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Page 665 Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48

exploratory analyses showed a longer PFS with combination therapy in patients with high PD-L1 IC2/3,
[94]
CD8 expression . The study also performed an unbiased RNA sequencing-based analysis of immune-
[95]
related gene expression that had previously correlated with mCRPC responses to immunotherapy , and
found longer PFS with combination therapy in patients harbouring genes related to pre-existing immunity
such as TAP-1, CXCL9, interferon signalling . The multicohort phase 2 KEYNOTE-199 trial examined
[94]
combination pembrolizumab with enzalutamide in mCRPC patients whose disease were refractory to
enzalutamide. In the cohorts with measurable disease and bone-predominant disease (cohorts 4 and 5), the
disease control rate was 51% and ORR was 12%. The duration of response was almost 6 months in 60% of
responders . This strategy is being evaluated further in an ongoing phase 3 trial [Table 1].
[96]

Systemic chemotherapy and ICIs
Chemotherapy may potentiate antitumour immunity by various mechanisms, including the release of TAAs
and enhancing antigen presentation, stimulating the activity of cytotoxic T lymphocytes [97,98] . Importantly,
chemotherapy may reduce immunosuppressive cell populations such as MDSCs and regulatory T cells,
known to maintain prostate cancer immune evasion [99,100] . Preclinical studies have suggested that
chemotherapy does improve antitumour immune responses, showing that the addition of taxanes can cause
a shift in macrophage populations toward the M1-like (immune-activating) phenotype and reduce
regulatory T cell and MDSC populations in mouse models [101,102] . The multicohort phase 2 trial CheckMate
9KD showed that combination nivolumab and docetaxel in 41 chemotherapy-naive mCRPC patients who
have progressed on novel hormonal agents achieved an ORR of 36.8%, radiologic PFS of 8.2 months and
PSA response of 46.3% . KEYNOTE-365 is an ongoing multicohort phase 1b/2 study examining
[103]
combination pembrolizumab and docetaxel in mCRPC patients, yielding an ORR of 18%, PSA response of
[104]
28%, radiologic PFS of 8.3 months, and OS of 20.4 months . Ongoing phase 3 trials (CheckMate7DX and
KEYNOTE-921) evaluating the superiority of combination chemotherapy with immunotherapy over
chemotherapy alone will shed light in this area [Table 1].

Radiopharmaceuticals and ICIs
177Lu-PSMA-617 has gained regulatory approval for the treatment of mCRPC patients who have been
treated with androgen receptor (AR) pathway inhibition and taxane chemotherapy, based on positive results
[105]
on a phase 3 trial . In murine models, targeted radionuclide therapy (TRT) may increase PD-L1
expression on T cells and the combination of TRT with ICIs leads to increased infiltration of CD8 T
[106]
cells . There is, hence, interest in combining radionuclide therapy with ICIs. Despite low clinical response
(ORR 6.8%, PSA response 4.5%, radiologic PFS 3 months) seen on a phase 1b trial combining Atezolizumab
and Radium-223 in mCRPC , the interim results of another phase 1b/2 PRINCE trial are relatively
[107]
promising. In this study, 37 mCRPC patients who have progressed on a novel hormonal agent and
docetaxel were treated with pembrolizumab and 177Lu-PSMA-617, yielding an ORR of 78%, PSA response
of 73%, and 24-week radiologic PFS of 65% [Table 1].
[108]

FUTURE DIRECTIONS AND CONCLUSIONS
Research is ongoing to identify more immunogenic targets and pair them with the multiple TAAs that
prostate cancer expresses. Amongst these, cellular-based therapy is an area that deserves special mention.
Adoptive cell therapy involves the engineering of patients’ T lymphocytes to target specific viruses or
tumours. The use of chimeric antigen receptors (CAR) allows for the creation of artificial T-cell receptors
[109]
used in adoptive cell therapy . A first-in-human phase 1 study of 13 CRPC patients tested PSMA-
targeting CAR T cells armoured with a dominant-negative TGF-β receptor. TGF-β is an inhibitory factor
found at high levels within the prostate TME. In this study, 4 patients had a ≥ 30% reduction in PSA and 1
patient had a > 98% reduction in PSA. Five patients experienced grade 2 or higher cytokine-release
[110]
syndrome (CRS) . Another CAR T therapy using P-PSMA-101, which targets PSMA, was evaluated in 10