Skip to main content

Preclinical Analyses Support Clinical Investigation of Combined Anti-CD19 CAR-T Cell, JCAR017 with Ibrutinib for the Treatment of Chronic Lymphocytic Leukemia

Conference Correspondent - Conference Correspondent, ASH 2016 - Chronic Lymphocytic Leukemia

Chronic lymphocytic leukemia (CLL) drives systemic immune suppression and T-cell dysfunction in patients, highlighting an important consideration in this setting for the manufacturing and efficacy of adoptive cell therapies using autologous T cells.1 In clinical studies, anti-CD19 CAR-T cells produce durable and complete responses in leukemic and some lymphomatous B-cell malignancies. Whereas preconditioning with cyclophosphamide and fludarabine has improved CAR-T responses in CLL patients, reported complete response rates still have been below 50%; additional therapeutic strategies likely will be required. Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK), has potent activity on ITK and TEC family kinases that could affect CAR-T cell biology. Recent work highlighted the ability of ibrutinib to restore CLL patient T-cell functionality, enhance CAR-T production, and potentially improve clinical efficacy.2 Additional preclinical work demonstrated improved tumor clearance when anti-CD19 CAR-T cells were combined with ibrutinib in several murine tumor models. Qin and colleagues report a preclinical evaluation of CAR-T functionality and in vivo efficacy for the second-generation anti-CD19 CAR-T product candidate, JCAR017, in the presence of either ibrutinib or acalabrutinib to determine feasibility for clinical use in CLL.

A series of in vitro studies assessed the functional activity of JCAR017 cells (derived from 3 healthy donors), in combination with ibrutinib (500-0.05 nM), across a dose range covering the Cmax and Cmin. Cytolytic activity was monitored by co-culturing CAR-T cells with ibrutinib-resistant K562 CD19 tumor cells at an effector-to-target ratio of 2.5:1. Ibrutinib, at concentrations tested, did not inhibit the cytolytic function of JCAR017 cells. For cells derived from some donors, addition of ibrutinib appeared to increase target killing. Similar results were observed with acalabrutinib. To address ibrutinib effects on JCAR017 activation, cell surface markers and cytokines were tracked over 4 days following stimulation with irradiated K562 CD19 cells. No significant effect was observed on JCAR017 surface expression of CD25, CD38, CD39, CD95, CD62L, CCR7, or CD45RO, or of EGFRt, a surrogate transduction marker. With addition of ibrutinib, a modest decrease in the percentage of cells expressing CD69, CD107a, and PD-1 was observed. With 5 nM and 50 nM of ibrutinib, there was a 19.5% (P<0.01) average increase in IFNγ production. At supraphysiological concentrations (500 nM), a 20% (P<0.05) decrease in IL-2 production was observed, suggesting ibrutinib at high concentrations may dampen T-cell activation.

The in vivo antitumor activity of JCAR017 in combination with ibrutinib was assessed using NSG mice injected with 5 x 105 Nalm6-luciferase cells. After tumor engraftment, a suboptimal dose (5 x 105) of JCAR017 cells was transferred to mice and ibrutinib (25 mg/kg daily) was administered for the duration of the study. Ibrutinib treatment alone had no effect on tumor burden compared with vehicle treatment. However, mice treated with a suboptimal JCAR017 dose + ibrutinib showed decreased tumor burden (P<0.05) and increased median survival from 44 days to >80 days (P<0.001) compared with the group receiving the suboptimal JCAR017 dose + vehicle. Taken together, the authors conclude that neither ibrutinib nor acalabrutinib had negative effects on JCAR017 cytolytic activity against CD19-expressing tumor cells in vitro. Moreover, ibrutinib and acalabrutinib enhance intrinsic JCAR017 activity and may improve outcomes in CLL patients treated with anti-CD19 CAR-T therapy, irrespective of BTK mutational status. A phase 1b study of JCAR017 in combination with ibrutinib for BTK inhibitor relapsed/refractory CLL is planned.

Qin J, et al. ASH 2016. Abstract 3231.

  1. Nicholas NS, et al. Biochim Biophys Acta. 2016;1863:471-482.
  2. Fraietta JA, et al. Blood. 2016;127:1117-1127.
Related Items
Omadacycline for Acute Bacterial Skin and Skin Structure Infections: Integrated Analysis of Randomized Clinical Trials
December 2018 Vol 11, No 9 published on December 27, 2018 in Conference Correspondent
Improved Quality of Life in Adults with Acute Bacterial Skin and Skin Structure Infections with Omadacycline or Linezolid Therapy
December 2018 Vol 11, No 9 published on December 27, 2018 in Conference Correspondent
Omadacycline In Vitro Activity Against a Molecularly Characterized Collection of Clinical Isolates with Known Tetracycline Resistance Mechanisms
December 2018 Vol 11, No 9 published on December 27, 2018 in Conference Correspondent
Integrated Safety Summary of Omadacycline, A Novel Aminomethylcycline Antibiotic
December 2018 Vol 11, No 9 published on December 27, 2018 in Conference Correspondent
Improvements in Remission and Low Disease Activity Achieved with Ongoing Sarilumab Treatment in Patients with RA
Conference Correspondent published on November 9, 2017 in ACR 2017, Conference Correspondent
Last modified: August 30, 2021