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. WagnerNarendranath Epperla, Amy D. Rock, John Lee, Allegra A. Petti, Patrick Soon-Shiong, Todd A. Fehniger

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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, doseescalation 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. CITEseq 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.

Original languageEnglish
Pages (from-to)3339-3350
Number of pages12
JournalClinical Cancer Research
Volume27
Issue number12
DOIs
StatePublished - Jun 2021

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