Immunotherapy: A Glimmer of Hope for Metastatic Prostate Cancer

Vishal Jindal


Chin Clin Oncol. 2018;7(6) 

In This Article

Immune Checkpoint Inhibitors

Ipilimumab is a monoclonal antibody which acts against CTLA-4 (cytotoxic T-lymphocyte associated protein 4) and up regulates the activity of cytotoxic T cells. It was approved by FDA for melanoma as it improved the survival and increased antitumor efficacy. CTLA-4 is a protein receptor that is present on surface of T lymphocytes. When APC activate T cells to fight against foreign antigens, there are costimulatory molecules like CD28 and B-7 which enhances the immune response. But along with that there are immune check points like CTLA-4 which binds B7, counteract the costimulatory effect of CD28 and negatively regulate the immune response.[25,26] Cancer cells exploit this property of CTLA-4, enhances their action and subsides the immune response. Ipilimumab acts against CTLA-4 and suppress the immune checkpoints therefore causes activation and proliferation of cytotoxic T cells which helps in degradation and lysis of tumor cells.[27,28]

In patients with prostate cancer some of early phase 1 trials were conducted investigating effect of CTLA-4 blockage.[29–31] Until now two phase 3 trials have studied the effect of ipilimumab on OS of patients with mCRPC. The first trial was done to assess the use ipilimumab after radiotherapy in patients with mCRPC who have progressed after docetaxel chemotherapy.[32] Total 799 patients were enrolled, in which at least one bone metastasis from CRPC should be there. Patients were assigned into 1:1 ratio to receive ipilimumab 10 mg/kg or placebo, every 3 weeks for up to four doses with maintenance ipilimumab or placebo every 3 monthly until progression of disease. The trial failed to show improvement in OS as it was 11.2 months in ipilimumab arm and 10 months in placebo arm. But there was improvement in PFS which was statistically significant (ipilimumab 4 months vs. placebo 3 months). The most common grade 3–4 adverse events were immune related, occurring in 26% of ipilimumab group and 3% of placebo group. In this study, subgroup analysis was also conducted which showed higher chances of benefit from ipilimumab therapy in patients with absence of visceral metastasis, low Alkaline phosphatase and hemoglobin more than 11 g/dL.

Second study was done to evaluate treatment with ipilimumab in chemotherapy naïve asymptomatic or minimally symptomatic mCRPC patients, without visceral metastasis.[33] Patients were assigned in 2:1 ratio to ipilimumab and placebo therapy. Medial OS was statistically comparable in both the groups (ipilimumab 28.7 months and placebo 29.7 months). But the PFS was better in ipilimumab group (ipilimumab 5.6 months and placebo 3.8 months). Immune related adverse events occurred in 31% of ipilimumab arm and 2% of placebo. Above mentioned two studies have shown that ipilimumab has no benefit in OS, but it improves PFS and PSA response rate suggest antitumor activity. So if ipilimumab used in combination with other therapies it may still benefit mCRPC patients (Table 3).

PD-1/PD-L1 Inhibitors

PD-1 is a transmembrane glycoprotein,[34] which is expressed on surface of activated cytotoxic T cells, B cells, dendritic cells, natural killer (NK) cells and macrophages.[35] PD-1 regulates immune response and programmed cell death. It is basically an immune checkpoint receptor which controls the inflammatory reaction and reduce T cell activity in peripheral tissue therefore prevents autoimmunity.[36,37] There are two ligands PD-L1 (programmed death ligand-1) and PD-L2 (programmed death ligand 2), they are present on cancer cells, and when these ligands bind with PD-1 they suppress the immune reaction.[38] It is one of the mechanisms of evasion of immunity by cancer cells. PD-1/PD-L1 inhibitors block these receptors so there is no signal to suppress immune response.[39] It leads to activation and proliferation of cytotoxic T cells which lead to degradation and lysis of tumor cells. Recent studies have shown that PD-1/PD-L1 inhibitors are efficacious in improving OS in various cancers. FDA approved Nivolumab (PD-1 inhibitor) in metastatic melanoma, non-small cell lung cancer and renal cancer and Pembrolizumab (PD-L1 inhibitor) in treatment of advanced melanoma.[40–42]

In phase 1 trial of nivolumab, there was no objective clinical response in patients with mCRPC. Three phase 1 dose escalation studies were conducted to study the response of nivolumab in mCRPC, total 27 patients were enrolled but there was no measurable clinical response.[43–45] Thus targeting PD-1 as monotherapy for mCRPC was curtailed. The most likely reason for failure of monotherapy of PD-1 inhibitor is, paucity of PD-L1 expression in tumor microenvironment,[46] as expression of PD-L1 in tumor tissue is associated with immune response.[47] Expression of immune check points is a dynamic process, with more infiltration of T cells there is upregulation of PD-L1 expression. Sipuleucel-T and Ipilimumab can enhance the T cell infiltration in the tumor microenvironment and therefore may increase the efficacy of PD-1/PD-L1 inhibitors. In 2016 Annual Meeting of the European Society of Medical Oncology, results were presented from an ongoing phase 2 trial of pembrolizumab in CRPC patients who progressed on enzalutamide therapy (NCT02312557). In this study patients were given pembrolizumab 200 mg IV every 3 weekly for four doses along with enzalutamide therapy. Out of 20 patients 4 had reduction on PSA more than 50%. This response rate of 20% is promising and if it is combined with other forms of therapy results may become better. Table 4 summarizes the studies going on monotherapy and combination therapy of PD-1/PD-L1 inhibitors.