title: Third-generation CD28/4-1BB chimeric antigen receptor T cells for chemotherapy relapsed or refractory acute lymphoblastic leukaemia: a non-randomised, open-label phase I trial protocol.
abstract: There is no curative treatment available for patients with chemotherapy relapsed or refractory CD19+ B cells-derived acute lymphoblastic leukaemia (r/r B-ALL). Although CD19-targeting second-generation (2nd-G) chimeric antigen receptor (CAR)-modified T cells carrying CD28 or 4-1BB domains have demonstrated potency in patients with advanced B-ALL, these 2 signalling domains endow CAR-T cells with different and complementary functional properties. Preclinical results have shown that third-generation (3rd-G) CAR-T cells combining 4-1BB and CD28 signalling domains have superior activation and proliferation capacity compared with 2nd-G CAR-T cells carrying CD28 domain. The aim of the current study is therefore to investigate the safety and efficacy of 3rd-G CAR-T cells in adults with r/r B-ALL.
  
  
  
  This study is a phase I clinical trial for patients with r/r B-ALL to test the safety and preliminary efficacy of 3rd-G CAR-T cells. Before receiving lymphodepleting conditioning regimen, the peripheral blood mononuclear cells from eligible patients will be leukapheresed, and the T cells will be purified, activated, transduced and expanded ex vivo. On day 6 in the protocol, a single dose of 1 million CAR-T cells per kg will be administrated intravenously. The phenotypes of infused CAR-T cells, copy number of CAR transgene and plasma cytokines will be assayed for 2 years after CAR-T infusion using flow cytometry, real-time quantitative PCR and cytometric bead array, respectively. Moreover, several predictive plasma cytokines including interferon-γ, interleukin (IL)-6, IL-8, Soluble Interleukin (sIL)-2R-α, solubleglycoprotein (sgp)130, sIL-6R, Monocyte chemoattractant protein (MCP1), Macrophage inflammatory protein (MIP1)-α, MIP1-β and Granulocyte-macrophage colony-stimulating factor (GM-CSF), which are highly associated with severe cytokine release syndrome (CRS), will be used to forecast CRS to allow doing earlier intervention, and CRS will be managed based on a revised CRS grading system. In addition, patients with grade 3 or 4 neurotoxicities or persistent B-cell aplasia will be treated with dexamethasone (10 mg intravenously every 6 hours) or IgG, respectively. Descriptive and analytical analyses will be performed.
  
  
  
  Ethical approval for the study was granted on 10 July 2014 (YLJS-2014-7-10). Written informed consent will be taken from all participants. The results of the study will be reported, through peer-reviewed journals, conference presentations and an internal organisational report.
  
  
  
  NCT02186860.
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Tang
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Ang
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Guo-Liang
authors.initials: GL
authors.lastname: Hu
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Cao
authors.affiliation: Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: Dan-Hong
authors.initials: DH
authors.lastname: Wang
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.|Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Cell and Gene Therapy Center, Academy of Military Medical Sciences, Beijing, China.|Department of Hematopoietic Stem Cell Transplantation, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China.
authors.forename: Hu
authors.initials: H
authors.lastname: Chen
mesh_terms: D000328:Adult; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018106:CD28 Antigens / Q000187:drug effects / Q000276:immunology; D045744:Cell Line, Tumor; D017321:Clinical Trials, Phase I as Topic; D016219:Immunotherapy, Adoptive; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D065228:Non-Randomized Controlled Trials as Topic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D011948:Receptors, Antigen, T-Cell / Q000187:drug effects / Q000276:immunology; D012008:Recurrence; D012074:Remission Induction; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9 / Q000187:drug effects / Q000276:immunology
chemical_list: D018106:CD28 Antigens; D011948:Receptors, Antigen, T-Cell; C505714:TNFRSF9 protein, human; D053261:Tumor Necrosis Factor Receptor Superfamily, Member 9
keywords: IMMUNOLOGY; Third-generation; acute lymphoblastic leukemia; chimeric antigen receptor