Phase I Trial of N-803, an IL15 Receptor Agonist, with Rituximab in Patients with Indolent Non-Hodgkin Lymphoma
Jennifer A Foltz, Brian T Hess, Veronika Bachanova, Nancy L Bartlett, Melissa M Berrien-Elliott, Ethan McClain, Michelle Becker-Hapak, Mark Foster, Timothy Schappe, Brad Kahl, Neha Mehta-Shah, Amanda F Cashen, Nancy D Marin, Kristen McDaniels, Chaz Moreno, Matthew Mosior, Feng Gao, Obi L Griffith, Malachi Griffith, Julia A Wagner, Narendranath Epperla, Amy D Rock, John Lee, Allegra A Petti, Patrick Soon-Shiong, Todd A Fehniger, Jennifer A Foltz, Brian T Hess, Veronika Bachanova, Nancy L Bartlett, Melissa M Berrien-Elliott, Ethan McClain, Michelle Becker-Hapak, Mark Foster, Timothy Schappe, Brad Kahl, Neha Mehta-Shah, Amanda F Cashen, Nancy D Marin, Kristen McDaniels, Chaz Moreno, Matthew Mosior, Feng Gao, Obi L Griffith, Malachi Griffith, Julia A Wagner, Narendranath Epperla, Amy D Rock, John Lee, Allegra A Petti, Patrick Soon-Shiong, Todd A Fehniger
Abstract
Purpose: N-803 is an IL15 receptor superagonist complex, designed to optimize in vivo persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8+ T cells. Monoclonal antibodies (mAbs) direct Fc receptor-bearing immune cells, including NK cells, to recognize and eliminate cancer targets. The ability of IL15R agonists to enhance tumor-targeting mAbs in patients has not been reported previously.
Patients and methods: Relapsed/refractory patients with indolent non-Hodgkin lymphoma were treated with rituximab and intravenous or subcutaneous N-803 on an open-label, dose-escalation phase I study using a 3+3 design (NCT02384954). Primary endpoint was maximum tolerated dose. Immune correlates were performed using multidimensional analysis via mass cytometry and cellular indexing of transcriptomes and epitopes by sequencing (CITE-seq) which simultaneously measures protein and single-cell RNA expression.
Results: This immunotherapy combination was safe and well tolerated and resulted in durable clinical responses including in rituximab-refractory patients. Subcutaneous N-803 plus rituximab induced sustained proliferation, expansion, and activation of peripheral blood NK cells and CD8 T cells, with increased NK cell and T cells present 8 weeks following last N-803 treatment. CITE-seq revealed a therapy-altered NK cell molecular program, including enhancement of AP-1 transcription factor. Furthermore, the monocyte transcriptional program was remodeled with enhanced MHC expression and antigen-presentation genes.
Conclusions: N-803 combines with mAbs to enhance tumor targeting in patients, and warrants further investigation in combination with immunotherapies.
Conflict of interest statement
Conflict of Interest Statement: This clinical trial was supported by ImmunityBio (previously Altor BioScience). ADR, JL, and PS-S are employees or have financial interest in ImmunityBio. TAF has consulted for Nektar, Wugen, Indapta, Kiadis, Orca Bio, and has received research funding from ImmunityBio, Affimed, and Compass Therapeutics. BK has received research funding and consulting fees from Roche, Genentech, and Celgene. NMS has received research funding from Verastem Pharmaceuticals, Corvus Pharmaceuticals, Innate Pharmaceuticals, Bristol Myers Squibb, Genetech/Roche, Celgene and consulted for Kiowa Hakka Kirin, C4 Therapeutics, Karyopharma Therapeutics. NE has received funding from Verastem-Speaker’s Bureau and Pharmacyclics-Honoraria. JAF has pending patents (WO 2019/152387, US 63/018,108) unrelated to the present work that are licensed to Kiadis, and a monoclonal antibody unrelated to the present work licensed to EMD Millipore. MBH is a co-inventor on a patent (US2010/0159594A1). MMBE is a consultant and has equity interest in Wugen, and may receive royalty income based on a technology developed by TAF and MMBE and licensed by Washington University to Wugen. MMBE has received travel funds from Fluidigm. All other authors have no conflicts of interest to report.
©2021 American Association for Cancer Research.
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Source: PubMed