CART19 Cells Effects in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma

Summary

Phase I Dose Escalation Study of CART19 Cells for Adult Patients With Relapsed / Refractory Acute Lymphoblastic Leukemia and Non-Hodgkin's Lymphoma.

Timeline

Start

2021-06-02

Primary completion

2025-06-01

Completion

2025-12-12

Publications

• Background Maude SL, Frey N, Shaw PA, Aplenc R, Barrett DM, Bunin NJ, Chew A, Gonzalez VE, Zheng Z, Lacey SF, Mahnke YD, Melenhorst JJ, Rheingold SR, Shen A, Teachey DT, Levine BL, June CH, Porter DL, Grupp SA. Chimeric antigen receptor T cells for sustained remissions in leukemia. N Engl J Med. 2014 Oct 16;371(16):1507-17. doi: 10.1056/NEJMoa1407222.
• Background Porter DL, Hwang WT, Frey NV, Lacey SF, Shaw PA, Loren AW, Bagg A, Marcucci KT, Shen A, Gonzalez V, Ambrose D, Grupp SA, Chew A, Zheng Z, Milone MC, Levine BL, Melenhorst JJ, June CH. Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia. Sci Transl Med. 2015 Sep 2;7(303):303ra139. doi: 10.1126/scitranslmed.aac5415.
• Background Hartmann J, Schussler-Lenz M, Bondanza A, Buchholz CJ. Clinical development of CAR T cells-challenges and opportunities in translating innovative treatment concepts. EMBO Mol Med. 2017 Sep;9(9):1183-1197. doi: 10.15252/emmm.201607485.
• Background Hamada M, Nishio N, Okuno Y, Suzuki S, Kawashima N, Muramatsu H, Tsubota S, Wilson MH, Morita D, Kataoka S, Ichikawa D, Murakami N, Taniguchi R, Suzuki K, Kojima D, Sekiya Y, Nishikawa E, Narita A, Hama A, Kojima S, Nakazawa Y, Takahashi Y. Integration Mapping of piggyBac-Mediated CD19 Chimeric Antigen Receptor T Cells Analyzed by Novel Tagmentation-Assisted PCR. EBioMedicine. 2018 Aug;34:18-26. doi: 10.1016/j.ebiom.2018.07.008. Epub 2018 Aug 3.
• Background Tipanee J, VandenDriessche T, Chuah MK. Transposons: Moving Forward from Preclinical Studies to Clinical Trials. Hum Gene Ther. 2017 Nov;28(11):1087-1104. doi: 10.1089/hum.2017.128. Epub 2017 Aug 22.
• Background Kebriaei P, Singh H, Huls MH, Figliola MJ, Bassett R, Olivares S, Jena B, Dawson MJ, Kumaresan PR, Su S, Maiti S, Dai J, Moriarity B, Forget MA, Senyukov V, Orozco A, Liu T, McCarty J, Jackson RN, Moyes JS, Rondon G, Qazilbash M, Ciurea S, Alousi A, Nieto Y, Rezvani K, Marin D, Popat U, Hosing C, Shpall EJ, Kantarjian H, Keating M, Wierda W, Do KA, Largaespada DA, Lee DA, Hackett PB, Champlin RE, Cooper LJ. Phase I trials using Sleeping Beauty to generate CD19-specific CAR T cells. J Clin Invest. 2016 Sep 1;126(9):3363-76. doi: 10.1172/JCI86721. Epub 2016 Aug 2.
• Background Otahal P, Prukova D, Kral V, Fabry M, Vockova P, Lateckova L, Trneny M, Klener P. Lenalidomide enhances antitumor functions of chimeric antigen receptor modified T cells. Oncoimmunology. 2015 Dec 3;5(4):e1115940. doi: 10.1080/2162402X.2015.1115940. eCollection 2016 Apr.
• Background Yusa K, Zhou L, Li MA, Bradley A, Craig NL. A hyperactive piggyBac transposase for mammalian applications. Proc Natl Acad Sci U S A. 2011 Jan 25;108(4):1531-6. doi: 10.1073/pnas.1008322108. Epub 2011 Jan 4.
• Background Ptackova P, Musil J, Stach M, Lesny P, Nemeckova S, Kral V, Fabry M, Otahal P. A new approach to CAR T-cell gene engineering and cultivation using piggyBac transposon in the presence of IL-4, IL-7 and IL-21. Cytotherapy. 2018 Apr;20(4):507-520. doi: 10.1016/j.jcyt.2017.10.001. Epub 2018 Feb 21.
• Background Milone MC, Fish JD, Carpenito C, Carroll RG, Binder GK, Teachey D, Samanta M, Lakhal M, Gloss B, Danet-Desnoyers G, Campana D, Riley JL, Grupp SA, June CH. Chimeric receptors containing CD137 signal transduction domains mediate enhanced survival of T cells and increased antileukemic efficacy in vivo. Mol Ther. 2009 Aug;17(8):1453-64. doi: 10.1038/mt.2009.83. Epub 2009 Apr 21.
• Background Riviere I, Sadelain M. Chimeric Antigen Receptors: A Cell and Gene Therapy Perspective. Mol Ther. 2017 May 3;25(5):1117-1124. doi: 10.1016/j.ymthe.2017.03.034. Epub 2017 Apr 26.
• Background Norelli M, Casucci M, Bonini C, Bondanza A. Clinical pharmacology of CAR-T cells: Linking cellular pharmacodynamics to pharmacokinetics and antitumor effects. Biochim Biophys Acta. 2016 Jan;1865(1):90-100. doi: 10.1016/j.bbcan.2015.12.001. Epub 2015 Dec 31.
• Background Lamers CH, Sleijfer S, van Steenbergen S, van Elzakker P, van Krimpen B, Groot C, Vulto A, den Bakker M, Oosterwijk E, Debets R, Gratama JW. Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity. Mol Ther. 2013 Apr;21(4):904-12. doi: 10.1038/mt.2013.17. Epub 2013 Feb 19.
• Background Till BG, Jensen MC, Wang J, Chen EY, Wood BL, Greisman HA, Qian X, James SE, Raubitschek A, Forman SJ, Gopal AK, Pagel JM, Lindgren CG, Greenberg PD, Riddell SR, Press OW. Adoptive immunotherapy for indolent non-Hodgkin lymphoma and mantle cell lymphoma using genetically modified autologous CD20-specific T cells. Blood. 2008 Sep 15;112(6):2261-71. doi: 10.1182/blood-2007-12-128843. Epub 2008 May 28.
• Background Porter DL, Levine BL, Kalos M, Bagg A, June CH. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011 Aug 25;365(8):725-33. doi: 10.1056/NEJMoa1103849. Epub 2011 Aug 10.
• Background Turtle CJ, Hanafi LA, Berger C, Gooley TA, Cherian S, Hudecek M, Sommermeyer D, Melville K, Pender B, Budiarto TM, Robinson E, Steevens NN, Chaney C, Soma L, Chen X, Yeung C, Wood B, Li D, Cao J, Heimfeld S, Jensen MC, Riddell SR, Maloney DG. CD19 CAR-T cells of defined CD4+:CD8+ composition in adult B cell ALL patients. J Clin Invest. 2016 Jun 1;126(6):2123-38. doi: 10.1172/JCI85309. Epub 2016 Apr 25.
• Background Davila ML, Riviere I, Wang X, Bartido S, Park J, Curran K, Chung SS, Stefanski J, Borquez-Ojeda O, Olszewska M, Qu J, Wasielewska T, He Q, Fink M, Shinglot H, Youssif M, Satter M, Wang Y, Hosey J, Quintanilla H, Halton E, Bernal Y, Bouhassira DC, Arcila ME, Gonen M, Roboz GJ, Maslak P, Douer D, Frattini MG, Giralt S, Sadelain M, Brentjens R. Efficacy and toxicity management of 19-28z CAR T cell therapy in B cell acute lymphoblastic leukemia. Sci Transl Med. 2014 Feb 19;6(224):224ra25. doi: 10.1126/scitranslmed.3008226.
• Background Mueller KT, Waldron E, Grupp SA, Levine JE, Laetsch TW, Pulsipher MA, Boyer MW, August KJ, Hamilton J, Awasthi R, Stein AM, Sickert D, Chakraborty A, Levine BL, June CH, Tomassian L, Shah SS, Leung M, Taran T, Wood PA, Maude SL. Clinical Pharmacology of Tisagenlecleucel in B-cell Acute Lymphoblastic Leukemia. Clin Cancer Res. 2018 Dec 15;24(24):6175-6184. doi: 10.1158/1078-0432.CCR-18-0758. Epub 2018 Sep 6.
• Background Schuster SJ, Bishop MR, Tam CS, Waller EK, Borchmann P, McGuirk JP, Jager U, Jaglowski S, Andreadis C, Westin JR, Fleury I, Bachanova V, Foley SR, Ho PJ, Mielke S, Magenau JM, Holte H, Pantano S, Pacaud LB, Awasthi R, Chu J, Anak O, Salles G, Maziarz RT; JULIET Investigators. Tisagenlecleucel in Adult Relapsed or Refractory Diffuse Large B-Cell Lymphoma. N Engl J Med. 2019 Jan 3;380(1):45-56. doi: 10.1056/NEJMoa1804980. Epub 2018 Dec 1.
• Background Singh H, Figliola MJ, Dawson MJ, Olivares S, Zhang L, Yang G, Maiti S, Manuri P, Senyukov V, Jena B, Kebriaei P, Champlin RE, Huls H, Cooper LJ. Manufacture of clinical-grade CD19-specific T cells stably expressing chimeric antigen receptor using Sleeping Beauty system and artificial antigen presenting cells. PLoS One. 2013 May 31;8(5):e64138. doi: 10.1371/journal.pone.0064138. Print 2013.
• Background Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC. Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst. 1997 Aug 6;89(15):1138-47. doi: 10.1093/jnci/89.15.1138.
• Background Kershaw MH, Westwood JA, Parker LL, Wang G, Eshhar Z, Mavroukakis SA, White DE, Wunderlich JR, Canevari S, Rogers-Freezer L, Chen CC, Yang JC, Rosenberg SA, Hwu P. A phase I study on adoptive immunotherapy using gene-modified T cells for ovarian cancer. Clin Cancer Res. 2006 Oct 15;12(20 Pt 1):6106-15. doi: 10.1158/1078-0432.CCR-06-1183.
• Background Park JR, Digiusto DL, Slovak M, Wright C, Naranjo A, Wagner J, Meechoovet HB, Bautista C, Chang WC, Ostberg JR, Jensen MC. Adoptive transfer of chimeric antigen receptor re-directed cytolytic T lymphocyte clones in patients with neuroblastoma. Mol Ther. 2007 Apr;15(4):825-33. doi: 10.1038/sj.mt.6300104. Epub 2007 Feb 13.
• Background Kochenderfer JN, Dudley ME, Kassim SH, Somerville RP, Carpenter RO, Stetler-Stevenson M, Yang JC, Phan GQ, Hughes MS, Sherry RM, Raffeld M, Feldman S, Lu L, Li YF, Ngo LT, Goy A, Feldman T, Spaner DE, Wang ML, Chen CC, Kranick SM, Nath A, Nathan DA, Morton KE, Toomey MA, Rosenberg SA. 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. 2015 Feb 20;33(6):540-9. doi: 10.1200/JCO.2014.56.2025. Epub 2014 Aug 25.
• Background Kochenderfer JN, Dudley ME, Feldman SA, Wilson WH, Spaner DE, Maric I, Stetler-Stevenson M, Phan GQ, Hughes MS, Sherry RM, Yang JC, Kammula US, Devillier L, Carpenter R, Nathan DA, Morgan RA, Laurencot C, Rosenberg SA. 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. 2012 Mar 22;119(12):2709-20. doi: 10.1182/blood-2011-10-384388. Epub 2011 Dec 8.
• Background Hay KA, Hanafi LA, Li D, Gust J, Liles WC, Wurfel MM, Lopez JA, Chen J, Chung D, Harju-Baker S, Cherian S, Chen X, Riddell SR, Maloney DG, Turtle CJ. Kinetics and biomarkers of severe cytokine release syndrome after CD19 chimeric antigen receptor-modified T-cell therapy. Blood. 2017 Nov 23;130(21):2295-2306. doi: 10.1182/blood-2017-06-793141. Epub 2017 Sep 18.
• Background Comerota AJ, Throm RC, Miller KA, Henry T, Chronos N, Laird J, Sequeira R, Kent CK, Bacchetta M, Goldman C, Salenius JP, Schmieder FA, Pilsudski R. Naked plasmid DNA encoding fibroblast growth factor type 1 for the treatment of end-stage unreconstructible lower extremity ischemia: preliminary results of a phase I trial. J Vasc Surg. 2002 May;35(5):930-6. doi: 10.1067/mva.2002.123677.
• Background Powell RJ, Simons M, Mendelsohn FO, Daniel G, Henry TD, Koga M, Morishita R, Annex BH. Results of a double-blind, placebo-controlled study to assess the safety of intramuscular injection of hepatocyte growth factor plasmid to improve limb perfusion in patients with critical limb ischemia. Circulation. 2008 Jul 1;118(1):58-65. doi: 10.1161/CIRCULATIONAHA.107.727347. Epub 2008 Jun 16.
• Background Gonin P, Gaillard C. Gene transfer vector biodistribution: pivotal safety studies in clinical gene therapy development. Gene Ther. 2004 Oct;11 Suppl 1:S98-S108. doi: 10.1038/sj.gt.3302378.
• Background Dotti G. T lymphocytes are not immune. Mol Ther. 2013 Jun;21(6):1114-5. doi: 10.1038/mt.2013.102. No abstract available.
• Background Saha S, Woodard LE, Charron EM, Welch RC, Rooney CM, Wilson MH. Evaluating the potential for undesired genomic effects of the piggyBac transposon system in human cells. Nucleic Acids Res. 2015 Feb 18;43(3):1770-82. doi: 10.1093/nar/gkv017. Epub 2015 Jan 20.
• Background Heinrich T, Rengstl B, Muik A, Petkova M, Schmid F, Wistinghausen R, Warner K, Crispatzu G, Hansmann ML, Herling M, von Laer D, Newrzela S. Mature T-cell lymphomagenesis induced by retroviral insertional activation of Janus kinase 1. Mol Ther. 2013 Jun;21(6):1160-8. doi: 10.1038/mt.2013.67. Epub 2013 Apr 23.
• Background Hacein-Bey-Abina S, von Kalle C, Schmidt M, Le Deist F, Wulffraat N, McIntyre E, Radford I, Villeval JL, Fraser CC, Cavazzana-Calvo M, Fischer A. A serious adverse event after successful gene therapy for X-linked severe combined immunodeficiency. N Engl J Med. 2003 Jan 16;348(3):255-6. doi: 10.1056/NEJM200301163480314. No abstract available.
• Background Wang W, Lin C, Lu D, Ning Z, Cox T, Melvin D, Wang X, Bradley A, Liu P. Chromosomal transposition of PiggyBac in mouse embryonic stem cells. Proc Natl Acad Sci U S A. 2008 Jul 8;105(27):9290-5. doi: 10.1073/pnas.0801017105. Epub 2008 Jun 25.
• Background Rad R, Rad L, Wang W, Cadinanos J, Vassiliou G, Rice S, Campos LS, Yusa K, Banerjee R, Li MA, de la Rosa J, Strong A, Lu D, Ellis P, Conte N, Yang FT, Liu P, Bradley A. PiggyBac transposon mutagenesis: a tool for cancer gene discovery in mice. Science. 2010 Nov 19;330(6007):1104-7. doi: 10.1126/science.1193004. Epub 2010 Oct 14.
• Background Fedoroff NV. Presidential address. Transposable elements, epigenetics, and genome evolution. Science. 2012 Nov 9;338(6108):758-67. doi: 10.1126/science.338.6108.758. No abstract available.
• Background Hackett PB, Largaespada DA, Switzer KC, Cooper LJ. Evaluating risks of insertional mutagenesis by DNA transposons in gene therapy. Transl Res. 2013 Apr;161(4):265-83. doi: 10.1016/j.trsl.2012.12.005. Epub 2013 Jan 10.
• Background Zhao S, Jiang E, Chen S, Gu Y, Shangguan AJ, Lv T, Luo L, Yu Z. PiggyBac transposon vectors: the tools of the human gene encoding. Transl Lung Cancer Res. 2016 Feb;5(1):120-5. doi: 10.3978/j.issn.2218-6751.2016.01.05.
• Background Fraietta JA, Lacey SF, Orlando EJ, Pruteanu-Malinici I, Gohil M, Lundh S, Boesteanu AC, Wang Y, O'Connor RS, Hwang WT, Pequignot E, Ambrose DE, Zhang C, Wilcox N, Bedoya F, Dorfmeier C, Chen F, Tian L, Parakandi H, Gupta M, Young RM, Johnson FB, Kulikovskaya I, Liu L, Xu J, Kassim SH, Davis MM, Levine BL, Frey NV, Siegel DL, Huang AC, Wherry EJ, Bitter H, Brogdon JL, Porter DL, June CH, Melenhorst JJ. Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. Nat Med. 2018 May;24(5):563-571. doi: 10.1038/s41591-018-0010-1. Epub 2018 Apr 30.
• Background Milone MC, Bhoj VG. The Pharmacology of T Cell Therapies. Mol Ther Methods Clin Dev. 2018 Jan 31;8:210-221. doi: 10.1016/j.omtm.2018.01.010. eCollection 2018 Mar 16.
• Background Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia. N Engl J Med. 2018 Feb 1;378(5):439-448. doi: 10.1056/NEJMoa1709866.
• Background Lee DW, Santomasso BD, Locke FL, Ghobadi A, Turtle CJ, Brudno JN, Maus MV, Park JH, Mead E, Pavletic S, Go WY, Eldjerou L, Gardner RA, Frey N, Curran KJ, Peggs K, Pasquini M, DiPersio JF, van den Brink MRM, Komanduri KV, Grupp SA, Neelapu SS. ASTCT Consensus Grading for Cytokine Release Syndrome and Neurologic Toxicity Associated with Immune Effector Cells. Biol Blood Marrow Transplant. 2019 Apr;25(4):625-638. doi: 10.1016/j.bbmt.2018.12.758. Epub 2018 Dec 25.

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