# Correlative biomarkers of IL-6 blockade combined with checkpoint inhibition

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $610,766

## Abstract

This proposal is based on an analysis of serum from melanoma patients treated with the PD-1 antibody
nivolumab (NIVO) showing that high levels of IL-6 and acute phase reactants (APP) induced by IL-6 like C-
reactive protein (CRP) are associated with poor survival. We hypothesize that CRP and other APP induced
by IL-6 are associated with resistance to checkpoint inhibition in melanoma, and are immunosuppressive.
This is supported by our preliminary data showing that CRP levels are associated with low response rates
and short survival with NIVO or ipilimumab (IPI). IL-6 promotes the synthesis of CRP and other APPs from
the liver, and its levels are also associated with low response rates, short survival and therapeutic resistance
in patients receiving NIVO, IPI or combination immune checkpoint blockade (ICB). Patients with low IL-6 at
baseline or after treatment with ICB have high response rates and long survivals. To overcome the immune
suppression observed with CRP and reverse ICB resistance associated with high IL-6, we will add the IL-6
receptor blocking antibody tocilizumab to IPI and NIVO in patients with metastatic melanoma. Our overarching
hypothesis is that levels of IL-6 and CRP in baseline serum and other biomarkers in serum, PBMCs and tumor
will predict efficacy and toxicity in a phase II trial of IPI/NIVO with tocilizumab and that IL-6 blockade will
augment the efficacy of, and reduce toxicity from combined ICB. These biomarkers will provide insight into
host/tumor mediators of ICB and help direct patients to the most effective immunotherapy based on their
baseline and on-treatment levels of IL-6/CRP and other biomarkers. Co-primary endpoints of the trial include
best overall response rate and toxicity since IL-6 blockade has also been shown to reduce immune-related
adverse events with immunotherapy. A Simon two-stage design trial will include 67 patients that will receive
the triple combination and will be supported by BMS. In this proposal, we wish to support the correlative
marker studies based on that phase II trial. Analyses of the serum, tumor and peripheral blood will be carried
out to establish biomarkers of efficacy and toxicity and help understand the basis for resistance to combination
ICB in melanoma based on three specific aims: 1. To determine if baseline levels, or on-treatment changes
in a serum mass spectrometry-MALDI-TOF protein signature and acute phase reactants and cytokines are
associated with response and toxicity in a phase II trial of IPI/NIVO with the IL-6 receptor blocking antibody
tocilizumab; 2. To determine if baseline or on-treatment changes in peripheral blood and tumor T cell
phenotype and function assessed by multi-parameter flow cytometry, Ab-Seq and IsoLight assays, peripheral
blood dendritic cell phenotype and function and tumor class I and II expression, PD-L1 levels and RNA seq
signatures are associated with response and toxicity in a phase II study of IPI/NIVO with tocilizumab; and 3.
To integrat...

## Key facts

- **NIH application ID:** 10039468
- **Project number:** 1R01CA244936-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Jeffrey S Weber
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $610,766
- **Award type:** 1
- **Project period:** 2020-07-02 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10039468

## Citation

> US National Institutes of Health, RePORTER application 10039468, Correlative biomarkers of IL-6 blockade combined with checkpoint inhibition (1R01CA244936-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10039468. Licensed CC0.

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