Autologous CD19-Targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy Journal Article

Authors: Geyer, M. B.; Rivière, I.; Sénéchal, B.; Wang, X.; Wang, Y.; Purdon, T. J.; Hsu, M.; Devlin, S. M.; Halton, E.; Lamanna, N.; Rademaker, J.; Sadelain, M.; Brentjens, R. J.; Park, J. H.
Article Title: Autologous CD19-Targeted CAR T cells in patients with residual CLL following initial purine analog-based therapy
Abstract: Geyer et al. report the results of a phase I trial investigating CD19-targeted CAR T cells as consolidative therapy in patients with residual CLL following initial chemoimmunotherapy. Although this therapy was well tolerated, and 2 of 8 patients achieved a complete response, CAR T cell expansion was limited, likely, in part, because of suboptimal lymphodepletion. 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. © 2018
Keywords: adult; clinical article; treatment response; aged; middle aged; fatigue; neutropenia; rituximab; polymerase chain reaction; interleukin 2; low drug dose; leukopenia; thrombocytopenia; vomiting; interleukin 10; cohort analysis; cyclophosphamide; chill; fever; flushing; hyperglycemia; lymphocytopenia; pruritus; hypoalbuminemia; feasibility study; immunotherapy; minimal residual disease; quantitative analysis; patient safety; interleukin 6; autoantigen; hypoglycemia; purine derivative; chronic lymphatic leukemia; cd19 antigen; cd28 antigen; pentostatin; transforming growth factor alpha; hypernatremia; hypocalcemia; nose obstruction; immunotoxicity; intracellular signaling; chronic lymphocytic leukemia; international normalized ratio; adoptive cellular therapy; body weight loss; chimeric antigen receptors; consolidation chemotherapy; human; male; article; car t cells; chimeric antigen receptor t-cell immunotherapy
Journal Title: Molecular Therapy
Volume: 26
Issue: 8
ISSN: 1525-0016
Publisher: Nature Publishing Group  
Date Published: 2018-08-01
Start Page: 1896
End Page: 1905
Language: English
DOI: 10.1016/j.ymthe.2018.05.018
PROVIDER: scopus
PMCID: PMC6094824
PUBMED: 29910179
Notes: Article -- Export Date: 4 September 2018 -- Source: Scopus
Altmetric Score
MSK Authors
  1. Meier Hsu
    104 Hsu
  2. Renier J Brentjens
    189 Brentjens
  3. Jae Hong Park
    132 Park
  4. Elizabeth F Halton
    18 Halton
  5. Michel W J Sadelain
    452 Sadelain
  6. Isabelle C Riviere
    161 Riviere
  7. Xiuyan Wang
    62 Wang
  8. Sean McCarthy Devlin
    288 Devlin
  9. Terence John Purdon
    32 Purdon
  10. Yongzeng   Wang
    12 Wang
  11. Mark Blaine Geyer
    14 Geyer