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Page 663 Sooi et al. Cancer Drug Resist 2023;6:656-73 https://dx.doi.org/10.20517/cdr.2023.48

[59]
benefit seen from the phase 3 IMPACT trial . It is prepared from autologous peripheral blood
mononuclear cells obtained by leukapheresis, and pulsed ex vivo with PAP2024, a unique fusion protein of
granulocyte-macrophage colony-stimulating factor (GM-CSF) and prostatic acid phosphatase (PAP).
GM-CSF fosters the maturation of dendritic cells and other APCs to present PAP to the patient’s T cells,
resulting in PAP-specific T-cell proliferation targeting the PAP-expressing prostate cancer cells for killing.
Both humoural and cellular responses have been reported, with peripheral immune responses to PAP and
measures of APC activation correlating with improvements in OS [60,61] . Despite success with the use of
sipuleucel-T, other vaccines studied have not been as successful. G-VAX is another cell-based GM-CSF-
secreting vaccine that utilises irradiated TAAs . The TAAs are derived from two cell lines: one hormone-
[62]
sensitive (LNCaP) and one hormone-resistant (PC3) . Despite initially promising results in asymptomatic
[63]
mCRPC, the phase 3 VITAL 1 and VITAL 2 trials in asymptomatic mCRPC and symptomatic mCRPC
patients, respectively, failed to show the OS benefit of G-VAX plus docetaxel against docetaxel alone. Both
studies were terminated early based on futility assessments. A viral-based vaccine, PROSTVAC, utilizes
recombinant poxviruses that express PSA with immune-enhancing costimulatory molecules to stimulate
immune response [64,65] . In addition to induced modified human PSA, they contain three costimulatory
domains for T cells (B7.1, leukocyte function-associated antigen-3, and intercellular adhesion molecule-1),
called TRICOM . The phase 3 PROSPECT trial was unable to demonstrate the OS benefit of PROSTVAC
[66]
[67]
against placebo control .
Given the increase in T cell infiltration and inflammation within TME with sipuleucel-T [60,61] , it is therefore
postulated that synergy might be observed with the combined use of vaccines and ICIs. Ipilimumab and
PROSTVAC were combined in a phase 1 dose-escalation trial, showing evidence of improved clinical and
[68]
immunologic outcomes. The median OS was 34.4 months , which appears to be numerically larger than
PROSTVAC alone in its original study . There was a PSA reduction in 54% of patients and a PSA decline
[67]
of more than 50% was seen in 25% of patients. ADXS31-142 is a live, attenuated, bioengineered listeria-
based vaccine targeting PSA. It is being studied as part of the KEYNOTE-046 trial, with current results
showing a median OS of 33.7 months for patients treated with combination vaccine and pembrolizumab .
[69]
Other ongoing studies of vaccine therapy with ICIs are listed in Table 1.

Tyrosine kinase inhibitors and ICIs
[7,8]
Prostate cancers have dysregulated vasculature that promotes an immunosuppressive TME . These
include promoting a shift in TAMs toward M2-like immunosuppressive phenotype, reduced maturation of
dendritic cells which results in reduced antigen presentation, and increased PD-L1 expression . Vascular
[70]
endothelial growth factor (VEGF) overexpression has been found to prevent the differentiation of
[71]
monocytes into dendritic cells . Meanwhile, an improvement in the regulation of local vascular in
preclinical models was associated with the assimilation of TAMs with M1-like immune-stimulatory
phenotype, increased CD4+ and CD8+ T-cell infiltration into the TME, and reduction of MDSCs [72-75] . These
suggest that targeting angiogenesis in tumours can inhibit tumour-induced dysregulation of local
vasculature and promote immunogenicity in the TME, forming the basis of combining antiangiogenesis
agents with ICIs. Indeed, it has been shown in renal cell carcinoma that anti-VEGF therapy leads to a
reduction in immune inhibitory stimuli such as regulatory T-cells and MDSCs [76,77] . Aside from VEGFR
targeting, the TAM family of receptor tyrosine kinases comprising TYRO3, AXL and MER has been shown
to promote immune suppression as well, making it an attractive target [78,79] .

Cabozantinib is a multi-kinase inhibitor targeting MET, VEGFR-1, -2 and -3, AXL, RET, ROS1, TYRO3,
MER, KIT, TRKB, FLT-3, and TIE-2 . Preclinical data suggests that it has an effect on the TME by
[80]
reprogramming M2 TAMs to “pro-inflammatory” M1 macrophages, in addition to reducing MDSCs and T
[81]
regulatory cells . A dose-expansion cohort in the phase 1b COSMIC-021 trial evaluated the combination