A unique new cancer treatment uses gene therapy to induce a cancer-fighting immune response whose intensity can then be controlled with a pill. The combination could help tailor treatment to a patient’s individual response.
The treatment uses the body’s own cells or tumor cells to produce extra copies of a naturally occurring hormone-like molecule called IL-12, which regulates anticancer immune responses. Last week, Ziopharm Oncology announced a clinical study of the treatment for patients with breast cancer. The company is already testing it in patients with melanoma.
Many researchers have explored techniques that rev up the natural response the body uses to detect and attack cancerous cells (see, for example, “Engineering Better Immune Cells” and “Priming the Body to Tackle Cancer”). But controlling the killer cells of the immune system can sometimes be a challenge, as researchers found in the 1990s when cancer patients who were given IL-12 in a clinical trial died from toxic side effects.
“IL-12 is a very potent [immune system regulator] and can generate a lot of side effects,” says Per Basse, a physician-scientist at the University of Pittsburgh School of Medicine, who studies immune cells and their ability to fight cancer. “As a clinician, I would like to be able to dial it up and down so that if it all starts to look not so good, you can stop the process,” he says.
To avoid the dangerous side of the molecule, Ziopharm’s system is designed to control IL-12 with a combined genetic and pharmaceutical switch. A virus is injected into the tumor to deliver the gene for IL-12. The gene starts out in “off mode,” so it doesn’t actually produce any IL-12. To activate the gene, a patient has to take a pill that delivers another molecule. The advantage is that any patient who starts to experience nasty side effects from the IL-12 can stop taking the pill. “If things go awry, you have an escape valve,” says Ziopharm’s CEO, Jonathan Lewis.
The key to the “inducible” system is a version of the receptor that controls molting in arthropods (insects, spiders, and crustaceans), modified so that it determines whether the IL-12 gene is on. The gene for that receptor, which is also delivered into the body by a virus, is always on, but its protein product and thus IL-12 expression is activated by the pill. Ziopharm licensed the control system from Intrexon for use in its oncology treatment.
“The inducibility is a great idea, but the trick is getting something that you can get into the tumor,” says Ralph Weichselbaum, a cancer researcher at the University of Chicago, who has worked on a cancer therapy induced by radiation. Currently, Ziopharm injects the gene-toting virus directly into patients’ tumors, but Lewis says the plan is to inject it into muscles in the future. “Muscle cells are extremely good protein production factories,” he says.
But even injecting the virus into a single tumor has an effect on other tumors—both in lab animals and in humans. In animal studies, the tumor that receives the injection will at first get bigger because immune cells are accumulating in response to the IL-12. “Then it will get smaller and go away,” says Lewis. Tumors that received no injection will do the same thing—grow, then shrink, and then disappear. “We are seeing similar things in people,” says Lewis.
Eventually, the system could be used to deliver multiple genetic treatments at once, says Lewis. “With one injection you could be able to control three or four [cancer-fighting] proteins in different ways.”
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