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Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48 Page 666

heavily-pre-treated CRPC patients, yielding PSA decline in 7 patients, with 4 patients having > 50%
[111]
reduction in PSA. CRS was seen in 60% of patients . Other CAR T products targeting Epithelial cell
adhesion molecule (EpCAM) and Natural Killer Group 2D (NKG2D) have shown activity in prostate
cancer patients as well [112,113] . Other potential targets of interest with adoptive cell therapy include PSA, PAP,
PSCA, and B7-H3 , and Table 2 shows a list of ongoing clinical trials.
[114]
Bispecific T cell engager (BiTE) antibodies is another technology that has been developed to target TAAs
such as PSMA in prostate cancer cells. Structurally, these are bispecific monoclonal antibodies that can
crosslink TAAs with the coreceptors on T cells, generating an antitumour immune response.
Pasotuxizumab is a bispecific monoclonal antibody that crosslinks CD3 and PSMA, and its efficacy has been
studied in 16 mCRPC patients on a phase 1 trial, showing ≥ 50% decline in PSA in 3 patients, of which two
were long-term responders treated for 14.0 and 19.4 months, respectively. 81% of the patients had adverse
events of grade ≥ 3 . The efficacy of AMG 160, a BiTE product that binds CD3 on T cells and PSMA on
[115]
cancer cells, was evaluated in mCRPC patients on a phase 1 trial. In the preliminary report, 27% of patients
had confirmed PSA responses and 84% of patients experienced CRS (10% grade ≥ 3) . The study also had
[116]
a subset of patients who received AMG 160 with pembrolizumab, and such a combination will likely be
examined in future studies as well. Other potential BITE targets including STEAP, CEACAM5, DLL3,
HER2 are being studied [117,118] , and a list of ongoing trials can be seen in Table 2. Figure 3 shows a schematic
diagram of BiTE therapy.

On the horizon, relevant and novel targets to modulate antitumour immunity in prostate cancer may
include the targeting of relevant immune-metabolic pathways, such as the adenosine receptor [119-121] , or
cytokine-directed efforts, such as IL-8 involved in the differentiation of TAM to M2 phenotype (promotes
[124]
immune resistance and tumour metastasis) [122,123] , IL-23 which is a cytokine secreted by MDSCs and
TGF-β which promotes tumour growth and immunosuppression in the TME . Targeting cell signalling
[81]
pathways such as the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) pathway
has also been shown to downregulate immunosuppressive cells such as T regulatory cells and may have a
role in improving ICI efficacy in prostate cancer [125,126] . For example, in prostate cancer mouse models,
intermittent PI3K inhibition was able to alleviate PTEN-null cancer cell-intrinsic immunosuppressive
[127]
activity and turn “cold” tumours into T cell-inflamed ones . Novel immune checkpoints may be worth
exploiting in prostate cancer. Increased expression of V domain Ig suppressor of T Cell activation (VISTA)
was found to promote immune resistance following Ipilimumab treatment, which may serve as a new
immunotherapeutic target in advanced prostate cancer .
[128]

There are presently limited biomarkers that can identify prostate cancer patients who may benefit from ICI
therapy. It appears that combination strategies to promote immunogenicity within the “cold” TME of
prostate cancer can increase the effect of ICIs. We recognise that the majority of the existing efforts are
presently in the preclinical or early phase setting and may not be ready for use in the clinics yet. It would
nevertheless be interesting to monitor this space for future developments.