Page 57 - Read Online

Bibi et al. J Transl Genet Genom 2024;8:119-161 https://dx.doi.org/10.20517/jtgg.2023.50 Page 147

Despite promising results, immunomodulatory gene therapy for prostate cancer has not yet received clinical
approval. Various clinical trials are underway evaluate the effectiveness and safety in combination with
other treatments such as radiation, chemotherapy, hormone therapy, and immunotherapy. These trials seek
to optimize delivery strategies, dosing regimens, gene combinations, and treatment sequences, as well as to
identify potential biomarkers of resistance and response [294,311] .

RECENT PROGRESS IN GENE THERAPY FOR PROSTATE CANCER
Recent developments in gene therapy have shown promising results in the fight against prostate cancer,
particularly through the authorization of rucaparib and Olaparib. These drugs, known as PARP (poly ADP-
ribose polymerase) inhibitors, are effective in subjects with mutations in DNA damage repair genes, offering
new hope for individuals with metastatic Castration-Resistant Prostate Cancer (mCRPC). By blocking the
enzyme responsible for DNA repair in cancer cells, PARP inhibitors induce cell death. Specifically, olaparib
has been found to delay disease progression, alleviate pain, and potentially extend the lives of patients with
mutations in the BRCA1, BRCA2, and ATM genes, as evidenced by a large, multinational phase 3 trial .
[312]
Furthermore, rucaparib has shown comparable benefits for subjects with mCRPC harboring mutations in
[313]
genes such as BRCA1, BRCA2, or PALB2 .
Beyond these therapies, pembrolizumab, an immunotherapy medication that stimulates T cells to combat
cancer cells, and 177-lutetium-PSMA-617, a radiotherapeutic agent that targets PSMA-positive prostate
cancer cells, are currently undergoing clinical trials. These trials aim to explore the potential of nonviral
gene transfer methods for treating prostate cancer cells in patients with mCRPC who have responded to
traditional therapy . Nonviral transfer vehicles, while presenting certain drawbacks, such as low
[295]
transfection efficiency, poor specificity, and limited duration of gene expression, are generally considered
less immunogenic, less toxic, and more adaptable than viral vectors. Recent advancements in this area
include the use of lipid nanoparticles (LNPs) for delivering mRNA encoding various proteins, polymeric
micelles for CRISPR/Cas9-mediated gene editing, and bisphosphonate nanocomplexes for siRNA targeting
different genes [284,305-307] .

One notable advancement involves the use of RALA peptide as a nonviral vector to deliver plasmids
expressing inducible nitric oxide synthase (iNOS), a powerful antitumor agent that promotes cancer cell
apoptosis and inhibits angiogenesis in prostate cancer cells. A study has demonstrated that RALA/iNOS
composite nanoparticles are both safer and more effective in combating tumors compared to RALA alone
[314]
or free iNOS plasmids .
DISCUSSION
Over the past few decades, tremendous progress has been made in prostate cancer treatment. However,
navigating the complexities of employing immune therapy in prostate cancer presents both challenges and
potential breakthroughs. Despite the initial attractiveness of targeting the disease due to its slow
progression, clinical trials, especially in metastatic castration-resistant prostate cancer (mCRPC), face
hurdles in achieving optimal efficacy. These challenges stem from compromised immune systems in
patients, characterized by deficiencies in cellular immunity and reduced natural killer cell activity.
Additionally, the intricate microenvironment of prostate tumors further complicates immune cell function.
Nevertheless, emerging evidence and advancements in CAR-T therapy offer hope for tackling challenging
cases. A comprehensive understanding of cytokines, chemokines, and immune cell dynamics is imperative
for developing effective immunotherapies [315,316] . Despite acknowledged limitations, cautious optimism
prevails regarding the future of immunotherapy in advanced prostate cancer.