Publication Date:
2019-11-13
Description:
Background: Programmed death-ligand 1 (PD-L1) is expressed in many T-cell malignancies, including 75-100% of advanced cutaneous T-cell lymphomas, 75% of ALK-negaive anaplastic large cell lymphoma (ALCL), and 28% of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS). In 27% of patients with adult T-cell leukemia/lymphoma (ATLL) expression of PD-L1 is upregulated through 3'-UTR disruption; however, immune checkpoint inhibition has been associated with hyperprogression in three patients with indolent ATLL. In T-cell malignancies, PD-L1 expression was associated with worse outcomes. Avelumab is a fully human IgG1 anti-PD-L1 antibody which inhibits PD-1/PD-L1 interactions; unlike other approved immune checkpoint inhibitors, it also induces lysis of tumor cells in vitro via antibody-dependent cell-mediated cytotoxicity (ADCC). As ADCC is mediated by natural killer (NK) cells, agents which increase NK cell number and activity may act sinergistically with avelumab. Administration of recombinant human (rh)IL-15 by continuous intravenous infusion (CIV) into adult cancer patients has produced a 15-75-fold expansion in the number of circulating NK cells at well-tolerated doses. Preclinical syngeneic and xenograft murine lymphoid malignancy models have shown increased efficacy with combined administration of IL-15 and anti-tumor antibodies compared to either alone. We therefore hypothesized that rhIL-15 may increase the efficacy of avelumab in PD-L1 expressing T-cell malignancies, and are testing the combination in a phase I trial. Primary objective: determine the safety, toxicity profile and the maximum tolerated dose of CIV IL- 15 administration in combination with with a fixed dose of avelumab. Secondary objectives: 1) determine the efficacy of combined CIV rhIL-15 and avelumab treatment to patients with T-cell lymphomas other than ATL (overal response, duration of response, progression-free survival, event-free survival, and overall survival), 2) correlate response with level of PD-L1 expression in tumor cells (
Print ISSN:
0006-4971
Electronic ISSN:
1528-0020
Topics:
Biology
,
Medicine
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