sakemura, R. et al. A Tet-on inducible system for controlling CD19-chimeric antigen receptor expression upon drug administration. Cancer Immunol. Res. 4, 658–668 (2016).
Dai, H., Wang, Y., Lu, X. & Han, W. Chimeric Antigen receptors modified T-cells for cancer therapy. J. Natl Cancer Inst. 108, djv439 (2016).
Morgan, R. A. et al. Case report of a serious adverse event following the administration of T cells transduced with a chimeric antigen receptor recognizing ERBB2. Mol. Ther. 18, 843–851 (2010).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).
Parkhurst, M. R. et al. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19, 620–626 (2011).
Lamers, C. H. et al. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol. Ther. 21, 904–912 (2013).
Lamers, C. H. et al. Treatment of metastatic renal cell carcinoma with autologous T-lymphocytes genetically retargeted against carbonic anhydrase IX: first clinical experience. J. Clin. Oncol. 24, e20–e22 (2006).
Maus, M. V. et al. T cells expressing chimeric antigen receptors can cause anaphylaxis in humans. Cancer Immunol. Res. 1, 26–31 (2013).
Brentjens, R., Yeh, R., Bernal, Y., Riviere, I. & Sadelain, M. Treatment of chronic lymphocytic leukemia with genetically targeted autologous T cells: case report of an unforeseen adverse event in a phase I clinical trial. Mol. Ther. 18, 666–668 (2010).
Chong, E. A. et al. Chimeric antigen receptor modified T cells directed against CD19 (CTL019) in patients with poor prognosis, relapsed or refractory CD19+ follicular lymphoma: prolonged remissions relative to antecedent therapy [abstract]. Blood 128, 1100 (2016).
Locke, F. L. et al. A phase 2 multicenter trial of KTE-C19 (anti-CD19 CAR T Cells) in patients with chemorefractory primary mediastinal B-cell lymphoma (PMBCL) and transformed follicular lymphoma (TFL): interim results from ZUMA-1 [abstract]. Blood 128, 998 (2016).
Russell, J. A. et al. Vasopressin versus norepinephrine infusion in patients with septic shock. N. Engl. J. Med. 358, 877–887 (2008).
Frisen, L. Swelling of the optic nerve head: a staging scheme. J. Neurol. Neurosurg. Psychiatry 45, 13–18 (1982).