Immunotherapy for prostate cancer: prostate cancer vaccines
1, Autologous vaccines: Sipuleucel-T is an autologous vaccine in which the patient's own peripheral blood mononuclear cells, along with APCs, are retrieved via leukapheresis. The cells are then activated with a recombinant fusion protein consisting of PAP linked to granulocyte-macrophage colony stimulating factor (GM-CSF), an immune cell activator.
2, Cell-based vaccines: GVAX is an allogenic cell-based prostate cancer vaccine that is composed of both hormone-sensitive and -naïve prostate cancer cell lines that have been genetically modified to bear GM-CSF. GM-CSF results in recruitment of DCs, which
then present antigens to T-cells invoking an anti-tumour cascade of immune responses. The whole tumour cell is used as the antigen, rather than just the PAP, as in sipuleucel- T, facilitating both humoural and cellular immune responses.
3, DNA-based vaccines: DNA-based vaccines consist of bacterial plasmids constructed to contain the coding sequence of a targeted antigen, which can be taken up by cells. These transformed cells express genes that can induce an immune response.
Bacterial plasmids are attractive in their simplicity, stability, and cost-effectiveness, which can be encoded with adjuvants and cytokines to increase their immune response. Phase I trials have been done targeting various TAAs, including PSA, PSMA, PAP, and the cancer-testis antigen NY-ESO-1.
4, Viral-based vaccines: Prostvac-VF is a vaccine comprised of two recombinant viral vectors that each encode for PSA and three immune costimulatory molecules including: co-stimulatory molecule for T cells (B7-1); intracellular adhesion molecule 1, and lymphocyte function-associated antigen 3. The vaccinia virus-based vector is used for priming and is followed by fowl pox virus-based vector boosts. This helps to overcome the host anti-vector antibody responses to the original vector. GM-CSF is co-administered to further boost immune response. The virus infects APCs, promoting cell surface protein expression and interaction with T-cells that facilitate a targeted immune response and cell-mediated tumour cell destruction. Current trials are testing Prostvac-VF in men with castration-resistant disease, as well as in combination with other traditional therapies and immunotherapies.
Immunotherapy for prostate cancer: immune checkpoint blockade
Immune responses are kept in balance by immune checkpoints that oppose co-stimulatory pathways, as well as clonal selection, activation, proliferation, trafficking, and effector function. Under normal conditions, these mechanisms help maintain self-tolerance, duration, and strength of immune responses, and aim to minimize damage to surrounding self-tissues. Alteration of these pathways in tumour cells re-directs T cell-mediated immunity such that checkpoint regulating molecules altered within the tumour or surrounding immune cells send a negative signal into the binding T cell, thus leading to its exhaustion. Recent successful immunotherapies have extensively exploited these mechanisms to enhance immune-mediated tumour cell destruction. The most representative ones are CTLA-4 based immunotherapy and PDL-1/PD-1 axis-based immunotherapy.
CTLA-4 is a co-inhibitory signal that binds B7 with greater affinity. CTLA-4 blockade removes the inhibition and results in T cell activation against tumour cells. Ipilimumab is a human monoclonal antibody against CTLA-4, first approved for metastatic melanoma in 2011. Several current trials are testing ipilimumab in patients with prostate cancer as a monotherapy and in combination settings. To date, monotherapy with ipilimumab in a phase III trial assessing men with castration-resistant disease was negative overall; however, there has been demonstration of good biochemical response and there was a signal of a survival benefit in subgroups of patients with favourable prognostic features.
Programmed cell death (PD) 1 is a cell surface molecule on T-cells that interacts with ligands, including PD-L1. This interaction inhibits downstream T cell receptor signalling, preventing T cell activation leading to their exhaustion and subsequent apoptosis. PD-L1 is expressed on a variety of cells, such as T, epithelial, endothelial, and tumour cells after exposure to IFN-γ. This interaction helps to regulate the immune response by reducing autoimmunity and developing self-tolerance. Similar to CTLA-4 targeting by ipilimumab, PD-1 is an additional but non-redundant pathway for which inhibition results in a targeted anti-tumour
response. Currently, the PD-1 based antibody, pembrolizumab is being investigated in a phase II trial in metastatic castration-resistant prostate cancer (CRPC) after androgen-deprivation therapy (ADT) (NCT02312557). Pidlizumab is another PD-1 monoclonal antibody currently being investigated in metastatic CRPC in combination with Sipuleucel-T and cyclophosphamide (NCT01420965).
Ren R et al. A primer on tumour immunology and prostate cancer immunotherapy[J]. Canadian Urological Association Journal, 2016, 10(1-2): 60-5.
Saad F et al. Current and emerging immunotherapies for castration-resistant prostate cancer. Urology 2015;85:976-86.