Natural dendritic cell vaccinations generate immune responses that correlate with clinical outcome in patients with chemo-naive castration-resistant prostate cancer

Abstract

Abstract Background Clinical benefit of cellular immunotherapy has been shown in patients with castration-resistant prostate cancer (CRPC). We investigated the immunological response and clinical outcome of vaccination with blood-derived myeloid and plasmacytoid dendritic cells (mDCs and pDCs). Methods In this randomized phase IIa trial, 21 chemo-naive CRPC patients received maximally 9 vaccinations with mature mDCs, pDCs or a combination of mDCs plus pDCs. DCs were stimulated with protamine/mRNA and loaded with tumor-associated antigens NY-ESO-1, MAGE-C2 and MUC1. Primary endpoint was the immunological response after DC vaccination, which was monitored in peripheral blood and in T cell cultures of biopsies of post-treatment delayed-type hypersensitivity (DTH)-skin tests. Main secondary endpoints were safety, feasibility, radiological PFS (rPFS) and OS. Radiological responses were assessed by regular as well as ferumoxtran-10 enriched MRI and 68Ga-PSMA PET/CT scans according to RECIST 1.1, PCWG2 criteria and immune-related response criteria. Results Both tetramer/dextramer-positive (dm+) and IFN-γ-producing (IFN-γ+) DTH-skin test-derived antigen specific T cells were present more frequently in patients with radiological non-progressive disease compared to progressive patients (5/13 (38%) vs. 0/8 (0%)). In dm+ and IFN-γ+ patients median rPFS was 18.8 months vs. 5.1 months in patients without IFN-γ+ antigen-specific T cells (p\xa0=\xa00.02). The overall median rPFS was 9.5 months. All DC vaccines were well tolerated with grade 1-2 toxicity. Immunological outcomes and clinical correlates will be presented. Conclusions Immunotherapy with primary DC subsets induced functional antigen-specific T cells. The presence of functional antigen-specific T cells correlated with longer rPFS. Clinical trial identification NCT02692976. Legal entity responsible for the study Jolanda de Vries and Winald Gerritsen. Funding This work was supported by Stichting Afweer Tegen Kanker, Dr. Paul A.J. Speth Stichting and H2020 EU grant PROCROP (grant No 635122). Carl G. Figdor received ERC Adv Grant PATHFINDER (269019) and the NWO Spinoza grant. I. Jolanda M. de Vries received NWO-Vici grant (918.14.655). Disclosure All authors have declared no conflicts of interest.