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Table S1 from Blockade of IL1β and PD1 with Combination Chemotherapy Reduces Systemic Myeloid Suppression in Metastatic Pancreatic Cancer with Heterogeneous Effects in the Tumor

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posted on 2024-09-03, 07:21 authored by Paul E. Oberstein, Andressa Dias Costa, Emily A. Kawaler, Victoire Cardot-Ruffino, Osama E. Rahma, Nina Beri, Harshabad Singh, Thomas A. Abrams, Leah H. Biller, James M. Cleary, Peter Enzinger, Brandon M. Huffman, Nadine J. McCleary, Kimberly J. Perez, Douglas A. Rubinson, Benjamin L. Schlechter, Rishi Surana, Matthew B. Yurgelun, S. Jennifer Wang, Joshua Remland, Lauren K. Brais, Naima Bollenrucher, Eugena Chang, Lestat R. Ali, Patrick J. Lenehan, Igor Dolgalev, Gregor Werba, Cibelle Lima, C. Elizabeth Keheler, Keri M. Sullivan, Michael Dougan, Cristina Hajdu, Maya Dajee, Marc R. Pelletier, Saloney Nazeer, Matthew Squires, Dafna Bar-Sagi, Brian M. Wolpin, Jonathan A. Nowak, Diane M. Simeone, Stephanie K. Dougan

Supplemental Table 1: Selected Adverse Events reported in ≥5 subjects (any grade) or ≥3 subjects for Grade 3 from patients in SR-1. Select immune-related adverse events are also shown.

Funding

National Cancer Institute (NCI)

United States Department of Health and Human Services

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National Institute of Allergy and Infectious Diseases (NIAID)

United States Department of Health and Human Services

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History

ARTICLE 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.