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Page 66 Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46

NCT04221542 I STEAP1 (BiTE) AMG509 mCRPC DLT, AE profile
NCT04702737 Ib DLL3 (BiTE) Tarlatamab (AMG757 (HLE)) NEPC DLT, AE profile, ORR
ADA: Anti-drug antibody; AE: adverse event; BITE: bispecific T-cell engager; CAR-T: chimeric antigen receptor therapy; DLL3: delta-like protein 3;
DLT: dose-limiting toxicity; EpCAM: epithelial cell adhesion molecule; KLK2: kallikrein-related peptidase 2; MTD: maximum tolerated dose; ORR:
objective response rate; PSCA: prostate stem cell antigen; PSMA: prostate-specific membrane antigen; STEAP1: six-transmembrane epithelial
antigen of the prostate-1.

Gleason grades and has been associated with advanced disease and poor prognosis [95-100] .

Due to its expression profile, PSCA is an attractive TAA target for novel immunotherapy. Several ongoing,
early-phase clinical trials are currently underway to explore BiTE and CAR-T therapy aimed at PSCA.
Three ongoing phase I clinical trials are currently investigating the safety and tolerability profile of
autologous anti-PSCA CAR-T drug delivery (NCT03873805, NCT05805371) and the combination of PD-1
silent PSMA/PSCA targeted CAR-T therapy (NCT05732948). BPX-601 (NCT02744287) was a PSCA CAR-
T investigated in a phase I trial that was recently terminated due to dose-limiting toxicities. There are
currently no active PSCA BiTE studies; however, a recent phase I trial of GEM3PSCA (NCT03927573), a
PSCA × CD3 BiTE therapy, was terminated due to manufacturing challenges.

Six-transmembrane epithelial antigen of the prostate-1
Six-transmembrane epithelial antigen of the prostate-1 (STEAP-1) is a member of the STEAP1-4 protein
family. STEAP proteins are metalloproteinases that regulate iron and copper homeostasis, relieve oxidative
stress, and mediate the transferrin cycle [101-103] . STEAP proteins also serve an important role in apoptosis and
cellular proliferation . STEAP-1 is expressed at the surface of cell junctions in secretory prostate epithelial
[104]
cells [101,102,104,105] . Similar to other TAAs of interest, STEAP-1 is overexpressed in prostate cancer with an
estimated expression of > 80% and little to no expression in non-neoplastic tissues . Trace expression of
[106]
[74]
STEAP1 can be found in the bladder, ovaries, and bone marrow . When STEAP-1 is overexpressed, tumor
growth is promoted through unclear mechanisms. Hypothesized mechanisms suggest that during periods of
overexpression, cell-cell junction connexins are inhibited and intracellular communication is mediated via
STEAP1, which subsequently promotes stromal cell recruitment and malignant cell proliferation [101,104,106] .
However, numerous studies have demonstrated an immunogenic role of STEAP-1 and its antitumor activity
may be secondary to its effects on the immune milieu within the TME [74,101,106] .

STEAP1 has become a focus of T-cell immunomodulatory drug development, with novel CAR-T and BiTE
constructs actively being engineered [107-109] . AMG 509 is a BiTE therapy composed of two identical anti-
STEAP-1 domains that have shown promising in vivo results with strong antitumor activity through
[110]
increased cytotoxic T-cell activity and limited OTOT toxicity . AMG 509 is currently being evaluated in
the highly anticipated multicenter, open-label phase I study (NCT04221542) assessing the safety profile,
pharmacokinetics, and efficacy as monotherapy and in conjunction with enzalutamide or abiraterone
therapy . This ongoing study has thus far enrolled 97 patients who have been treated with various dose
[111]
levels of AMG 509. Early results have demonstrated that 15 patients (22.7%) had confirmed partial
responses and 30 (45.5%) had stable disease. Declines in PSA levels of 50% and 90% occurred in 42 (47%)
and 24 (27%), respectively. The most common adverse events were cytokine-release syndrome, mainly
grade 1 or 2 in 72%, fatigue in 53%, anemia in 45%, fever in 40%, and myalgia in 405 .
[112]

Additionally, STEAP-1 is the target for the development of numerous cancer vaccines. An mRNA vaccine
was studied in a phase I/II trial (NCT01817738) that was terminated after data failed to demonstrate any
signal in survival [101,113,114] .