Immunotherapy for Localized Prostate Cancer

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

“…CTLA-4 is a transmembrane protein that is expressed on T lymphocytes and competitively binds CD80 and CD86 on antigen-presenting cells (APCs), thereby creating a negative feedback loop that prevents T-cells from killing other cells, including cancer cells [ 62 ]. Ipilimumab, the ICI blocking the function of CTLA-4, started being tested in PCa clinical trials shortly after its FDA approval for the treatment of melanoma in 2011 [ 63 , 64 ].…”

“…PD-1 is another transmembrane protein expressed on T cells; its receptor interacts with the PD-1 ligand (PD-L1) that is expressed on both normal and malignant cells, and their interaction constitutes an important checkpoint of T lymphocyte inhibition [ 62 , 71 ]. PD-1 binding to PD-L1 on tumor cells results in an inhibition of apoptosis, T-lymphocyte tolerance and an increase in tumor cell survival [ 71 ].…”

“…PD-1 binding to PD-L1 on tumor cells results in an inhibition of apoptosis, T-lymphocyte tolerance and an increase in tumor cell survival [ 71 ]. ICIs that act as inhibitors of PD-1 include nivolumab and pembrolizumab, whereas ICIs of PD-L1 include atezolizumab, avelumab, and durvalumab [ 62 ]. Even though primary prostate cancers are characterized by an infiltration of PD-1 expressing CD8+ T cells, mCRPC shows minimal expression of the PD-L1 ligand, which represents a significant obstacle when applying anti-PD-1/PD-L1 monotherapy [ 59 , 72 , 73 ]; only mCRPC patients who have developed resistance to the anti-androgen enzalutamide have been associated with an upregulation of PD-L1 [ 74 ].…”

“…Clinical trials testing nivolumab or pembrolizumab as monotherapy in unselected mCRPC patients have produced unsatisfactory results in terms of demonstrating a significant survival benefit, with the only exceptions being partial responses in enzalutamide-resistant patients and in patients with microsatellite instability (MSI) [ 72 , 75 , 76 ]. Indeed, there is enough evidence to suggest that patients with DNA mismatch repair mechanism (MRM) mutations demonstrate anecdotal sensitivity and may derive benefit from treatment with pembrolizumab, possibly due to the higher rate of TAAs and MSI, despite these being relatively uncommon in PCa [ 62 , 76 , 77 , 78 ]. Preliminary data from recent clinical trials seem to be more encouraging, as pembrolizumab monotherapy has been shown (i) to induce durable objective responses and minimal adverse events in a subset of patients with heavily pre-treated, advanced PD-L1-positive PCa (NCT02054806) [ 79 ] and (ii) to evoke anti-tumor activity with durable clinical responses and significant OS estimates in a subset of treatment-refractory (docetaxel and one or more targeted endocrine therapies) mCRPC patients (NCT02787005) [ 80 ].…”

“…However, despite the promising results of pre-clinical and clinical studies, immune checkpoint blockade-based immunotherapy appears to be less efficient in PCa as compared to other cancer types; this is mostly due to the fact that prostate cancer is a “cold” tumor, characterized by minimal T-cell infiltration, low TMB, low PD-1 expression and downregulated or non-existent MHC class I expression, a necessary prerequisite for successful immune checkpoint inhibition [ 62 ]. In order to overcome therapeutic limitations, to enhance the therapeutic potential of ICIs and to extend the survival benefit to larger subsets of patients, many studies are currently investigating combinations of two different types of ICIs, or ICIs with other treatment modalities.…”