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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.
SUBMITTER: Foltz JA
PROVIDER: S-EPMC8197753 | biostudies-literature | 2021 Jun
REPOSITORIES: biostudies-literature
Foltz Jennifer A JA Hess Brian T BT Bachanova Veronika V Bartlett Nancy L NL Berrien-Elliott Melissa M MM McClain Ethan E Becker-Hapak Michelle M Foster Mark M Schappe Timothy T Kahl Brad B Mehta-Shah Neha N Cashen Amanda F AF Marin Nancy D ND McDaniels Kristen K Moreno Chaz C Mosior Matthew M Gao Feng F Griffith Obi L OL Griffith Malachi M Wagner Julia A JA Epperla Narendranath N Rock Amy D AD Lee John J Petti Allegra A AA Soon-Shiong Patrick P Fehniger Todd A TA
Clinical cancer research : an official journal of the American Association for Cancer Research 20210408 12
<h4>Purpose</h4>N-803 is an IL15 receptor superagonist complex, designed to optimize <i>in vivo</i> persistence and trans-presentation, thereby activating and expanding natural killer (NK) cells and CD8<sup>+</sup> 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.<h4>Patients and methods</h4>Relapse ...[more]