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Page 68 Bhasin et al. J Transl Genet Genom 2024;8:55-76 https://dx.doi.org/10.20517/jtgg.2023.46

development targeting B7-H3 is rapidly underway, encompassing multiple classes of therapy including
ADCs (DS- 7300/MGC018), checkpoint inhibitors, tri-specific killer engager agents (TriKE), CAR natural
killer cell agents (CAR-NK), and CAR-T therapies [126,127,132,133] . Topline results from early-phase studies of
[127]
these therapies are demonstrating a favorable safety profile . Studies employing B7-H3 targeting CAR-T
therapies are ongoing (NCT04432649, NCT05515185).

PERSPECTIVES & FUTURE DIRECTIONS
Immunotherapy in prostate cancer represents an emerging treatment modality with promising therapeutic
efficacy. Thus far, ICI has demonstrated only modest treatment responses; however, T-cell redirecting
therapies are in the early stages of development and current progress should not be overlooked. The
identification of multiple TAAs within neoplastic prostatic tissue has allowed for rapid developments in
immuno-oncology. Nevertheless, barriers to the effective implementation of immunotherapy for patients
with prostate cancer remain. Novel drug design targeting an appropriate TAA has the potential to overcome
cancer immune evasion, which is a primary obstacle hindering immunotherapy in prostate cancer. Through
immune evasion, tumors can escape immune-mediated elimination through three key mechanisms: (1) loss
of antigenicity; (2) loss of immunogenicity; and (3) an immunosuppressive tumor microenvironment [135,136] .
MHC class I downregulation is common in advanced prostate cancer and contributes to the loss of
antigenicity and prevents subsequent immune-mediated mechanisms of cancer elimination [137,138] . Further,
tumor cells have demonstrated the ability to secrete immunosuppressive cytokines, recruit regulatory T-cell
subsets, and suppress antitumor effects that result in the alteration of the TME and create a “cold”
immunosuppressive environment [135,139,140] . Implementation of ICIs in prostate cancer had little impact on
altering the immune milieu of the TME. While newly engineered BiTE and CAR-T therapies hold promise
in overcoming the multiple barriers created by immune evasion mechanisms, multimodal combination
therapy across multiple classes of immunotherapy has the potential to synergistically target malignant cells
while also converting the TME from a “cold” to “hot”. Additional studies with well-designed correlative
analyses are required to further characterize immune escape mechanisms within the TME with respect to
multimodality combination approaches.

Treatment-related toxicity with T-cell redirection therapy, namely CRS and OTOT, has resulted in the early
termination of several clinical trials. Despite early concerns, studies have suggested that the administration
of steroid and tocilizumab does not blunt T-cell response or negatively affect treatment efficacy, and that
early intervention on toxicity may optimally prevent morbidity and allow for maximal benefit from
therapy [141,142] .

OTOT toxicity has decreased with the advent of highly specific TAA selection and with newly proposed
mechanisms to mitigate this toxicity, one of which is decreased scFvs affinity for the TAA, as high specificity
has been shown to lead to increased tumor effects but also increased OTOT effects. Novel strategies
requiring further investigation include multistep activation parameters to ensure the drug is present within
the TME, such as selective activation within an acidic pH or hypoxic tumor environment, or switches -
permanent or reversible - that allow for inactivation of the drug as a safety mechanism to avoid severe AEs.
Alternative strategies include regional administration of therapies, rather than systemic administration, in
[47]
an attempt to concentrate antitumor activity to the TME without undesired systemic toxicity .
BiTE therapy initially faced logistical challenges due to a short half-life which necessitated continuous IV
administration, while subcutaneous administration of the drug resulted in the formation of anti-drug
antibodies, rendering this therapeutic class clinically impractical.