Blood Eosinophilia is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

Abstract

Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA.

Methods: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears.

Results: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2-111 months), compared to a median of 20 months (range 0-119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06).

Conclusion: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials.

Keywords: biomarkers; dendritic cell vaccines; eosinophils.

Figure 1

Representative images of patients with (A) higher and (B) lower number of eosinophils in blood smears (original magnification 400×).

Figure 2

Intention-to-treat analysis for a cut-off of 20% eosinophils in peripheral blood. DC-vaccinated patients who developed eosinophilia ≥ 20% at any point during the course of vaccinations showed a clear trend toward longer survival (p = 0.03). In these patients, survival was prolonged with a median of 58 months (range 2–111 months; n = 9), compared with a median of 20 months (range 0–119 months; n = 58).Eos: eosinophilia; OS: overall survival.

Figure 3

Intention-to-treat analysis for a cut-off of 10% eosinophils in peripheral blood. With a cut-off at a percentage of eosinophils of 10%, the median OS for patients with eosinophilia greater than 10% (n = 41) was 32 months, compared with 18 months for patients with less than 10% eosinophils (n = 26). Eos: eosinophilia; OS: overall survival.

Figure 4

Per-protocol analysis to evaluate the early change in eosinophil count between the first and the second DC vaccines. In 12% of the patients (n = 5), an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which appeared to correlate with survival (65 vs. 24 months; p = 0.06). DC: dendritic cells; Eos: eosinophilia; OS: overall survival.

Figure 5

Analysis of the prevaccination eosinophil counts with OS. Prevaccination eosinophil levels did not associate with better outcome. There were nine patients with a preexisting eosinophilia of 5% or more, compared to 48 patients with preexisting values of less than 5%. Eos: eosinophilia; OS: overall survival.