Decade-Long Remissions of Leukemia Sustained By the Persistence of Activated CD4+ CAR T-Cells

J Joseph Melenhorst,Irina Kulikovskaya,David L Porter,Saar Gill,Frederic D Bushman,E John Wherry,Lifeng Tian,Kai Tan,Meng Wang,Shovik Bandyopadhyay,Cécile Alanio,Sayantan Maji,Iulian Pruteanu-Malinici,Anne Chew,Don L Siegel,Regina M Young ,Gregory M Chen ,Peng Gao ,Megan M Davis ,Jennifer L Brogdon ,David E Ambrose ,Christopher L Nobles ,Joseph A Fraietta ,Simon F Lacey ,Noelle V Frey ,Bruce L Levine ,Carl H June

doi:10.1182/blood-2021-152664

Abstract

Decade-Long Remissions of Leukemia Sustained By the Persistence of Activated CD4+ CAR T-Cells

Highlights

By reprogramming patient T lymphocytes with a chimeric antigen receptor (CAR)specific for CD19, we[1,2,3,4] and others[5,6,7] demonstrated that durable remissions are attainable in relapsed, refractory B cell leukemias and lymphomas
CAR T-cells were detectable by flow cytometry across time points (Fig. 1a-c); at the time of the most recent research phlebotomy, which was at 10 years post-infusion for patient 1 and 9 years for patient 2, CTL019 cells remained detectable and represented 0.8% and 0.1% of all T-cells respectively (Fig. 1b-c)
29 productively rearranged immunoglobulin heavy (IgH) sequences have been at background levels since 12 and 6 months after anti-CD19 CAR T-cell treatment in patients 1 and 2, respectively (Extended Data Table 1), confirming the B cell aplasia findings by flow cytometry

Summary

Introduction

By reprogramming patient T lymphocytes with a chimeric antigen receptor (CAR)specific for CD19, we[1,2,3,4] and others[5,6,7] demonstrated that durable remissions are attainable in relapsed, refractory B cell leukemias and lymphomas. The first two CLL patients were infused in the summer of 2010 with anti-CD19 CAR T (CTL019) cells, and responded with complete remissions and persistence of the infused CAR T-cells[1]. Persistence of CAR T-cells in acute lymphoid leukemia (ALL) and CLL is a key characteristic of durable clinical responses[2,8,9,10], yet the characteristics of long-term persisting CAR T-cells have not been extensively studied. The particular persistence of anti-CD19 CAR T-cells in these first two complete-responding CLL patients allowed us to interrogate molecular and functional attributes of highly effective anti-CLL T cells. We report that these two patients have remained in remission at last follow-up >10 years post-infusion, and we have mapped the fate of CTL019 cells using bulk and single-cell multi-omic approaches

Methods

Results

Conclusion