Page 107 - Read Online

Oboma et al. J Transl Genet Genom. 2025;9:62-75 https://dx.doi.org/10.20517/jtgg.2024.74 Page 68

focus on determining the optimal dosing, safety profiles, and early signs of efficacy before progressing to
larger-scale studies. One of the prominent gene therapy trials is evaluating the use of adenoviral vectors to
deliver tumor suppressor genes like p53 directly to prostate tumors. These trials are investigating whether
restoring the function of the p53 gene can halt tumor progression or lead to tumor shrinkage in patients
with advanced prostate cancer. Early results from these trials have shown modest reductions in tumor size
and stabilizations of the disease, although more extensive studies are needed to assess long-term
outcomes . See Figure 3.
[44]

Additionally, CRISPR-Cas9 technology is being tested in clinical settings to knock out specific mutations
associated with resistance to androgen deprivation therapy (ADT), as presented in Figure 3. The potential
for CRISPR to modify androgen receptor (AR) genes and restore sensitivity to ADT is a major focus in
prostate cancer treatment. Preliminary data from phase I trials suggest that CRISPR-mediated gene editing
has successfully reduced tumor burden in a small number of patients, though challenges such as off-target
effects and efficient delivery of the CRISPR components need to be addressed before wider clinical
implementation . In terms of cell therapy, CAR T cell therapy targeting prostate-specific membrane
[45]
antigen (PSMA) has entered phase I/II trials. These trials are investigating the safety and preliminary
efficacy of CAR T cells in patients with metastatic castration-resistant prostate cancer (mCRPC) who have
exhausted standard treatments. Early trial data suggest that CAR T cell therapy has led to partial tumor
responses in some patients, though immune-related adverse events such as cytokine release syndrome
[35]
(CRS) have been reported45 . These adverse effects are being closely monitored, with researchers working
to refine CAR T cell designs to reduce toxicity and enhance therapeutic benefits. Cytokine release syndrome
(CRS) is a potentially life-threatening condition that can occur after gene editing therapies, particularly
those using CAR T cells or other immunotherapies. Signs and symptoms of CRS include high fever above
38 °C, fatigue, headaches, muscular pain, joint pain, diarrhea, Nausea and vomiting, and skin rash .
[46]

Given the limitations of gene and cell therapies when used alone, there is increasing interest in combining
these therapies with existing treatment modalities such as chemotherapy, radiation, and immunotherapy.
For example, sipuleucel-T, a dendritic cell-based vaccine, is used in combination with immune checkpoint
inhibitors like PD-1 inhibitors to enhance the immune response against prostate cancer cells. Early-phase
trials have shown that combining sipuleucel-T with checkpoint inhibitors can lead to enhanced immune
activation and longer overall survival compared to sipuleucel-T alone . Similarly, combining CAR T cell
[28]
therapy with checkpoint inhibitors is being explored to overcome the immune exhaustion that sometimes
occurs after CAR T cell infusion. By blocking inhibitory signals in the tumor microenvironment, checkpoint
inhibitors can enhance the persistence and function of CAR T cells, potentially leading to more durable
[47]
responses in prostate cancer . Several challenges remain in translating gene and cell therapies into
standard prostate cancer treatments. Safety concerns are a significant barrier, particularly with CAR T cell
[48]
therapy, where adverse events like CRS and neurotoxicity can be life-threatening . Efforts to mitigate these
side effects, such as using suicide genes to control CAR T cell activity, have optimized safety profiles. Gene
and cell therapies are expensive to develop and manufacture, with personalized treatments like CAR T cell
therapy costing hundreds of thousands of dollars per patient. Scaling these treatments for widespread use
will require advancements in manufacturing processes and the development of off-the-shelf therapies that
can be administered without the need for individualized cell modifications .
[49]

The clinical application of gene and cell therapies also raises ethical and regulatory concerns. The use of
CRISPR-Cas9 and other gene-editing technologies, in particular, has sparked debate over the potential for
germline editing. While germline editing is not currently being pursued in prostate cancer trials, the rapid
advancement of gene-editing technologies has led to calls for stricter regulatory oversight to ensure that