Systemic inflammation is a determinant of outcomes of CD40 agonist–based therapy in pancreatic cancer patients
Max M. Wattenberg, Veronica M. Herrera, Michael A. Giannone, Whitney L. Gladney, Erica L. Carpenter, Gregory L. Beatty
Max M. Wattenberg, Veronica M. Herrera, Michael A. Giannone, Whitney L. Gladney, Erica L. Carpenter, Gregory L. Beatty
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Research Article Immunology Oncology

Systemic inflammation is a determinant of outcomes of CD40 agonist–based therapy in pancreatic cancer patients

Abstract

Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies.

Authors

Max M. Wattenberg, Veronica M. Herrera, Michael A. Giannone, Whitney L. Gladney, Erica L. Carpenter, Gregory L. Beatty

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Figure 2

CD4+ T cell activation is not associated with outcomes of CD40 agonist–based chemoimmunotherapy.

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CD4+ T cell activation is not associated with outcomes of CD40 agonist–b...
(A) Representative contour plots of HLA-DR+CD38+CD8+ T cells. (B) Quantification of HLA-DR+CD38+CD8+ T cells (as a percentage of CD8+ T cells). Mean ± SEM is shown. (C) Representative contour plots of HLA-DR+CD38+CD4+ T cells. (D) Quantification of HLA-DR+CD38+CD4+ T cells (as a percentage of CD4+ T cells). Shown is mean ± SEM. (E) Patients with stable (FC < 1.6) or increased (FC > 1.6) HLA-DR+CD38+CD4+ T cells between baseline and day 8. Wilcoxon’s matched pairs test was performed. (F) Overall survival (OS) was estimated by Kaplan-Meier methodology, and the log-rank test was used to determine significance. (G) Patients were dichotomized as having decreased (FC < 1.0) or increased (FC > 1.0) HLA-DR+CD38+CD8+ T cells between baseline and day 8, and Kaplan-Meier methodology and the log-rank test were used to compare OS. Day 1, n = 17; day 3, n = 13; day 5, n = 12; day 8, n = 15, day 28, n = 14. (B and D) Mixed effects analysis with Dunnett’s multiple-comparison test was performed. *P < 0.05; **P < 0.01; ***P < 0.001. FC, fold change.