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Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46 Page 67

Tumor-associated antigens for neuroendocrine prostate cancer
Neuroendocrine prostate cancer (NEPC) is a poorly differentiated neuroendocrine carcinoma that broadly
[115]
encompasses pure small cell, large cell, or mixed neuroendocrine carcinomas . NEPC rarely occurs de
novo and comprises less than 2% of all prostate cancers. However, upwards of 10%-15% of patients with
metastatic castrate-resistant prostate cancer have been noted to develop treatment-related NEPC (t-NEPC)
[116]
following treatment with androgen signaling inhibitors . Evidence suggests that the development of t-
NEPC may occur secondary to the inactivation of TP53 and RB1, which serve as epigenetic regulators.
Diagnosis is often challenging and delayed as it typically presents in patients who have been diagnosed with
advanced disease and are undergoing treatment directed at prostatic adenocarcinoma. Current treatment
guidelines recommend first-line platinum-based chemotherapy regimens, but no standard treatment
guidelines exist for second-line therapy and beyond [28,74,117] . Recent studies have demonstrated high
expression of delta-like protein 3 (DLL3), a notch ligand, in NEPC disease. DLL3 was initially discovered
due to overexpression of the antigen in small cell lung cancer (SCLC) surface epithelial cells [118-119] , but DLL3
antigen expression has recently been described in 76.6% of evaluated NEPC cases. As such, DLL3 has
emerged as a possible TAA target for immunotherapy. Tarlatamab (AMG 757) is a BiTE therapy currently
under investigation in the phase Ib setting (NCT04702737) for the treatment of de novo or t-NEPC. There
is also a CAR-T targeting DLL3 under investigation in SCLC (AMG 119) and it may have a potential
application to NEPC depending on study results [74,117,120] .

Recent studies have identified cell adhesion molecule 5, CEA (CEACAM5), as another highly expressed
antigen specific to NEPC, and CEACAM5 may serve as a target TAA for future drug development. In vitro
studies have demonstrated the successful creation of anti-CEA CAR-T cells with tumor growth delay and
eradication [74,121,122] . While immunotherapy targeting the treatment of NEPC is in its early stages, there is an
urgent and unmet need for novel therapies in this histology and future immunotherapy studies are likely to
be forthcoming.

Alternative immunomodulatory targets for T-cell redirecting therapy
B7-H3 (CD276)
B7-H3 is a surface membrane protein that is a newly identified member of the B7 immunomodulator
protein family. More well-known member proteins include PD-L1, PD-1, and CTLA-4 [123-125] . While
originally hypothesized to promote costimulatory immune activation, recent data suggest a dual role, with
both costimulatory and, more predominantly, coinhibitory role for the antigen [125-129] . In addition, emerging
studies have demonstrated that higher levels of B7-H3 have been associated with increased tumor survival,
metastasis, and resistance to chemotherapy [125-130] . Furthermore, elevated levels of the antigen have been
associated with higher Gleason scores, development of castrate-resistant metastatic disease, and poor overall
prognosis . Nonetheless, much is yet to be discovered regarding B7-H3’s immunologic and functional role
[131]
within the TME. Similar to other TAAs of interest, B7-H3 has limited expression in normal tissue, with
increased expression detected in solid tumor malignancies. Moreover, B7-H3 has been noted to
overexpressed in greater than 80% of metastatic castrate-resistant prostate cancer cases, with overexpression
also noted in CNS tumors (glioblastoma, neuroblastoma), ovarian, pancreatic, breast, colorectal, renal cell,
non- small cell lung, and cutaneous squamous cell carcinoma [125,128-130] .

Preclinical work targeting B7-H3 has demonstrated promising antitumor activity [125,127,130-134] . Other studies
have demonstrated that defects in tumor suppressor genes, namely TP53 and PTEN, have been associated
with increased B7-H3 levels. Other preclinical studies have observed that monoclonal antibodies, such as
enoblituzumab, have been combined with PD-L1 inhibitors with dramatic success and have spurred further
combination treatment approaches with ipilimumab, a CTLA-4 inhibitor, with clinical studies currently
underway in patients with melanoma and non-small cell lung cancer (NCT02381314) [132-133] . Further drug