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Page 136 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

[10]
elements in the tumor environment, making them unresponsive to these inhibitors . Recent research,
however, has indicated positive outcomes with immune checkpoint inhibitors (ICIs) and their
combinations in specific patient groups with high PD-L1 expression, mutations in CDK12, elevated
mutational pressure in tumors, and tumors displaying more mismatch repair deficiency (dMMR) and
microsatellite instability (MSI) levels [11,247] . Immune checkpoint inhibitors are thus restricted to certain
prostate cancer subtypes that have particular genetic or molecular characteristics that render them more
recognizable or susceptible to the immune system [Figure 4]. Among these subtypes are:

1. Increased microsatellite instability (MSI-H) or mutational changes in the mismatch repair (MMR) genes
in prostate cancer: Uncommon prostate cancer subtypes with an increment in mutation rate and the ability
to create aberrant proteins that the immune system may mistake for foreign substances. In some patients
with MSI-H or MMR-deficient prostate cancer, ICI drugs that target PD-1 or PD-L1, such as
pembrolizumab and nivolumab, have been proven to be effective [246,248,249] .

2. Prostate tumors with high PD-L1 expression: Some cancer cells express a protein that can attach to the
immune cells of PD-1 receptor and stop those cells from attacking the cancer cells. By blocking this
interaction, ICIs that target PD-1 and PD-L1 can activate the body's defenses against cancer cells. According
to certain research, prostate tumors with more PD-L1 display may respond to ICIs more favorably than
those with low PD-L13 expression [246,248] .

3. High tumor mutational burden (TMB) prostate tumors: This is a measurement of the quantity of DNA
mutations present in cancer cells. More aberrant proteins that the immune system may identify as foreign
can result from a high TMB. Prostate tumors with high TMB may respond better to ICIs that target the
PD-1 or PD-L1 proteins, compared to prostate cancers with low TMB [246,248,250] .

4. Prostate tumors with CDK12 mutations: Transcription and DNA repair are the major role played by this
gene. Genomic instability and a rise in the development of neoantigens—new or altered peptides identified
as outsider by the immune system - can result from mutations in CDK12. Prostate tumors with CDK12
mutations may respond better to immune system checkpoint medications focused on PD-1 or PD-L1 than
those without [246,248] .

Overview of clinical trials involving immune checkpoint inhibitors in prostate cancer
Sipuleucel-T, an active cellular immunotherapy, demonstrated the clinical significance of the immune
system in advanced prostate cancer (PCa). In a phase III trial, asymptomatic or minimally symptomatic
metastatic castration-resistant PCa (mCRPC) patients receiving sipuleucel-T had a 22% lower risk of death
compared to the placebo group (HR 0.78, 95%CI: 0.61-0.98), leading to a 4.1-month improvement in
median overall survival. This underscores the potential of immune system modulation to benefit and
[110]
improve outcomes in mCRPC . In patients (CA184-095) with mildly symptomatic mCRPC who had not
received chemotherapy, high-dose ipilimumab (10 mg/kg) monotherapy did not result in a better median
OS compared to the placebo (28.7 months vs. 29.7 months; HR = 1.11, 95%CI: 26.1-34.2 months,
P = 0.3667). However, compared to placebo, there were greater times to systemic nonhormonal cytotoxic
therapy, a longer time to progression-free survival (5.6 months vs. 3.8 months; HR = 0.67, 95.87%CI: 0.55-
0.81), and a larger PSA response rate (23% vs. 8%). All of these data suggested antitumor activity. In
comparison to the 3 mg/kg dose used in melanoma, more treatment-related grade 3 to 4 adverse events
(TRAEs) were reported (40% vs. 23%), and there were 9 treatment-related deaths [246,251] (Table 1 Completed
Immune checkpoint inhibitors Phase 3 clinical trials in prostate cancer [251-258] ).