Interleukin-15 augments NK cell–mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies

• Published in: Blood advances Vol. 7; no. 3; pp. 384 - 394
• Main Authors: Miljkovic, Milos D., Dubois, Sigrid P., Müller, Jürgen R., Bryant, Bonita, Ma, Elaine, Conlon, Kevin C., Waldmann, Thomas A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 14.02.2023; The American Society of Hematology
• Subjects: Alemtuzumab - therapeutic use; Animals; Antibodies, Monoclonal - therapeutic use; Antibody-Dependent Cell Cytotoxicity; CD52 Antigen - metabolism; Humans; Immunobiology and Immunotherapy; Immunologic Factors; Interleukin-15; Killer Cells, Natural; Mice; Neoplasms - drug therapy
• ISSN: 2473-9529; 2473-9537
• DOI: 10.1182/bloodadvances.2021006440

•Treatment with IL-15 before alemtuzumab was safe and led to decreased number and proliferative activity of T-cell leukemic cells.•IL-15 was associated with increased activation and proliferation of patient-derived NK and CD8+ T cells, increasing their ADCC capacity. [Display omitted] Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell–mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 μg/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.