A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia

Clin Cancer Res. 2018 Dec 15;24(24):6185-6194. doi: 10.1158/1078-0432.CCR-18-0426. Epub 2018 Aug 10.


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.

Trial registration: ClinicalTrials.gov NCT02132624.

Publication types

  • Clinical Trial, Phase I
  • Clinical Trial, Phase II
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antigens, CD19* / immunology
  • Antigens, CD19* / metabolism
  • Batch Cell Culture Techniques
  • Cell Separation
  • Female
  • Humans
  • Immunity, Cellular
  • Immunotherapy, Adoptive* / adverse effects
  • Immunotherapy, Adoptive* / methods
  • Leukemia / diagnosis
  • Leukemia / immunology*
  • Leukemia / mortality
  • Leukemia / therapy*
  • Lymphocyte Count
  • Lymphoma / diagnosis
  • Lymphoma / immunology*
  • Lymphoma / mortality
  • Lymphoma / therapy*
  • Male
  • Middle Aged
  • Receptors, Antigen, T-Cell* / genetics
  • Receptors, Antigen, T-Cell* / metabolism
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • Survival Analysis
  • T-Lymphocytes* / immunology
  • T-Lymphocytes* / metabolism
  • Transgenes
  • Treatment Outcome
  • Young Adult


  • Antigens, CD19
  • Receptors, Antigen, T-Cell
  • Recombinant Fusion Proteins

Associated data

  • EudraCT/2013-001393-19
  • ClinicalTrials.gov/NCT02132624