Lymphoid and myeloid biomarkers for clinical outcome of combined immunotherapy with granulocyte-macrophage colony-stimulating factor-tranduced allogeneic prostate cancer cells (GVAX) and ipilimumab in castration-resistant prostate cancer patients.
Alfons J. van den Eertwegh, MD, PhD
Background: In a phase-I dose escalation trial in patients with castration-resistant prostate cancer we showed that GVAX and ipilimumab had an acceptable safety profile. Moreover, we observed tumor responses and prolonged survival as compared to the Halabi predicted overall survival (OS). However, ipilimumab can also lead to severe immune-related adverse events. To avoid unnecessary exposure to this risk, it is essential to identify biomarkers that correlate with clinical activity.
Methods: Patients had castration-resistant prostate cancer and were chemotherapy-naïve. They received bi-weekly GVAX for a 24 week period combined with monthly intravenous administrations of ipilimumab. Each cohort of 3 patients received an escalating dose of ipilimumab at 0·3, 1·0, 3·0 or 5·0 mg/kg. In an expansion cohort 16 patients were treated with GVAX and 3·0 mg/kg ipilimumab. Flowcytometric monitoring of lymphoid and myeloid subsets in blood were performed.
Results: We observed a significantly prolonged OS for patients with high pre-treatment frequencies of CD4+CTLA-4+, CD4+PD-1+, or differentiated CD8+ T cells, or low pre-treatment frequencies of differentiated CD4+ T cells or CD4+CD25hiFoxP3+ regulatory T cells. In contrast, increased frequencies of granulocytic Myeloid-Derived Suppressor Cells (MDSC) and high pre-treatment frequencies of monocytic CD14+HLA-DRlo/- MDSC were associated with reduced OS. Treatment-induced CD4+ T cell differentiation and CD4+ and CD8+ T cell activation was associated with clinical benefit. Moreover, treatment-induced activation of CD1c+ conventional Dendritic Cells (cDC) and 6-sulfo LacNAc+ inflammatory DC were associated with significantly prolonged OS.
Conclusions: Together these data provide an immune profile to predict clinical outcome. Importantly, cluster analysis revealed pre-treatment, CRPC-associated expression of CTLA-4+ by CD4+ T cells to be a dominant predictor for OS after GVAX/ipilimumab. This potentially biomarker for patient selection should be validated in patients treated with ipilimumab.