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Page 659 Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48

Figure 2. The immunologically “cold” tumour microenvironment in prostate cancer.

response by exploiting CTLA-4, and this forms the basis of targeting CTLA-4 with monoclonal antibodies
such as ipilimumab. Inhibition of CTLA-4 activity causes activation and proliferation of cytotoxic T cells
against tumour cells [30,31] . To date, two phase 3 trials have looked at the activity of ipilimumab in mCRPC
patients. The first study, CA 184-043, recruited 799 mCRPC patients with at least one bone metastasis and
have progressed on docetaxel chemotherapy. Patients were randomised to receive either one fraction of
bone-directed radiation therapy followed by ipilimumab at 10 mg/kg or placebo. There was no overall
survival benefit seen in this study (median OS 11.2 vs. 10 months, HR 0.85, 95% CI 0.72-1.00), but a
[32]
progression-free survival (PFS) benefit (4.0 vs. 3.1 months, HR 0.70, 95% CI 0.61-0.82) was seen . The
second study by Beer et al. (2017) randomised 602 mCRPC patients who were chemotherapy-naive and had
no visceral metastases to ipilimumab at 10 mg/kg vs. placebo. The study showed no overall survival benefit
(median OS 28.7 vs. 29.7 months; HR 1.11, 95% CI 0.88-1.39), although a PFS benefit (median PFS 5.6 vs. 3.8
months; HR 0.67; 95% CI 0.55-0.81) was observed. Exploratory analyses further showed a higher prostate-
[33]
specific antigen (PSA) response rate with ipilimumab (23%) than with placebo (8%) . Taken together, the
PFS and PSA response with ipilimumab suggests antitumour activity despite the lack of survival benefit.

PD-1 is a transmembrane glycoprotein found on the surfaces of activated cytotoxic T cells, B cells, dendritic
cells, NK cells, and macrophages . The binding of PD-1 to its ligands programmed death ligands 1 and 2
[34]
(PD-L1 and PD-L2) found on cancer cells delivers inhibitory signals for T-cell activation, suppressing an
immune response [35,36] . Monoclonal antibodies targeting PD-1/PD-L1, such as nivolumab and
pembrolizumab, have shown activity in multiple cancer types, leading to regulatory approval for their
use [37,38] . Pembrolizumab was studied in the phase 1b KEYNOTE-028 and phase 2 KEYNOTE-199 trials as
monotherapy in mCRPC, showing poor responses [39,40] . The objective response rate (ORR) was 5% in PD-L1
combined positive score (CPS) ≥ 1 patients in KEYNOTE-199, compared with 3% for patients with a
negative PD-L1 expression . Three phase 1 dose-escalation trials of nivolumab monotherapy in mCRPC
[39]
patients likewise showed no objective response [41-43] . As mentioned, the paucity of PD-L1 expression in the
TME in prostate cancer patients could account for this. Despite the glaringly low response rates for
anti-PD(L)1/anti-CTLA4 monotherapies in unselected prostate cancer, the expression of immune