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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 61

expression in non-neoplastic tissue [47,48] . Initial T-cell redirection therapy observed several severe OTOT
adverse events (AEs), including gastrointestinal hemorrhage, mucosal toxicity, hepatotoxicity, pulmonary
effusions, and respiratory distress [48-51] . As a result, ongoing selection of TAAs for T-cell redirection therapy
has been meticulous, with hopes of improving the safety profile and tolerability of these classes of therapy.

Tumor-associated antigens as targets in immuno-oncology
Prostatic acid phosphatase
Prostatic acid phosphatase (PAP) is a glycoprotein synthesized and secreted by prostate epithelial cells and
has served as one of the earliest TAAs for immunotherapy in prostate cancer, with an estimated expression
of 81.8% to 91% in mCRPC [11,52,53] . Sipuleucel-T is an autologous cellular immunotherapy designed to direct
the immune response towards PAP-expressing tissue. Sipuleucel-T is currently the only FDA-approved
immunotherapy for the treatment of metastatic prostate cancer and serves as a category 1 NCCN treatment
[54]
recommendation for patients with mCRPC who are either asymptomatic or minimally symptomatic .
Sipuleucel-T therapy necessitates the harvest of autologous peripheral mononuclear cells (PMC) via
leukapheresis. These cells are subsequently cultured ex-vivo with a recombinant fusion protein consisting of
prostate antigen and PAP linked to granulocyte- macrophage colony-stimulating factor (GM-CSF), an
immune cell activator. Upon infusion into the patient, this product leads to the activation of antigen-
presenting cells (APC) targeting PAP, and the PMCs, along with the activated APCs, comprise a colloquially
termed “personalized cancer vaccine” .
[11]

The IMPACT study, which evaluated Sipuleucel-T, was a pivotal trial that played a role in the subsequent
FDA approval in 2010. IMPACT was a multicenter phase III trial with 512 patients that demonstrated a 4.1-
month improvement in median overall survival over placebo. AEs associated with the therapy were
manageable [11,55,56] . No future confirmatory clinical trials have been performed to corroborate the findings of
the IMPACT study.

Despite the observed survival benefits in metastatic castrate-resistant prostate cancer, Sipuleucel-T has failed
to become a mainstay of treatment, possibly due to its complex administration and limited long-term data.
However, the efficacy of Sipuleucel-T serves as proof of the principle that PAP may be an effective TAA for
further immune therapy development, and autologous T-cell therapy can, to some degree, increase T-cell
[55]
trafficking to tumor tissue and stimulate cytotoxic T lymphocyte activation .
Epithelial cell adhesion molecule
Epithelial cell adhesion molecule (EpCAM) is an epithelial cell adhesion molecule that plays an important
physiological role in the formation and functionality of adhesive cellular processes, including regulation of
cell-cell junctions, signaling pathways, cellular mobility, and cellular proliferation . EpCAM is largely
[57]
expressed in a variety of epithelial tissues including lung, colon, pancreas, bile ducts, breast tissue, and
embryonic stem cells [58,59] . However, EpCAM has been found to be overexpressed in solid tumor
malignancies of epithelial tissue origin, principally carcinomas [59,60] . Studies have found EpCAM expression
to be 2 to 4-fold higher in mCRPC . As such, EpCAM has been studied as a potential immunologic target
[61]
and a focus of drug development in T-cell immunotherapies.

Among solid tumor malignancies, first-generation BiTE development was designed with EpCAM as the
TAA immunologic target. Catumaxomab (Removab), a trifunctional BiTE, was the first solid tumor BiTE
therapy that was approved by the European Medicines Agency in 2009 for the treatment of EpCAM-
positive malignancies. Approval was based on the treatment of malignant ascites associated with epithelial
cancer after a phase II/III trial of 258 patients demonstrated improvement in puncture-free survival, overall