Prostate cancer cells succumb to ‘suicide gene therapy’

A long-term clinical trial of a gene therapy for prostate cancer that causes the immune system to attack tumor cells suggests it is effective and safe, researchers say.
prostate cancer gene therapy
The high-grade aggressive prostate cancer (on the left) showed no evidence of cancer (on the right) after treatment with gene therapy and radiotherapy.
Image credit: Houston Methodist

In prostate cancer, like many other cancers, tumor cells have various mechanisms for evading the immune system, which normally spots and destroys rogue cells.

The phase 2 trial tested an approach the researchers refer to as “suicide gene therapy” because it modifies the cancer cells so they send signals to the patient’s immune system to treat them as enemies and attack them.

The main message of the phase 2 trial is that the long-term outcome for prostate cancer patients receiving the suicide gene therapy in combination with radiotherapy – with or without hormonal therapy – is promising.

A report on the study, led by Houston Methodist Hospital in Texas, is published in the Journal of Radiation Oncology.

Senior author Brian Butler, professor and chair of radiation oncology, says:

“We have created a vaccine with the patient’s own cancer cells, a treatment that complements, and may even enhance, what we can achieve with traditional radiation and hormonal therapies.”

Promising result for justifying phase 3 trial

For the trial, which ran from 1999-2003, the team enrolled 66 prostate cancer patients and put them in two groups – Arm A and Arm B. In Arm A, the men received the gene therapy plus radiotherapy, while in Arm B, they received the gene therapy plus radiation and hormonal therapy.

Only men whose cancer was confined to the prostate were in Arm A, while the rest of the participants, whose cancer was more advanced, were put in Arm B. Also, Arm A patients received the experimental gene therapy twice during the study, while in Arm B, they received it three times.

The researchers followed the patients and found the 5-year overall survival for Arm A was 97%, and for Arm B it was 94%. This represents a 5-20% improvement compared with controls taken from historical studies.

The authors note that other measures also suggest the suicide gene therapy with radiotherapy produced better outcomes than those achieved with radiotherapy alone. Again, this is based on comparison with “historical controls.”

It is common practice to use historical controls in phase 2 trials, because while it is recognized they can have errors that are difficult to account for, they largely fit the purpose of the phase 2 trial, which is to provide enough evidence to justify investment in phase 3 trials.

Thus, only a randomized trial – with concurrent and not historical controls – can confirm whether the suicide gene therapy is better than radiotherapy alone.

Herpes virus gene inserted directly into tumor cells

In the trial, the team used an adenovirus – similar to the one that causes the common cold – to carry and insert the therapy agent directly into tumor cells.

The therapy agent is a herpes virus gene that produces the enzyme thymidine kinase, or TK, a widely used suicide agent for gene therapy of cancer.

Once the gene was inserted in the tumor cells and began making TK, the researchers gave the patients valacyclovir (brand name Valtrex) – a commonly used anti-herpes drug. Prof. Butler explains what happened next:

“The combination attacked the herpes DNA, and the TK-producing tumor cells self-destructed, which is why the procedure is called suicide gene therapy.”

He says once the activated valacyclovir starts killing cancer cells, it also signals the patient’s immune system to launch a massive attack.

Lead author Bin Teh, professor and vice-chair in radiation oncology, says they “firmly believe this will be a viable treatment strategy,” and:

“This is extremely pleasing to us, considering we had patients enrolled in our protocol after other physicians deemed them incurable.”

Another promising outcome of the phase 2 trial is that most of the patients experienced few or no side effects or complications, he adds.

The team has already embarked on a phase 3 patient trial of the suicide gene therapy, whose more formal name is “in-situ immunomodulatory gene therapy.” This is the final safety and evaluation before it can be put forward for approval by the Food and Drug Administration (FDA).

While prostate cancer is the second most common cancer in American men (skin cancer is the most common), it kills more men in the US than any other cancer.

Estimates from the National Cancer Institute suggest over 233,000 men in the US were diagnosed with prostate cancer and nearly 29,500 died of the disease in 2014.

Meanwhile, Medical News Today recently learned of new research that suggests androgen deprivation therapy (ADT) – a common therapy for prostate cancer that lowers levels of testosterone – may increase the risk of developing Alzheimer’s later on. The study also found the men who were on ADT the longest were the ones most likely to be diagnosed with Alzheimer’s disease later.

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