Chimeric antigen receptor T cells persist and induce sustained remissions in relapsed refractory chronic lymphocytic leukemia.

Abstract

Patients with multiply relapsed or refractory chronic lymphocytic leukemia (CLL) have a poor prognosis. Chimeric antigen receptor (CAR)-modified T cells targeting CD19 have the potential to improve on the low complete response rates with conventional therapies by inducing sustained remissions in patients with refractory B cell malignancies. We previously reported preliminary results on three patients with refractory CLL. We report the mature results from our initial trial using CAR-modified T cells to treat 14 patients with relapsed and refractory CLL. Autologous T cells transduced with a CD19-directed CAR (CTL019) lentiviral vector were infused into patients with relapsed/refractory CLL at doses of 0.14 × 10(8) to 11 × 10(8) CTL019 cells (median, 1.6 × 10(8) cells). Patients were monitored for toxicity, response, expansion, and persistence of circulating CTL019 T cells. The overall response rate in these heavily pretreated CLL patients was 8 of 14 (57%), with 4 complete remissions (CR) and 4 partial remissions (PR). The in vivo expansion of the CAR T cells correlated with clinical responses, and the CAR T cells persisted and remained functional beyond 4 years in the first two patients achieving CR. No patient in CR has relapsed. All responding patients developed B cell aplasia and experienced cytokine release syndrome, coincident with T cell proliferation. Minimal residual disease was not detectable in patients who achieved CR, suggesting that disease eradication may be possible in some patients with advanced CLL.

• Authors: David L Porter, Wei-Ting Hwang, Noelle V Frey, Simon F Lacey, Pamela A Shaw, Alison W Loren, Adam Bagg, Katherine T Marcucci, Angela Shen, Vanessa Gonzalez, David Ambrose, Stephan A Grupp, Anne Chew, Zhaohui Zheng, Michael C Milone, Bruce L Levine, Jan J Melenhorst, Carl H June
• Journal: Science translational medicine (Sci Transl Med) Vol. 7 Issue 303 Pg. 303ra139 (Sep 02 2015) ISSN: 1946-6242 [Electronic] United States
• PMID: 26333935 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015, American Association for the Advancement of Science.

Chemical References

• CTL019 chimeric antigen receptor
• Cytokines
• Receptors, Antigen, T-Cell

Topics

• Aged
• Cytokines (metabolism)
• Female
• Humans
• Immunotherapy
• Leukemia, Lymphocytic, Chronic, B-Cell (immunology, therapy)
• Macrophage Activation
• Male
• Middle Aged
• Receptors, Antigen, T-Cell (immunology)
• Remission Induction
• T-Lymphocytes (immunology)