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Page 146 Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50

Direct tumor injection
Direct tumor injection aims to eradicate prostate cancer cells by delivering genetic material directly into
tumors. In a phase-I trial, the efficacy of an IL-2 plasmid with a cytomegalovirus (CMV) promoter bound to
lipid-bilayer carrier molecules was evaluated in individuals with high-risk prostate cancer .
[306]
Qualified patients either experienced cancer recurrence after upfront radiation therapy or cryotherapy, or
-1
had advanced localized disease (confirmed by Gleason score 7 or higher and PSA greater than 10 ng mL ).
On days 1 and 7 of the research, transrectal intra-prostatic gene delivery was performed by injecting the
lipid bilayer molecules complexed with DNA into hypoechoic lesions identified by transrectal
ultrasonography (TRUS) in all males with biopsy-proven lesions. Of the twenty-four patients receiving
treatment, ten had recurrent illnesses and fourteen had localized illnesses. The therapy was well tolerated,
with 16 patients experiencing a brief drop in PSA levels on the first day after treatment. Furthermore, there
was evidence of enhanced peripheral blood lymphocyte proliferation and local T cell infiltration post-
injection. The expression of IL-2 DNA and mRNA persisted up to seven days after injection, likely due to
the transient effect of plasmid transporter vehicles in situ. This indicates that the plasmid system had a
temporary impact [306,307] . These data are promising, as some studies suggest that this therapy is a more
favorable therapy for the treatment of early-stage prostate cancer.

Gene apoptosis therapy
Prostate cancer stands as a leading cause of mortality among men worldwide. Current treatment options
such as radiation, hormone therapy, and prostatectomy often come with unfavorable side effects and
varying levels of effectiveness across different stages of the disease. In this context, gene therapy emerges as
a promising and experimental approach for treating prostate cancer. One notable strategy within gene
therapy involves inducing cellular apoptosis in cancer cells [293,308,309] . A significant challenge posed by genetic
[309]
alterations in cancer cells is commonly the suppression of apoptosis, contributing to cancer progression .
However, the lack of delivery technologies that can selectively deliver therapeutic genes to tumors without
[293]
causing significant adverse effects following intravenous treatment currently limits its application . To
address this limitation, numerous nonviral delivery strategies have been developed. These strategies aim to
deliver DNA-based medicinal medicines precisely to the intended sites of action .
[293]
Immunomodulatory gene therapy
Immunomodulatory gene therapy is a type of gene treatment aimed at enhancing the immune system’s
ability to detect and destroy prostate cancer cells. The premise underlying this approach is the activation of
the antitumor response of the immune system and the subversion of the immunosuppressive mechanisms
of cancer cells by introducing genes into the TME that stimulate the production of immune mediators such
as cytokines, chemokines, or costimulatory molecules . Both viral and nonviral vehicles are used as
[310]
carriers to deliver therapeutic genes to target cancer cells in immunomodulatory gene therapy [294,310] .

An example of immunomodulatory gene therapy for prostate cancer involves the use of plasmid DNA
vectors to transport the interleukin-12 (IL-12) gene. IL-12 induces the production of a potent pro-
inflammatory cytokine, activating the innate and adaptive immune systems to combat tumor growth.

The balance between pro- and antitumor cytokines can also be influenced by IL-12 production in the TME,
which promotes the infiltration and activation of NK (natural killer) cells, macrophages, dendritic cells, and
T cells [294,311] . For prostate cancer, a phase I trial combining this treatment with radiation therapy has
[311]
demonstrated its viability, tolerability, and early signs of antitumor activity .