A New Immune Treatment Combination

BY MARK SCHOLZ, MD

In my last blog I contended that of all the different ways to treat cancer—hormone therapy, chemotherapy, radiation or surgery for example—immune therapy has the greatest potential to save lives: Only the immune system, by its very nature, has the ability to adapt to the many thousands of varieties of cancer.  Also, new breakthroughs in understanding how it works have led to real progress inharnessing the immune system to fight cancer. 

One discovery—that the immune system uses a specific type of immune cell called the “dendritic cell” to detect cancercells—led researchers at a company called Dendreon to develop a five-step process for enhancing dendritic cell function.

First the dendritic cells are filtered out of the blood for processing in the lab. Second, the dendritic cells are exposed to prostatic acid phosphatase (PAP), a protein that can be identified on the surface of almost all prostate cancer cells. Third, the dendritic cells are incubated with granulocyte macrophage cell stimulating factor (GM-CSF) which converts the dendritic cells from their dormant state into an activated form. Fourth, the activated dendritic cells are infused back into the patient’s blood. Fifth, once back in the body, the activated dendritic cells recruit the killer cells of the immune system, the T-cells, to attack the cancer cells, which are identified by having PAP on their surface.

This five-step process, called “Provenge,” is an elegant and clever way to enhance immune function. Two prospective, double-blind, placebo-controlled trials have proved the efficacy of Provenge.  However, one cannot help but wonder why—since Provenge is simply an enhancement of the immune system’s normal function—is all this artificial stimulation in the lab necessary?  Why aren’t the dendritic cells in the cancer patient’s immune system detecting the cancer cells spontaneously and recruiting T-cells to attack it?

Another breakthrough has been the discovery that a normally functioning immune system, like all the systems in our body, is tightly organized by a variety of controlling hormones. Obviously, both underactivity and over activity of any system, be it the heart, the pancreas or the immune system, can be dangerous.  Now, new research reveals that malignant cells actually manufacture and release excess amounts of controlling hormones that trick the immune system into remaining dormant.  Thus the natural process of immune system detection is directly inhibited by the cancer.

Provenge partially circumvents this problem by activating the dendritic cells outside the body in the lab. But the dendritic cells still face a hostile inhibitory environment after they are re-infused. The question arises, “Wouldn’t Provenge work even better if the immune environment in the cancer patient could be rendered more “friendly"?”

In this era of rapid technological advancement it is not surprising that amedicine designed for this specific purpose is already on the market! Yervoy, a monoclonal antibody from Bristol-Myers Squib, was FDA approved to treat malignant melanoma in 2011.   Yervoy enhances immune function by counteracting the excess amounts of suppressive hormones being released by the cancer. I heard one researcher characterize Yervoy as the most powerful method available for “taking the brakes off” the immune system.

Provenge and Yervoy used together are so attractive conceptually that the only question remaining is about the optimal method of delivery.  Yervoy, unlike Provenge, can have serious side effects.  In excess amounts it can induce the immune system to run wild and start attacking the organs in the body like the liver, thyroid and intestines. Caution dictates beginning with a small initial dosage of Yervoy.

In the study we will be conducting at Prostate Oncology Specialists in Marina del Rey the first three patients we treat will be given one-twelfth of a normal dose of Yervoy one week after the Provenge is completed.  The second group of three patients will receive a one-sixth dose of Yervoy.  The third group of three patients will get three-twelfths of a Yervoy dose. All patients will receive full-dose Provenge and will be closely monitored for disease response, immune function and for possible side effects.

Provenge and Yervoy are just two of the many exciting new methods being studied for harnessing the immune system to fight cancer.  However, to my knowledge, we at Prostate Oncology Specialists are privileged to be the first to test the effectiveness of these two exciting treatments in combination.  Our first patient is scheduled to start on trial this month. 

FDA Roulette

BY MARK SCHOLZ

The notoriously stingy and demanding FDA gave the go ahead for two new treatments for prostate cancer in 2010.  New approvals are rare because of the hundreds of millions of dollars required to undertake the type of studies that the FDA requires. The FDA wants studies that randomly allocate men into two comparison groups. One group gets the new medicine. The other group gets an ineffective fake called a placebo. FDA approval comes when men getting the new medicine live longer than those given the placebo.

Finding volunteers willing to participate in these types of studies is difficult. The men know there is a 50% chance they will get an ineffective placebo. Who wants to take the chance of getting a sugar pill as their treatment? Even so, some men are so desperate, they sign up, hoping to be among the lucky ones who receive the real McCoy.

These studies often run for years because the study ends when the study participants die from progressive cancer.  To find men willing to participate, the supervising companies that organize and run these studies need contractual relationships with a hundred or more study centers. Just keeping track of all these different patients, at so many different locations, over a period of several years, is in itself very costly.

Provenge is the first FDA approved treatment for prostate cancer that works by strengthening the immune system. Dendreon is the name of the company that has patented a process of harvesting immune cells out of the blood by means of a technique known as “plasmapharesis.” Plasmapharesis is a three hour process similar to dialysis that extracts immune cells from the blood. The harvested cells are then taken to a special laboratory and mixed with substances that enhance their aggressiveness against cancer.  The cells are then re-infused back into the same patient. 

Provenge’s primary appeal is the low incidence of side effects. The treatment, which does not rely on chemotherapy, is so revolutionary that at first the FDA was very skeptical. They dragged their feet for years, forcing the company to run their studies over and over.  Lo and behold, additional studies again demonstrated that Provenge-treated men were 30% more likely to be three years after their treatment with Provenge compared to the men who received a placebo. Dendreon should be commended for patiently persevering time after time when the FDA kept turning them down. Now men with prostate cancer have access to an effective treatment that has very few side effects.

The other new treatment recently approved by the FDA, Jevtana, falls into the more familiar category of chemotherapy.  Jevtana was approved in July 2010 based on a randomized survival study evaluating Jevtana compared to an older, ineffective type of chemotherapy called Mitoxantrone. 755 men were treated with either Jevtana or Mitoxantrone. The survival of men receiving Jevtana was 30% better then the men treated with Mitoxantrone.  

This remarkable achievement took some industry experts by surprise because the participants in the trial had all been treated previously and become resistant to another type of chemotherapy called Taxotere.  Historically, resistance to Taxotere has been a bad sign predicting resistance to all types of chemotherapy. Jevtana, unlike Provenge has the traditional side effects of chemotherapy such as tiredness, hair loss and increased risk for infection. Even so, reversing cancer in men with Taxotere-resistant disease is quite an accomplishment. 

The FDA finally agrees that both Jevtana and Provenge are proven to make men live longer. Studies are ongoing with these newly-approved medicines to see if combining them with other drugs can further enhance their effectiveness. In the meantime, men with prostate cancer need to be aware that these new and effective tools are available.