Autologous CD19-Targeted CAR T Cells in Patients With Residual CLL Following Initial Purine Analog-Based Therapy

Mol Ther. 2018 Aug 1;26(8):1896-1905. doi: 10.1016/j.ymthe.2018.05.018. Epub 2018 Jun 15.

Abstract

Patients with residual chronic lymphocytic leukemia (CLL) following initial purine analog-based chemoimmunotherapy exhibit a shorter duration of response and may benefit from novel therapeutic strategies. We and others have previously described the safety and efficacy of autologous T cells modified to express anti-CD19 chimeric antigen receptors (CARs) in patients with relapsed or refractory B cell acute lymphoblastic leukemia and CLL. Here we report the use of CD19-targeted CAR T cells incorporating the intracellular signaling domain of CD28 (19-28z) as a consolidative therapy in 8 patients with residual CLL following first-line chemoimmunotherapy with pentostatin, cyclophosphamide, and rituximab. Outpatients received low-dose conditioning therapy with cyclophosphamide (600 mg/m2), followed by escalating doses of 3 × 106, 1 × 107, or 3 × 107 19-28z CAR T cells/kg. An objective response was observed in 3 of 8 patients (38%), with a clinically complete response lasting more than 28 months observed in two patients. Self-limited fevers were observed post-CAR T cell infusion in 4 patients, contemporaneous with elevations in interleukin-6 (IL-6), IL-10, IL-2, and TGF-α. None developed severe cytokine release syndrome or neurotoxicity. CAR T cells were detectable post-infusion in 4 patients, with a longest observed persistence of 48 days by qPCR. Further strategies to enhance CAR T cell efficacy in CLL are under investigation.

Keywords: CAR T cells; adoptive cellular therapy; chimeric antigen receptors; chronic lymphocytic leukemia; immunotherapy.

Publication types

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

MeSH terms

  • Aged
  • Antigens, CD19 / metabolism*
  • Behavior Therapy
  • Cyclophosphamide / administration & dosage*
  • Cyclophosphamide / therapeutic use
  • Female
  • Humans
  • Immunotherapy, Adoptive / adverse effects*
  • Leukemia, Lymphocytic, Chronic, B-Cell / immunology
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy*
  • Male
  • Middle Aged
  • Neoplasm, Residual
  • Pentostatin / therapeutic use
  • Rituximab / therapeutic use
  • T-Lymphocytes / immunology
  • T-Lymphocytes / transplantation*
  • Transplantation, Autologous / adverse effects
  • Treatment Outcome

Substances

  • Antigens, CD19
  • Pentostatin
  • Rituximab
  • Cyclophosphamide