Abstract
BackgroundRadium-223 improves overall survival (OS) in men with bone metastatic castration-resistant prostate cancer (mCRPC). While the exact mechanism behind this survival benefit remains unclear, radium-induced immunological mechanisms might contribute to the OS advantage. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy.Materials and MethodsIn this prospective, single-arm, exploratory study, PBMCs of 30 mCRPC patients were collected before, during, and after treatment with radium-223. Lymphocyte and monocyte counts were analyzed to get insight into general immune cell trends. Next, we analyzed changes in T cell subsets, myeloid-derived suppressor cells (MDSCs), and immune checkpoint expression using linear regression models. Per subset, the 6-month change (% of baseline) was determined. Bootstrapped 95% confidence intervals were used to measure the degree of uncertainty of our findings.ResultsWe observed a substantial decrease in absolute lymphocyte counts (-0.12 * 10^9 cells/L per injection, 95% CI: -0.143 - -0.102). Simultaneously, an increase was observed in the proportion of T cells that expressed costimulatory (ICOS) or inhibitory (TIM-3, PD-L1, and PD-1) checkpoint molecules. Moreover, the fraction of two immunosuppressive subsets – the regulatory T cells and the monocytic MDSCs – increased throughout treatment. These findings were not more pronounced in patients with an alkaline phosphatase response during therapy.ConclusionImmune cell subsets in patients with mCRPC changed during radium-223 therapy, which warrants further research into the possible immunological consequences of these changes.
Highlights
Radium-223 dichloride was registered in 2013 to treat patients with symptomatic bone metastatic castrationresistant prostate cancer based on the results of the phase III, randomized controlled ALSYMPCA trial
We performed a comprehensive evaluation of the immunological changes in metastatic castration-resistant prostate cancer (mCRPC) patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy
We observed a substantial decrease in absolute lymphocyte counts (-0.12 * 10^9 cells/L per injection, 95% confidence interval (CI): -0.143 - -0.102)
Summary
Radium-223 dichloride (radium-223) was registered in 2013 to treat patients with symptomatic bone metastatic castrationresistant prostate cancer (mCRPC) based on the results of the phase III, randomized controlled ALSYMPCA trial. In this trial, radium-223 improved the overall survival (OS) and prolonged the time to a first symptomatic skeletal event [1]. Alpha particles are highly ionizing agents with low penetration power (≤100 μm) [2] Their radiation induces double-stranded DNA breaks in adjacent tumor cells, osteoblasts, and osteoclasts, resulting in tumor cell death and inhibition of pathological bone formation [3, 4]. We performed a comprehensive evaluation of the immunological changes in mCRPC patients by phenotyping the peripheral blood mononuclear cells (PBMCs) during radium-223 therapy
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