Phase 1 Study Evaluating the Safety, Preliminary Efficacy, and Pharmacodynamics of Recombinant Interleukin-15 in Combination With Nivolumab and Ipilimumab

Sep 23, 2026

Open-label, non-randomized Phase 1 study evaluated safety, tolerability, and preliminary efficacy of recombinant human interleukin-15 (rhIL-15) combined with nivolumab and ipilimumab in advanced, refractory cancers. A 3+3 dose-escalation design determined the maximum tolerated dose, with adverse events graded by CTCAE and responses assessed using RECIST and iRECIST. Pharmacodynamics measured immune-cell changes in peripheral blood and matched tumor biopsies. Thirty-one patients were enrolled; the triplet regimen showed a manageable safety profile and induced immune population shifts, while efficacy signals were limited.

LanguageEnglish

CategoryHealthcare

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Pages12

Reading Time30 min

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Abstract

Purpose

Methods

Results

Conclusions

Introduction

Background on immune checkpoint inhibitors

Rationale for combining cytokine therapy with ICIs

Open access Original research Phase 1 study evaluating the safety, preliminary efficacy, and pharmacodynamics of recombinant interleukin-15 in combination with nivolumab and ipilimumab in patients with refractory cancers Jibran Ahmed,1,2 Geraldine O’Sullivan Coyne,1,2 Larry V Rubinstein 3 , Sarah J Shin,1,2 Naoko Takebe,1,2 Ashley Bruns,1 Brooke Augustine,1 Jessica Mukherjee,1 Ning Ma,1 Kristin Fino,4 King Leung Fung,4 Katherine V Ferry-Galow,4 Barry C Johnson ,1 Ralph E Parchment,4 Howard Streicher,5 James H Doroshow,1,2 Alice P Chen1 To cite: Ahmed J, O’Sullivan Coyne G, Rubinstein LV, et al. Phase 1 study evaluating the safety, preliminary efficacy, and pharmacodynamics of recombinant interleukin-15 in combination with nivolumaband ipilimumab in patients with refractory cancers. Journal for ImmunoTherapy of Cancer 2025;13:e013252 . doi:10 . 1136/ jitc-2025-013252 ► Additional supplemental material is published online only. To view, please visit the journal online ([https://doi.org/10.1136/](https://doi.org/10.1136/)[ ](https://doi.org/10.1136/)[jitc-2025-013252](jitc-2025-013252)) . JA and GO’SC contributed equally. Accepted 09 October 2025 © Author(s) (or their employer(s)) 2025. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ Group. For numbered affiliations see end of article. Correspondence to Alice P Chen; [chenali@mail.nih.gov](chenali@mail.nih.gov) ABSTRACT Purpose Combinations of immune checkpoint inhibitors and cytokine therapies have shown promise in cancer immunotherapy. We aimed to evaluate the safety, tolerability, and preliminary efficacy of recombinant human interleukin-15 (rhIL-15) in combination with nivolumab and ipilimumab in patients with advanced, refractory cancers. Methods This open-label, non-randomized study employed a 3+3 dose-escalation design to determine the maximum tolerated dose (MTD) of rhIL-15 combined with fixed doses of nivolumab and ipilimumab. Safety and tolerability were assessed according to Common Terminology Criteria for Adverse Events (CTCAE) criteria, and preliminary efficacy was assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) and immune-related RECIST (iRECIST) criteria. Pharmacodynamic studies evaluated changes in immune cell populations in peripheral blood and paired baseline and on-treatment tumor biopsies. Results Thirty-one patients were enrolled, with a median age of 56 years (range: 24–81 years) . Five patients received rhIL-15 with either nivolumab or ipilimumab in safety run-in cohorts, 26 patients received rhIL-15 with nivolumab plus ipilimumab. The most common cancer types were gastrointestinal (n=7) or gynecologic (n=5) . The MTD was 1 µg/kg/day rhIL-15, 240 mg nivolumab, and 1 mg/kg ipilimumab. The triplet combination showed a manageable safety profile; the most common treatmentrelated adverse events (trAEs) were chills (20/26, 77%), fever (18/26, 69%), injection site reaction (15/26, 58%), anemia (14/26, 54%), and fatigue (14/26, 54%) . Lymphopenia (4/26, 15%) was the most common grade 3/4 trAE. Pharmacodynamic analysis of tumor biopsies revealed increases in CD8+, CD8+CD3ζpY142+ (ie, activated CD8+T cells), PD-1+CD3+, and CD45RO+CD3+(ie, memory T cells) in some patients. Tumor infiltration of natural killer (NK) and γδ T cells was also observed. NK cell populations in peripheral blood were modulated by WHAT IS ALREADY KNOWN ON THIS TOPIC | ⇒ Interleukin (IL)-15 is a cytokine that regulates T-cell responses and activates natural killer (NK) cells. It has been evaluated as monotherapy and in combination with immune checkpoint inhibitors (ICIs) . However, pharmacodynamic responses induced by these combinations have not been fully elucidated.
WHAT THIS STUDY ADDS | | --- | | ⇒ The combination of rhIL-15 with nivolumab and ipilimumab was administered with an acceptable safety profile. rhIL-15 induced expansion of NK and γδ T cells in some periphe

FAQs

What was the primary goal of this Phase 1 study?

To evaluate the safety, tolerability, and preliminary efficacy of rhIL-15 combined with nivolumab and ipilimumab in patients with advanced, refractory cancers.

How was dose escalation and maximum tolerated dose (MTD) determined?

The study used an open-label 3+3 dose-escalation design to identify the MTD of rhIL-15 when administered with fixed nivolumab and ipilimumab doses.

What safety and tolerability outcomes were reported?

The triplet combination showed a manageable safety profile, with common treatment-related adverse events including chills, fever, injection site reaction, anemia, and fatigue; lymphopenia was a notable grade 3/4 event.

What pharmacodynamic findings were observed?

Tumor biopsies and peripheral blood analyses showed changes in immune cell populations, including increases in activated and memory T-cell markers (e.g., CD8-related and CD45RO+ T cells) and evidence of NK and γδ T-cell infiltration in some patients.

Sep 23, 2026

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