Exploring Gene and Cell Therapies for Prostate Cancer

November 19 sees in International Men’s Day, and so this year we are aiming to raise awareness of prostate cancer (PC), a disease which will affect one in eight men in their lifetime. Gene and cell therapies are a beacon of hope in this regard, showing remarkable and highly encouraging results in the treatment and prevention of this disease.  

What is Prostate Cancer?

The prostate is a small gland found in males with the job of producing seminal fluid for the transport and sustainment of sperm cells. Cancer of the prostate is one of the most common types of cancer, and many forms of this disease are slow growing and typically confined to the prostate itself. However, some types of PC are opposingly aggressive and spread quickly; thus, tailored treatment regimens are required based upon diagnoses. Like all cancers, early detection is key to the best chance of survival and knowing the symptoms is vital.

The Symptoms of Prostate Cancer

In the initial stages of the disease, PC can present with little to no signs, hence regular screens are advised to men from the age of 50 and possibly earlier if there is a family history of the disease.

Advanced stages of PC may cause the following signs and symptoms:

• Reduced force in the stream of urine
• Blood in the semen/urine
• Erectile dysfunction
• Problems urinating
• Unexpected weight loss
• Bone pain

Statistically, older men and Black men are the most likely to develop PC. This disease is rare in men under 40 years of age. Approximately six cases in every 10 are diagnosed in men older than 65 and the average age of diagnosis is 66. Most men who are diagnosed with PC do not die of it, but this should not detract from the seriousness of PC.

Current Treatments

Active surveillance, also known as watchful waiting, is a technique employed for older men who are not presenting symptoms. Active surveillance calls for closely monitoring the patient’s condition without the administration of drugs until signs of the disease appear or alter the condition. If symptoms appear, the patient receives treatment to relieve symptoms and improve their quality of life. 

Surgery can be an option for PC treatment if the patient is in otherwise good health. Typical types of surgeries include radical prostatectomy, which removes the prostate, surrounding tissue and seminal vesicles. However, this drastic form of treatment can leave patients with urinary incontinence and impotence.

Radiation therapy treats cancerous regions with high-energy radiation with the aim of killing the cancer cells or inhibiting their growth. Different forms of radiation therapy are employed for PC treatment including external, internal, and radiopharmaceutical therapy. The choice of radiation therapy depends on the type and stage of the PC.

Drug therapies come in a wide variety of forms. Hormone therapy for example is used to block the action of hormones that facilitate cancer growth. Traditional chemotherapy can be used to kill cancer cells by stopping them from dividing. Finally, bisphosphonate therapy can be used to reduce bone disease when cancer has spread to the bone. Patients being treated with some hormone therapies are at increased risk of bone loss, and so bisphosphonates diminish the possibility of fractures.

Gene and Cell Therapy Research

Gene and cell therapies represent an exciting option for the treatment and prevention of PC. Consequently, there are currently  157 clinical trials involving gene therapies for prostate cancer and a staggering 1040 trials involving cell therapies. This highlights the wealth of fantastic research and advances currently being explored. Gene therapies work to correct the genetic defects which have given rise to the cancer whereas most cell therapy research looks at the delivery of immune cells with the goal of eradicating the cancer cells.

With regards to gene therapy, there are many papers that explore the genetics of PC, such as this paper published in Molecular Therapy Nucleic Acids. It  shows that Let-7c is downregulated in many PCs, and so could be a key candidate for gene therapy. Examples of exciting gene therapy research for PC include this paper which demonstrated delivery of bisphosphonates nanocomplexes using the RALA peptide as a non-viral vector and showed superior treatment outcomes compared to non-complexed bisphosphonates. In a paper from the same research group, Cole et al. (Acta Biomaterialia -2019) assessed delivery of pDNA coding for Prostate Stem Cell Antigen (mPSCA) using the RALA peptide to form cationic nanocomplexes. These nanocomplexes were loaded into a microneedle patch, allowing for pain-free delivery of the complexes to the skin, while the RALA peptide greatly enhanced the cellular uptake of the genetic cargo. The authors found that application of this patch resulted in local mPSCA expression in vivo (mouse) and elicited a tumour specific immune response.

Cell therapy is seeing many exciting leaps towards advanced treatments for PC. This paper from Yu et al., (2019) succinctly summarizes many of these advances. A highlight includes the use of CAR-T cells which showed potent killing ability in PC by targeting prostate-specific membrane antigen. I had the utmost pleasure of speaking with Naomi B. Haas, M.D., who is an associate professor of medicine at the Hospital of the University of Pennsylvania. Haas’ research interests include therapeutics for kidney and prostate cancer, and she had the following insight to share with regard to gene and cell therapies for prostate cancer:

“The development of initial gene and cellular therapies directed toward prostate cancer have brought a new direction toward a disease typically treated with hormonal or chemotherapy. For example, byte (bispecific antibody) therapy and chimeric antigen receptor therapies (CAR T) against the prostate specific membrane antigen (PSMA) or prostate stem cell antigen are actively under investigation in castrate resistant metastatic cancer which typically overexpresses these antigens. Another approach, radiolabelled lutein antibodies directed against PSMA have completed phase III trials and are certain to become mainstays of both imaging and treatment.”

 It is clear from this statement and the literature discussed that gene and cell therapy offers a lot of potential in the treatment and prevention of PC. The current treatment options which include active surveillance, drug therapy, and surgical intervention options have varying degrees of efficacy. Therefore, it is imperative that new generation therapeutics are developed, and thankfully it is evident that major leaps in this regard are being made.  

Dr. Mulholland is a postdoctoral research scientist in cancer genetics and Junior Research Fellow (Somerville College) at the University of Oxford. He is a member of the ASGCT Communications Committee.

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