Gunilla Enblad 1 , Hannah Karlsson 2 , Gustav Gammelgård 2 , Jessica Wenthe 2 , Tanja Lövgren 2 , Rose Marie Amini 2 , Kristina I Wikstrom 3 , Magnus Essand 2 , Barbara Savoldo 4 , Helene Hallböök 5 , Martin Höglund 5 , Gianpietro Dotti 4 , Malcolm K Brenner 4 , Hans Hagberg 2 , Angelica Loskog 2 Show Affiliations »
Abstract
PURPOSE: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19+ B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy. PATIENTS AND METHODS: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. RESULTS: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14+CD33+HLA-DR-) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2. CONCLUSIONS: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers. ©2018 American Association for Cancer Research.
PURPOSE: The chimeric antigen receptor (CAR ) T-cell therapy has been effective for patients with CD19 + B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy. PATIENTS AND METHODS: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array. RESULTS: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp , Fas ligand , and TRAIL . Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14 +CD33 +HLA-DR-) and low levels of IL6 , IL8 , NAP3 , sPDL1 , and sPDL2. CONCLUSIONS: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity . Immune profiling pre- and posttreatment can be used to find response biomarkers. ©2018 American Association for Cancer Research.
Entities: Chemical
Disease
Gene
Species
Year: 2018
PMID： 30097433 DOI： 10.1158/1078-0432.CCR-18-0426
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531