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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 63

In addition, PSMA-directed antibody-drug conjugate (ADC) therapy has also emerged as a novel treatment
strategy. ADCs are composed of monoclonal antibodies that target TAAs of interest and are chemically
linked to a cytotoxic agent that is delivered upon binding of the antigen. ADCs targeting PSMA under
development are primarily delivering antimicrotubule cytotoxic compounds including maytansinoid-1
(DM1) (NCT00052000, NCT00070837) and monomethyl auristatin E (MMAE) (NCT01414283,
[35]
NCT01695044) . The efficacy of PSMA targeting ADCs is currently being evaluated in phase I/II clinical
trials, with further research necessary to evaluate their therapeutic potential.

PSMA is also an attractive target for immunotherapy. CAR-T therapy targeting PSMA initially gained
interest when CAR-T preclinical studies demonstrated strong antitumor activity and a robust immunogenic
response including increased T-cell proliferation, cytolysis of tumor cells, and cytokine production in
in vitro mice studies [78,79] . Subsequent generations of PSMA CARs have demonstrated improved efficacy
through the addition of dominant-negative transforming growth factor (dnTGF-BRII), which inhibits an
immunosuppressive signaling cascade, and a monoclonal antibody target of IL-23, an inflammatory
cytokine involved in immunosuppression and angiogenesis [80,81] .

A second-generation anti-PSMA CAR-T therapy was studied in a phase I dose-escalation trial
(NCT01140373) with 7 enrolled patients who were treated with three different dosages. Patients in higher
dose cohorts experienced high-grade fevers that were associated with increased levels of inflammatory
cytokines (IL-4, 6, 8, 10, sIL-2ra) indicative of T-cell activation . Another phase I dose-escalation trial was
[82]
conducted with the enrollment of 5 patients treated with a first-generation anti-PSMA CAR, and findings
demonstrated a > 50% PSA decline in two out of five patients and a minor response in a third patient .
[83]
Several ongoing trials investigating the efficacy of anti-PSMA CAR-T therapy have demonstrated promising
preliminary results. In particular, an open-label, multicenter phase I dose-escalation trial (NCT04249947)
employing P-PSMA-101 CAR-T has demonstrated encouraging preliminary data. P-PSMA-101 is a CAR
designed with the piggyBac DNA Modification System which preferentially increases the production of
stem cell memory cells, leading to long-term immunoactivation with T-cell expansion and the potential to
alter the TME. Preliminary data of 10 heavily pre-treated patients with mCRPC who had received, on
average, seven lines of prior therapy demonstrated a PSA decline of > 50% in three patients and > 99% in
one patient. Further, three of the four patients demonstrated a complete radiographic response on PSMA-
PET imaging with a concurrent decline in circulating tumor cell (CTC) burden. Histologic examination of
one case demonstrated P-PSMA-101 CAR-T cell infiltration and a complete pathologic response with
resolution of metastatic disease on interval imaging and biopsy results. An encouraging safety profile was
also reported with only grade 1-3 AEs . Studies evaluating the efficacy of dnTGF-BRII are currently
[84]
ongoing, but preliminary data have identified dose-limiting toxicities despite efficacy in some, including
deep responses [35,85] .

PSMA targeting BiTE therapy is also in development with several ongoing clinical trials. Pasotuxizumab
(AMG 212 or BAY 2010112) was the first BiTE therapy in clinical study to target PSMA. In vitro study of
the drug demonstrated high PSMA antigen specificity , which ultimately led to the launch of a phase I
[86]
dose-escalation study (NCT01723475) to determine the safety and maximum tolerated dose (MTD). In this
study, 47 patients were enrolled in either a subcutaneous (SC) delivery group (31 patients) or a continuous
IV (cIV) group (16 patients).

Results of the trial were encouraging, with a PSA decline of > 50% in nine patients with SC dosing and three
patients with cIV dosing - two of whom demonstrated a sustained and durable response. However, all 31