https://orcid.org/0000-0002-2045-6238
KEY POINTS
Ibrutinib administration in combination with tisagenlecleucel was feasible and well tolerated by patients
Administration of ibrutinib prior to apheresis may reduce the proportion of senescent T cells in the final manufactured product
ABSTRACT
The mechanisms underlying chimeric antigen receptor (CAR)-T cell failure are not fully understood, however, T-cell differentiation and presence of an immunosuppressive tumor microenvironment are thought to contribute. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, has been shown to modify both T-cell phenotype and tumor microenvironment. Preliminary data suggest that combining ibrutinib with tisagenlecleucel may improve efficacy of CAR-T cell therapy; however, it is unknown whether the timing of ibrutinib treatment affects clinical outcomes. This phase Ib exploratory study assessed tisagenlecleucel in combination with ibrutinib for safety, efficacy, and feasibility in adult patients with r/r LBCL. Ibrutinib (560 mg/day) was started ≥21 days before apheresis (pre-apheresis arm, n=4) or after apheresis for ≥21 days before tisagenlecleucel infusion (post-apheresis arm, n=6). Both arms received ibrutinib continuously thereafter for up to 24 months post infusion. As of study termination (November 1, 2021), 10 patients were treated and underwent post-tisagenlecleucel response assessment. Final product manufactured from patients in the pre-apheresis arm had higher IFNγ and IL-2 release and a reduction in senescent T cells. Fewer patients in the pre-apheresis arm versus the post-apheresis arm experienced cytokine release syndrome (1/4 vs 5/6) or death (1/4 vs 4/6). Although increased tisagenlecleucel expansion was observed in the post-apheresis arm, a higher response rate was observed in the pre-apheresis arm (4/4 vs 3/6). Altogether, these findings suggest administering ibrutinib prior to leukapheresis may modify T-cell characteristics in the collected material, thereby improving final CAR-T cell product quality and clinical outcomes for patients with r/r LBLC treated with tisagenlecleucel. Clinical Trial Identifier: NCT03876028
Author notes
Currently employed by AstraZeneca; work was completed while employed by Novartis Institutes for BioMedical Research.
Currently employed by Miltenyi Biotec; work was completed while employed by Novartis Institutes for BioMedical Research.
Currently employed by Genentech; work was completed while employed by Novartis Pharmaceuticals Corporation.
Currently employed by AstraZeneca; work was completed while employed by Novartis Institutes for BioMedical Research.
City, State, and Country in which the work was done: Tampa, FL, USA, and Philadelphia, PA, USA
Portions of the data were presented at ASH 2020: Julio C. Chavez, Frederick L. Locke, Ellen Napier, Carl Simon, Andrew Lewandowski, Rakesh Awasthi, Boris Engels, Petrina Georgala, Attilio Bondanza, Stephen J. Schuster. Ibrutinib Before Apheresis May Improve Tisagenlecleucel Manufacturing in Relapsed/Refractory Adult Diffuse Large B-Cell Lymphoma: Initial Results From a Phase 1b Study. Blood. 2020;136(suppl 1):3-4.
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