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[51]
adverse events, including the development of secondary cancers .

Delivery challenges
A major limitation of gene and cell therapies is that they are not effective at the target site. For gene therapy,
the challenge is ensuring that the therapeutic gene is delivered to prostate tumor cells without affecting
healthy tissue. Most gene therapies rely on viral vectors to deliver the gene, but these vectors must be
accurately targeted to avoid off-target effects and toxicity. Non-viral methods, such as nanoparticles or
lipid-based systems, are being developed as alternatives but are still in the experimental stages and may not
[52]
yet provide the same level of efficiency as viral vectors . In cell therapies, particularly CAR T cell therapy,
the challenge lies in getting the CAR T cells to infiltrate the tumor microenvironment. Solid tumors like
prostate cancer have a highly immunosuppressive microenvironment, which makes it difficult for T cells to
penetrate the tumor and exert their effects. Prostate cancer tumors also tend to express low levels of
antigens, such as PSMA, making it harder for CAR T cells to recognize and attack the cancer cells; therefore,
[53]
overcoming these delivery challenges is critical for improving the efficacy of both gene and cell therapies .
Tumor resistance and heterogeneity
Gene and cell therapies for prostate cancer face the challenge of tumor heterogeneity. Different regions of
the tumor may have distinct genetic and molecular characteristics. This heterogeneity can make it difficult
for a single therapy to target all the cancerous cells. CRISPR-Cas9-based gene therapies may be able to
knock out a specific mutation in one part of the tumor, but other regions of the tumor may harbor different
[54]
mutations that allow them to continue growing . Similarly, tumors can develop resistance to therapies over
time, leading to treatment failure. In CAR T cell therapy, tumors may downregulate the expression of the
antigen that the CAR T cells are designed to target, often leading to immune escape and treatment failure.
This has been observed in some patients undergoing CAR T cell therapy for prostate cancer, where a loss of
[55]
PSMA expression allowed the tumor to evade the immune system and continue progressing . However,
endotoxins have been reported to increase the expression of PSMA, which counterbalances the problem
associated with PSMA reduction. Developing strategies to overcome tumor resistance, such as engineering
CAR T cells that target multiple antigens, is an area of active research.

Cost and accessibility
The high cost of gene and cell therapies is another major limitation, particularly the widespread clinical use.
CAR T cell therapy involves an individualized manufacturing process where a patient’s T cells are harvested,
genetically modified, expanded, and then re-infused. This process can cost hundreds of thousands of dollars
per patient, making it inaccessible to many individuals and unsustainable for a larger healthcare system .
[56]
Gene therapies also involve high costs due to the complexity of developing and producing viral vectors and
other delivery systems. These financial barriers limit the availability of gene and cell therapies to only a
small patient population, particularly those in high-income countries. Efforts to reduce costs through
automation, streamlining production, and the development of off-the-shelf cell therapies are ongoing, yet
these solutions are still years away from becoming widely available .
[48]

Ethical concerns
Ethical issues surrounding gene and cell therapy also pose significant challenges. The use of CRISPR-Cas9
technology raises concerns about the potential for germline editing, where genetic changes made in a
patient could be passed down to future generations. Although current clinical trials focus on somatic gene
editing (which affects only the patient), the rapid advancements in gene-editing technology have sparked
concerns about potential misuse, particularly for non-therapeutic purposes (e.g., designer babies) . There
[39]
are also ethical concerns regarding the fairness of access to these therapies, given their high cost and limited
availability. Gene and cell therapies are currently only available at a few specialized medical centers,