Immunotherapy as a Precision Medicine Tool for the Treatment of Prostate Cancer

Abstract

Prostate cancer (PCa) is the most frequently diagnosed type of cancer among Caucasian males over the age of 60 and is characterized by remarkable heterogeneity and clinical behavior, ranging from decades of indolence to highly lethal disease. Despite the significant progress in PCa systemic therapy, therapeutic response is usually transient, and invasive disease is associated with high mortality rates. Immunotherapy has emerged as an efficacious and non-toxic treatment alternative that perfectly fits the rationale of precision medicine, as it aims to treat patients on the basis of patient-specific, immune-targeted molecular traits, so as to achieve the maximum clinical benefit. Antibodies acting as immune checkpoint inhibitors and vaccines entailing tumor-specific antigens seem to be the most promising immunotherapeutic strategies in offering a significant survival advantage. Even though patients with localized disease and favorable prognostic characteristics seem to be the ones that markedly benefit from such interventions, there is substantial evidence to suggest that the survival benefit may also be extended to patients with more advanced disease. The identification of biomarkers that can be immunologically targeted in patients with disease progression is potentially amenable in this process and in achieving significant advances in the decision for precision treatment of PCa.

Keywords: immune checkpoint inhibitors; immunotherapy; precision medicine; predictive biomarkers; prostate cancer.

Figure 1

Immunotherapeutic strategies for prostate cancer fall into three main categories: (1) antibodies, (2) vaccines, and (3) adoptive cell transfer; these can be subdivided into smaller categories depending on the mode of action. Immunotherapeutic modalities in orange boxes represent strategies that have been shown to confer a survival advantage to prostate cancer (PCa) patients, whereas immunotherapies in blue boxes are either in pre-clinical/early clinical development or they have so far failed to demonstrate a survival benefit in terms of progression-free survival (PFS) or overall survival (OS). Similarly, orange arrows represent an immune response, whereas dotted blue arrows represent a possible but not yet confirmed immune response. Ad5: adenovirus type 5; AdV-tk: adenoviral vector containing a herpes virus-derived thymidine-kinase; CEA: carcinoembryonic antigen; DC: dendritic cell; GM-CSF: granulocyte-macrophage colony-stimulating factor; HLA: human leukocyte antigen; Lm: listeria monocytogenes; LLO: listeria monocytogenes (Lm)-listeriolysin O; LNCaP: lymph node-derived human prostate adenocarcinoma cell line; MUC-1: mucin-1; PAP: prostatic acid phosphatase; PC-3: prostate cancer cell line derived from bone metastasis; PD-1: programmed death receptor-1; PD-L1: programmed death-ligand 1; PSCA: prostate stem cell antigen; PSMA: prostate-specific membrane antigen; scFv: single chain variable fragment; STEAP: six transmembrane epithelial antigen of the prostate; TRICOM: TRIad of Co-stimulatory Molecules.