Natural Dendritic Cells for Immunotherapy of Chemo-naive Metastatic Castration-resistant Prostate Cancer Patients

Overview

Prostate cancer is the only type of cancer in which conventional dendritic cells (DC) treatment has a beneficial effect on the overall survival. In this study investigators aim to show immunologic efficacy of tumor-peptide loaded natural DC in metastatic castration-resistant prostate cancer patients (mCRPC). The immunomonitoring will include: 1. functional response and tetramer analysis of delayed-type hypersensitivity infiltrating lymphocytes against tumor peptides and 2. type I interferon (IFN) gene expression in peripheral blood mononuclear cells, and 3. proliferative, effector cytokine- and humoral responses to keyhole limpet hemocyanin, a immunogenic protein providing T cell help. The secondary objectives are the safety and feasibility of natural DC vaccinations, the influence on the quality of life during treatment with natural DC, and the clinical efficacy of treatment.

Immunotherapy with DC vaccines Prevention of infectious diseases through immunization is one of the greatest achievements of modern medicine. Nonetheless, considerable challenges remain for improving the efficacy of existing vaccines for therapeutic immunizations for diseases such as cancer. More than 10 years ago the first groups introduced tumor antigen-loaded DC-based vaccines in the clinic. Effective immune responses and favorable clinical outcomes have indeed been observed. Thus far, mainly conventional in vitro generated monocyte-derived DCs (moDC) have been used in clinical trials worldwide. Long lasting tumor specific T cell-mediated immunological responses are clearly linked to increased progression free survival as well as overall survival. However, moDC may not be the optimal source of DCs for DC vaccination studies, due to extensive culture periods and compounds required to obtain mature moDC. Two principal subsets of human blood DC, called plasmacytoid DC (pDC) and myeloid DC (mDC), are possibly a better alternative since they do not require extensive culture periods and are directly isolable from the peripheral-blood. Based on promising immunological and clinical outcome with pDC and mDC vaccinations in metastatic melanoma patients, further testing of these blood DC subsets is warranted. Based on these observations investigators are convinced that pDC and mDC employ different, and probably more optimal mechanisms to combat cancer. In addition, based on in vitro data and preclinical studies that suggest that natural DC act synergistically, investigators hypothesize that the combination of pDC and mDC may induce stronger anti-tumor immune responses as compared to pDC or mDC alone. Immunotherapy in prostate cancer Prostate cancer is the most common noncutaneous cancer in men. In recent years novel therapies have been studied extensively. Prostate cancer is usually diagnosed in men above 65 years of age. Depending on the severity of the disease, current treatment options for prostate cancer consist of active surveillance, prostatectomy, radiation therapy, hormonal therapy, or chemotherapy. Up to one-third of patients with a localized tumor eventually fails on local therapy and progress to advanced-stage or metastatic disease within 10 years. Although the majority of patients initially respond to anti-androgens, most tumors become resistant within 14 to 30 months. For men with mCRPC the median survival in phase III studies range from 15 to 19 months. The chemotherapeutic drug docetaxel was for several years the only treatment option for mCRPC, resulting in a median overall survival benefit of two to three months compared to mitoxantrone. In the past five years second-line chemotherapy (cabazitaxel), second-generation androgen deprivation therapy (abiraterone acetate plus prednisone and enzalutamide), cellular immunotherapy (sipuleucel-T), and a targeted alpha emitter (radium-223 treatment) have expanded the treatment repertoire for mCRPC. Sipuleucel-T, a DC-based vaccine for patients suffering from prostate cancer, has shown to be clinically effective and is approved by the Food and Drug Administration and European Medicines Agency for mCRPC patients. A major advantage of cellular immunotherapy when compared to chemotherapy, and even androgen deprivation therapy, is its low toxicity. Several other immunotherapeutic approached have been investigated and potential tumor antigens have been identified. Prostvac (vaccinia-prostate-specific antigen) was administered in a randomized phase II study with encouraging results. Ipilimumab had promising results in several phase II studies and in combination with a vaccine, such as GVAX. However, in a phase III study post-chemotherapy trial ipilimumab seemed not superior to placebo. Hence, only sipuleucel-T had clinical significant results in clinical trials. The promising immunological and clinical outcome with pDC and mDC in metastatic melanoma warrants further testing of these blood DC in prostate cancer. In this study investigators aim to show proof-of-principle of natural DC immunogenicity in prostate cancer patients: induction/enhancement of tumor-specific T cells by mDC and induction of an IFN signature by pDC. Investigators will also get insight if combining subsets improves immunogenicity and clinical outcome. Hence, there is an urgent need for a potent treatment modality together with a solid predictive and prognostic biomarker.