BACKGROUND Subgroups of patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) exhibit suboptimal outcomes after standard therapies, including oral kinase inhibitors. We and others have previously reported on the safety and efficacy of autologous CD19-targeted CAR T cells for these patients. Here, we report safety and long-term follow-up of CAR T cell therapy with or without conditioning chemotherapy for patients with R/R CLL and indolent B cell non-Hodgkin lymphoma (B-NHL).METHODS We conducted a phase I clinical trial investigating CD19-targeted CAR T cells incorporating a CD28 costimulatory domain (19–28z). Seventeen of twenty patients received conditioning chemotherapy prior to CAR T cell infusion. Five patients with CLL received ibrutinib at the time of autologous T cell collection and/or CAR T cell administration.RESULTS This analysis included 16 patients with R/R CLL and 4 patients with R/R indolent B-NHL. Cytokine release syndrome (CRS) was observed in all 20 patients, but grade 3 and 4 CRS and neurological events were uncommon (10% for each). Ex vivo expansion of T cells and proportions of CAR T cells with the CD62L+CD127+ immunophenotype were significantly greater (P = 0.047; CD8 subset, P = 0.0061, CD4 subset) in patients on ibrutinib at leukapheresis. Three of twelve evaluable CLL patients receiving conditioning chemotherapy achieved complete response (CR) (2 had minimal residual disease–negative CR). All patients achieving CR remained progression free at median follow-up of 53 months.CONCLUSION Conditioning chemotherapy and 19–28z CAR T cells were acceptably tolerated across investigated dose levels in heavily pretreated patients with R/R CLL and indolent B-NHL, and a subgroup of patients achieved durable CR. Ibrutinib therapy may modulate autologous T cell phenotype.TRIAL REGISTRATION ClinicalTrials.gov NCT00466531.FUNDING Juno Therapeutics and NIH/National Cancer Institute Cancer Center Support Grant (P30-CA08748).
Mark B. Geyer, Isabelle Rivière, Brigitte Sénéchal, Xiuyan Wang, Yongzeng Wang, Terence J. Purdon, Meier Hsu, Sean M. Devlin, M. Lia Palomba, Elizabeth Halton, Yvette Bernal, Dayenne G. van Leeuwen, Michel Sadelain, Jae H. Park, Renier J. Brentjens
This file is in Adobe Acrobat (PDF) format. If you have not installed and configured the Adobe Acrobat Reader on your system.
PDFs are designed to be printed out and read, but if you prefer to read them online, you may find it easier if you increase the view size to 125%.
Many versions of the free Acrobat Reader do not allow Save. You must instead save the PDF from the JCI Online page you downloaded it from. PC users: Right-click on the Download link and choose the option that says something like "Save Link As...". Mac users should hold the mouse button down on the link to get these same options.