Combination Immune Therapy—A Major Breakthrough

BY MARK SCHOLZ, MD

Normally it’s a rule for me in these blogs to avoid straying away from the theme of prostate cancer. I want my efforts to have a practical application for those struggling with this condition.  After all, prostate cancer is my specialty.

 

However, I am going to make a rare exception and break with my usual policy because of a stunning medical breakthrough in the treatment of advanced metastatic melanoma, a very deadly condition that until recently has been totally resistant to all forms of treatment.  The only exception has been a newly FDA-approved immunotherapy called Yervoy.

 

A month ago I wrote about the high hopes we have for immune therapy for prostate cancer.  I also wrote about a clinical trial we are conducting at Prostate Oncology Specialists that evaluates the combination of two different types of immune treatment, Provenge and Yervoy (see my blogs from March and April of this year for further details).

 

Immune therapy has tremendous potential for treating cancer since the immune system has unlimited potential to adapt to any cancer scenario.  As more and more new types of immune therapy are being discovered, it’s only logical to conduct clinical trials that combine them to see if the simultaneous use of two immune treatments will further enhance the anticancer effect.

 

The report I am so excited about was just published in the New England Journal ofMedicine (NEJM). Doctors from Memorial Sloan Kettering and from Yale evaluated the combination of two types of immune therapy in advanced melanoma—Ipilimumab (Yervoy) and Nivolumab.  In my previous blog I explained how Yervoy functions by taking the “brakes” off the immune system.  Nivolumab works in a similar fashion, but works on a different set of brakes.  (It turns out that the immune system has two separate brake systems).

 

While Yervoy by itself has already been shown to be effective for treating melanoma and is FDA approved for this purpose, Nivolumab is still going through clinical trials. Twelve weeks after the researchers administered Yervoy and Nivolumab simultaneously, one third of the patients had more than an 80% regression of all known tumors.

 

Furthermore, the side effects of giving the medicines in combination were no more severe than those encountered when either of the drugs was used by itself.

 

This report from the NEJM is very exciting because it provides proof for the concept that combining immune treatments will lead to enhanced anticancer effects. Moreover, another report of success using a combination of immune treatments was just released at the annual meeting of the American Society of Clinical Oncology (ASCO). Two-hundred and forty-five men with melanoma were treated either with Yervoy alone or with a combination of Yervoy plus Leukine.  The men treated with the combination of Yervoy plus Leukine lived 30% longer!

 

Leukine is an immune system stimulating medication that the FDA approved years ago for increasing white blood cell counts in patients treated with chemotherapy.  However, Leukine is also known to have anticancer effects as well. For example, it is used as an integral component in Provenge.  In addition, at the ASCO meeting in 2011, we published results from a trial we did in Marina del Rey in prostate cancer patients showing that Leukine plus low-dose cyclophosphamide (another immune-modulating drug) delays prostate cancer progression.

 

My dear friends and patients, I am amazed at how rapidly immunotherapy is progressing.  Not only are new and exciting medications being discovered,  innovative research evaluating combinations of these new powerful new medicines is leading to stunning cancer reversals in cases that as recently as a couple years ago were deemed totally hopeless.

 

Let me leave you with this final and encouraging thought.  The immune system is very egalitarian. Great results achieved in one type of cancer will inevitably translate into effective treatments for other types of cancer as well, including, of course, prostate cancer. The achievement of unprecedented anticancer effects with combination immune therapy in a stubborn and deadly cancer like melanoma bodes very well for significant breakthroughs to occur for prostate cancer as well. 

What is the Most Exciting New Treatment for Prostate Cancer?

BY MARK SCHOLZ, MD

As a medical oncologist specializing in prostate cancer, the question I am asked by patients almost daily is, “What new treatments are coming for prostate cancer?” Fortunately, there are so many new developments I am able to give answers that vary depending on the stage (or Shade, to use PCRI terminology) of the person asking, since they are usually interested in developments relevant to their specific situation.

However, if I am asked a slightly different question—“What type of new technology has the greatest potential for saving lives?”—my answer will always be the same for every patient: Immune therapy.  Let me explain why.

Before the intricate complexity of cancer biology was recognized—through the amazing work of thousands of biochemical researchers—people were hoping a single magic bullet could be discovered that would cure cancer.  That hope has been dashed because we now know there are innumerable variations of what we call “cancer.” Waiting for the discovery of a single type of treatment universally effective against all types of cancer is quite naive.

However, there is one intrinsic capacity in our bodies that successfully parries millions of different attacks on our health: the immune system. Therefore, if a cure for the myriad of different cancer types exists, it will probably result from successfully harnessing this incredible system.

One fallacy believed by almost all patients is that their cancer is the result of a weak immune system. Their logic is that their immune system somehow has to be weak considering that the cancer has not been kept under control. Actually, if we are going to speak figuratively about the immune system, the problem is better characterized as an issue of blindness rather than one of weakness.

Early success in using the immune system to overcome scourges such as polio caused cancer researchers to study vaccine type methods for stimulating the immune system to attack cancer,unfortunately with only modest results. The problem is that cancer cells have mechanisms that enable them to hide from the immune system.

The fairly recent discovery of this capacity for cancer to cloak itself represents both good news and bad. Without a specific target to attack, simply making the immune system “stronger” is useless. The good news is that a properly directed immune system can and will eradicate cancer.

Prostate cancer is one of the few types of cancer for which an immune therapy has been approved by the FDA. Dendreon, the company that manufactures the immune treatment called Provenge, has developed technology to remove and purify dendritic cells, the specific immune cells in the body that can detect cancer.  Once in the lab the dendritic cells are “force fed” with a cancer-specific protein. After being reinjected into the body, these invigorated immune cells recruit additional cells of the immune system that specifically focus their attack on the cancer cells displaying that cancer-specific protein.

Double-blind, placebo-controlled trials show Provenge slows cancer progression and prolongs survival just as well or even better than other standard treatments such as chemotherapy or second-line hormonal therapy. None of these treatments consistently eradicate cancer.  They do, however, act to keep it in check for a period of time.

To obtain better results the next logical step is combining one form of immune therapy—Provenge—with some other immune therapy with the hope of further enhancing the anti-cancer effect. My next blog will discuss a new study we are conducting in my clinical practice at Prostate Oncology Specialists using Provenge in combination with “Yervoy,” a monoclonal antibody from Bristol-Myers Squib. Generically Known as ipilimumab, Yervoy is an FDA-approved immune treatment shown to prolong life in people with metastatic melanoma.  Yervoy functions by “taking the brakes” off the immune system.

Sound exciting?  We think so.               

Happy New Year Announcement from Prostate Oncology Specialists

Jeffrey Turner, MD, Medical Oncologist, Joins Prostate Oncology Specialists in Marina del Rey, CA.

MARINA DEL REY, Ca., December 31, 2012 - Prostate Oncology Specialists is pleased to announce that Jeffrey Turner, MD has joined the prostate cancer specialist team. Dr. Turner is a board-certified internist and medical oncologist and will be specializing exclusively in prostate cancer with Mark Scholz and Richard Lam. Dr. Turner has been specializing in prostate cancer since 2009. He graduated cum laude from USC. Thereafter, he worked in research at UCLA studying infectious disease and molecular biology.  He earned his medical degree in Canada at Memorial University of Newfoundland and completed his internal medicine residency at the University of British Columbia and fellowship in medical oncology at the Medical University of South Carolina. Dr. Turner has published several articles on urologic cancers with an emphasis on prostate cancer.  He is a sub-investigator of a number of ongoing prostate cancer clinical trials.

Dr. Mark Scholz, Medical Director of Prostate Oncology Specialists commented, “Dr. Turner joins us during a time when the number of new prostate cancer treatments is exploding. He will add his expertise and knowledge to help patients make informed decisions. In 2012, we conducted clinical trials with Zytiga and Xtandi, agents that are now FDA approved.  We are presently evaluating new agents such as Curstersin, XL-184 and Ipilimumab in combination with Provenge.  We are happy to welcome a talented new member to the team who is familiar with all the many new treatment options for patients—this also includes Active Surveillance which is rapidly gaining acceptance as a viable treatment for prostate cancer.”

Active Surveillance remains very popular given the alternative risk of permanent side-effects from surgery, radiation, or cryotherapy. Dr. Turner added, “With the dramatic evolution of today's imaging techniques (including color Doppler ultrasound and MRI), Active Surveillance is best for men with Gleason 6, PSA<10, and clinical stage less than or equal to T2a.  Due to the fact that men with Gleason 6 prostate cancer have an incredibly low risk of mortality, Active Surveillance should remain a strong alternative.”
As skilled leaders in treating prostate cancer, our medical oncologists use PSA monitoring and color Doppler scanning to accurately monitor men on Active Surveillance. These techniques can detect early disease progression in men who may need to pursue treatment intervention.  

For more information about Active Surveillance or Prostate Oncology Specialists - visit: www.keepmyprostate.com or www.prostateoncology.com/activesurveillance

Provenge in 2012

BY MARK SCHOLZ, MD

Doctors finally seem to be comfortable with starting Provenge, a recently FDA approved immune therapy for prostate cancer.  Dendreon, the manufacturer of Provenge, just reported a sharp uptick in their quarterly financials, indicating that the use of Provenge is increasing as doctors increase the amount of the drug they order.

Although, Provenge has been on the market for 18 months but the medical community was slower to embrace this new treatment than was expected.  It seems that it has taken time for doctors to make peace with the fact that Provenge extends life, even though there is no lowering of PSA and very few side effects.

At Prostate Oncology Specialists, we recently completed an in-house review of the first 50 men treated with Provenge, I’ll jump right to the simple and somewhat mundane conclusion or our analysis: Provenge is relatively easy to give and side effects are uncommon.

Historically, the effectiveness of cancer treatments—like chemotherapy for example—has been closely associated with notable side effects. Side effects were often equated with effectiveness.  Even some of the new immune treatments, like Ipilimumab for example, usually have side effects. It’s ironic that patients receiving Ipilimumab on investigational trials are actually comforted when they get side effects—it confirms that they are not getting a placebo.

It’s also ironic that while doctors look for PSA decline as a measure of success, PSA has been rejected by the FDA as a method for measuring the effectiveness of drugs. The FDA demands a survival endpoint rather than changes in PSA.  (Personally, I think the FDA is crazy. I think that both PSA and survival endpoints are valid.)

Nevertheless, doctors and patients alike are confused. Their seemingly logical question is, “How can someone’s life be extended without PSA dropping?”  My explanation is as follows: When Provenge strengthens the immune system, is slows the rate of cancer growth.  Using the rise in PSA as analogous for cancer growth, Provenge slows the rate of PSA rise.

I am very comfortable with the idea that effective immune therapy slows cancer growth rather than reversing it.  This phenomenon of slowing the rate of PSA rise is exactly what we reported to the American Society of Clinical Oncology in 2010 when we presented our results with three medicines with immune activity, Leukine, Low-dose cytoxan and Celebrex.  The combination of these three agents caused substantial slowing in the rate of PSA rise.

Since Provenge is so well tolerated, the next logical step is to evaluate Provenge in combination with other immunologically active treatments.  MD Anderson is ramping up to do a trial of Provenge with full-dose Ipilimumab.  At Prostate Oncology Specialists we look forward to working with treatment options such as Provenge and Ipilimumab for our patients. Hopefully the net result will be greater than the sum of the parts.

MDV-3100—An Embarrassment of Blessings

BY MARK SCHOLZ

Every day in the office, as a practicing prostate oncologist, I confront serious problems:  PSA levels that are rising, treatments causing too many side effects, patients desperately worried about their future. And sometimes, given our limited tools, the solutions we can offer are only partial. However, every time the FDA approves a new treatment there is an excitement akin to opening gifts on Christmas morning. All of a sudden we have a shiny new tool in the tool chest to help us do a better job.

I’ve repeatedly gone on record criticizing the FDA for the inflexible format they use to approve any new drug.  They insist on survival as the only important measure of effectiveness. There has to be a better way to study new drugs than giving a placebo—an inert substance containing no active ingredient—to unfortunate people who already have a life-threatening illness. But this is the format our government demands—forcing pharmaceutical companies to prove that their new anti-cancer drug works by comparing them with sugar pills. And so the human sacrifices continue.

However, back to the good news, the spirit of Christmas morning. Medivation, the manufacturer of MDV-3100, a new drug that is estimated to be twenty times more potent than Casodex, recently reported a significant survival advantage in their study comparing MDV to  the of unfortunate souls who got placebos. In other words, Medivation cleanly jumped over the bar set by the FDA. Since MDV-3100 was not associated with any unexpected side effects, the FDA will be essentially forced to hold up its end of the bargain and release it soon for commercial use.

Some are saying that MDV is just a copycat of Zytiga, one more expensive testosterone blocking pill in an already busy marketplace. I disagree completely:

1.       Since MDV has few side effects, it can be easily combined with other popular treatments like Provenge and Taxotere.

2.       Since the mechanism of testosterone blockade is completely different from Zytiga, it’s possibly that the anticancer effects of Zytiga and MDV will multiplied if they are given together.

3.       Due to its ease of use, it will be popular with the urologists, the surgeons who are charged with managing most men with prostate cancer.

My “Christmases” seem to get better every year.  Last year the tool chest was expanded to include Zytiga, Provenge and Jevtana. And there are also some amazing new drugs waiting in the wings—Ipilimumab, Dasatinib, XL-184, Revlimid and more. We finally seem to be entering a new, hopeful era for prostate oncologists—and, most important, for their patients.

Whew, It’s Over!

BY MARK SCHOLZ

I just passed my annual stress test—the Prostate Cancer Research Institute (PCRI) conference. Lots of work, but certainly worth it--we had over 700 attendees from 41 states and 9 countries.  I was proud of all the 20 speakers, and particularly grateful for the contribution of Mark Moyad, MD who did a stellar job moderating.  Dr. Moyad and I reviewed some of the conference highlights on Sunday morning. They include reports on the following:

1. PET scans improve prostate imaging according to Dr. Dusing from Kansas City University and Dr. Kwon from the Mayo Clinic.

2. National Comprehensive Cancer Network (NCCN) guidelines recommend Active Surveillance for Low-Risk prostate cancer according to Dr. Klotz from the University of Toronto.

3. Multiple new chemotherapy combinations and agents—Carboplatin, Avastin, Xeloda, Custersin and Jevtana—are active against advanced prostate cancer according to Dr. Scholz.

4. Ipilimumab, an new immune treatment from Bristol Myers Squibb can induce dramatic remissions in advanced prostate cancer according to Dr. Kwon from Mayo Clinic.

5. A variety of very promising new agents—MDV-3100, TAK-700, XL-184—are in late stage trials.  Provenge, another new agent that works by stimulating the immune system is already FDA approved according to Charles Drake from Johns Hopkins.

The PCRI also announced at the conference, the launch of the Prostate Cancer Blue Community (PCBC); a web based prostate cancer community that is overseen by the PCRI helpline.  The PCBC has discussion forums about the conference and the different types of prostate cancer that we have broken down into Shades of Blue so that men can connect with other men in their same category of prostate cancer. The PCBC can be accessed at www.pcribc.org.