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Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic
Paul E Oberstein1,2, Andressa Dias Costa3, Emily A Kawaler2,4
1Department of Medicine, NYU Langone Health, New York, New York.
Abstract:
Innate inflammation promotes tumor development, although the role of innate inflammatory cytokines in established human tumors is unclear. Herein, we report clinical and translational results from a phase Ib trial testing whether IL1β blockade in human pancreatic cancer would alleviate myeloid immunosuppression and reveal antitumor T-cell responses to PD1 blockade. Patients with treatment-naïve advanced pancreatic ductal adenocarcinoma (n = 10) were treated with canakinumab, a high-affinity monoclonal human antiinterleukin-1β (IL1β), the PD1 blocking antibody spartalizumab, and gemcitabine/n(ab)paclitaxel. Analysis of paired peripheral blood from patients in the trial versus patients receiving multiagent chemotherapy showed a modest increase in HLA-DR+CD38+ activated CD8+ T cells and a decrease in circulating monocytic myeloid-derived suppressor cells (MDSC) by flow cytometry for patients in the trial but not in controls. Similarly, we used patient serum to differentiate monocytic MDSCs in vitro and showed that functional inhibition of T-cell proliferation was reduced when using on-treatment serum samples from patients in the trial but not when using serum from patients treated with chemotherapy alone. Within the tumor, we observed few changes in suppressive myeloid-cell populations or activated T cells as assessed by single-cell transcriptional profiling or multiplex immunofluorescence, although increases in CD8+ T cells suggest that improvements in the tumor immune microenvironment might be revealed by a larger study. Overall, the data indicate that exposure to PD1 and IL1β blockade induced a modest reactivation of peripheral CD8+ T cells and decreased circulating monocytic MDSCs; however, these changes did not lead to similarly uniform alterations in the tumor microenvironment.
Insights
Blocking interleukin-1 beta (IL1β) with canakinumab alongside PD1 blockade in pancreatic cancer modestly reactivated peripheral CD8+ T cells and reduced myeloid-derived suppressor cells (MDSCs). However, these effects did not significantly alter the tumor microenvironment in this early trial.
Area of Science:
- Immunology
- Oncology
- Translational Medicine
Background:
- Innate inflammation influences tumor progression, but the role of inflammatory cytokines in established human cancers remains poorly understood.
- Understanding the impact of cytokine blockade on the tumor immune microenvironment is crucial for developing effective cancer therapies.
Purpose of the Study:
- To evaluate the clinical and translational effects of interleukin-1 beta (IL1β) blockade combined with PD1 blockade in patients with advanced pancreatic cancer.
- To determine if IL1β blockade can overcome myeloid-derived suppressor cells (MDSCs) and enhance anti-tumor T-cell responses to PD1 blockade.
Main Methods:
- A phase Ib clinical trial involving 10 treatment-naïve patients with advanced pancreatic ductal adenocarcinoma.
- Patients received canakinumab (anti-IL1β), spartalizumab (anti-PD1), and chemotherapy (gemcitabine/nab-paclitaxel).
- Analysis included flow cytometry of peripheral blood, in vitro assays using patient serum, and single-cell transcriptional profiling/multiplex immunofluorescence of tumor tissue.
Main Results:
- Treatment led to a modest increase in activated CD8+ T cells and a decrease in circulating monocytic MDSCs in peripheral blood.
- Patient serum from the trial reduced the inhibitory effect of MDSCs on T-cell proliferation in vitro.
- Limited changes were observed within the tumor microenvironment, although a trend towards increased CD8+ T cells was noted.
Conclusions:
- Combined IL1β and PD1 blockade can induce peripheral immune changes, including T-cell reactivation and MDSC reduction, in pancreatic cancer.
- These peripheral immune alterations did not consistently translate to significant changes within the tumor microenvironment in this study.
- Larger studies are warranted to further investigate the potential of this combination therapy to improve the tumor immune microenvironment.
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