Journal
CLINICAL CANCER RESEARCH
Volume 27, Issue 12, Pages 3339-3350Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-20-4575
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Funding
- ImmunityBio
- NIH [T32 HL007088]
- SPORE in Leukemia [P50CA171963]
- American Association of Immunologists Intersect Fellowship Program for Computational Scientists and Immunologists
- MGI Pilot Grant
- Jamie Erin Follicular Lymphoma Research Fund
- NCI CCSG [P30 C091842]
- [R44 CA195812]
- [K12CA167540]
- [R01CA205239]
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The combination therapy of N-803 with rituximab demonstrated safety and durable clinical responses in patients with indolent non-Hodgkin lymphoma, including rituximab-refractory patients. Analysis using CITE-seq revealed altered molecular programs in NK cells and monocytes post-treatment, suggesting the potential for further investigation of N-803 in combination with immunotherapies.
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. 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.
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