Immune Therapy for Prostate Cancer

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Our immune systems are true marvels—they keep our teeming intestinal bacteria under control; they fight off a barrage of invading viruses, and they successfully eradicate most cancers at inception long before they ever become a problem. Important discoveries in the field of immunotherapy over the last 20 years, have led to significant new developments in therapies that further enhance immune system function.

Evolution of Immunotherapy

Before reviewing immunotherapy options for prostate cancer, note that there have been many false starts and premature declarations of victory along the road to effective immunotherapy. For example, the FDA approved interleukin 2 for melanoma 20 years ago. Despite an only 10 percent response rate and severely toxic effects, interleukin 2 gave a glimmer of hope at a time when metastatic melanoma was totally hopeless and untreatable. The drug was a small but hopeful encouragement of future, more effective, therapy.

Now we are hearing of dramatic turnarounds in the field of melanoma treatment. For example, recently the media told us to prepare for President Jimmy Carter’s end—his melanoma had spread into the brain. Then an apparent miracle—a new immunotherapy drug—had rendered him cancer-free. Fake news? Not at all. Modern immunotherapy can turn hopeless cases into remissions.

How has the radical progress come about? There has been a tremendous deepening in our understanding of the immune system’s inner workings. In simple terms, we now know that the immune system consists of three major components:

  1. Regulatory cells, called TRegs, keep over-activity of the immune system from getting out of control.
  1. Killer-T cells attack the cancer cells and kill them.
  2. Dendritic cells work as detector cells, ferreting out and locating the cancer and then directing the immune system so it knows which cells to destroy. Dendritic cells, after they detect the cancer, guide the killer cells to “home in” and attack the cancer.

Provenge for Prostate Cancer

Prostate cancer was a relatively early participant to the immune party when Provenge was approved by the FDA in 2010. FDA approval was based on the results of a randomized, double-blind, placebo-controlled, clinical trial that indicated that Provenge improved life expectancy for men with advanced prostate cancer by 22.5 percent.

Provenge works by an innovative method that enhances dendritic cell activity. As noted earlier, the dendritic cells are the “bloodhounds” of the immune system, able to sniff out and locate cancer cells. The Provenge process relies on blood extraction with leukapharesis to remove the dendritic cells. These cells are then processed in the lab, enabling them to recognize prostatic acid phosphatase (PAP)—a common molecular feature located on the surface of prostate cancer cells. Once activated, the dendritic cells are infused back into the patient’s blood where they stimulate the killer T cells to better identify and attack the cancer cells, since they have been enabled to identify the PAP surface feature and use it as target.

Provenge might be considered the ultimate in personalized cancer therapy because dendritic cells are filtered from the blood of each patient, enhanced in the laboratory to attack prostate cancer cells, and then reinfused back into that same patient. As exciting as this technology sounds it may be surprising to hear that doctors and patients have only slowly warmed to the idea of using Provenge. This lethargic attitude toward adopting Provenge was unexpected when Provenge first came on the market, given the popularity of many immune-enhancing alternative therapies such as graviola, shiitake mushrooms, pau de arco, and essiac tea.

Why should there be any hesitation to use an FDA approved type of immune therapy?

Criticisms

Critics pointed out that Provenge is expensive and that the average recipient only lives an extra three or four months. However, in the real world of cancer therapy (not the world of clinical trials) this is a wrong assumption. Men participating in clinical trials are not representative of typical prostate cancer patients receiving FDA approved therapies. Generally, men undergoing clinical trials have much more advanced disease. This is because patients delay entering a clinical trial until after the standard treatments fail.

Therefore, the survival of men in a clinical trial tends to be relatively short, regardless of the type of treatment being administered. Nevertheless, any medication proven to prolong survival under these unfavorable circumstances must be consequential. That is why medications showing a survival prolongation receive FDA approval. The point is that the medication will show better results when used to treat men at an earlier stage.

Treatment at Different Stages

The premise that Provenge has a bigger impact when it is used to treat prostate cancer at an earlier stage was investigated through a reanalysis of the original data that led to Provenge’s initial approval by the FDA. The reanalysis showed that men with early-stage disease did indeed have a much greater degree of survival prolongation. In fact, the amount of survival prolongation became progressively larger when Provenge was begun sooner.

In this reanalysis, four groups of men, categorized by their different PSA levels at the start of Provenge treatment, were evaluated: men with PSA levels below 22, men with PSA between 22 and 50, men with PSA between 50 and 134, and men with PSA greater than 134.

The table below summarizes the survival of men treated with Provenge, compared with the men treated with placebo, subdivided by the level of PSA at the start of Provenge. The net survival difference (in months) between the Provenge and placebo is listed last.

Patients Grouped by PSA Grouped at Start of Provenge (Survival in Months)

PSA Level

≤22

22–50 

50–134  

>134

Number of Patients

128

128

128

128

Provenge

41.3

27.1

20.4

18.4

Placebo

28.3

20.1

15.0

15.6

Survival Difference

13.0

7.1

5.4

2.8

                                          
As the table illustrates, a survival advantage existed for all the Provenge-treated groups compared to the placebo-treated men. However, the amount of survival improvement was greatest in men who began Provenge when PSA was lowest.  Men who started Provenge when their PSA was under 22 lived 13 months longer than men at a similar stage who were placebo-treated. Men at very advanced stages, with PSA levels over 134, only lived a few months longer than the men who received placebo.

Application

Naysayers question Provenge’s efficacy for another reason. Most types of effective prostate therapy, such as hormonal therapy and chemotherapy, induce a decline in PSA levels. But with Provenge this usually isn’t the case. People wonder therefore, how can Provenge prolong survival?

They forget that the effectiveness of standard prostate cancer therapies, such as chemotherapy and hormone blockade, is only sustained by continuous application. Once treatment is stopped the anticancer effects cease and the cancer resumes growing.

The immune system, on the other hand, once activated, has a persistent ongoing effect. Therefore, even if Provenge only causes a minimal retardation in disease progression, since the effect is continuous there is a cumulative effect over the remainder of a patient’s lifetime. And the longer a man lives, the greater the magnitude of the benefit.

Tracking Cancer Metastases

Based on the data presented in the table above, one logically concludes that Provenge should be started immediately in any man who has been diagnosed with clinically significant prostate cancer. Unfortunately, insurance companies only cover Provenge treatment after men develop hormone (Lupron) resistance and cancer metastases. Since in most cases hormone resistance occurs before metastases, men with relapsed prostate cancer who are controlling their PSA with Lupron should be on the lookout for any rise in PSA. Hormone resistance is defined as a rise in PSA while on Lupron or any Lupron-like drug.

At the first indication that PSA is beginning to rise, men should begin a vigorous search for metastases. Presently, PET scans are the best way to find metastases while the PSA is still in a relatively low range, say under two. There are a variety of different types of PET scans to consider using: F18 bone scans, Axumin, C11 acetate, C11 choline, or a Gallium68 PSMA. If these scans fail to detect metastatic disease initially, they should be repeated at least every six months until the metastatic disease is located, after which Provenge should be initiated promptly.

Another Type of Immunotherapy

Over the last 30 years many attempts to harness the immune system have failed. We are beginning to learn that these failures are due to over-activity of the immune system’s regulatory component. Whenever the body generates any new immune activity, the activity itself stimulates self-regulation to quell the burgeoning immune response. This is to prevent the development of destructive immune diseases such as lupus, rheumatoid arthritis, or multiple sclerosis.

Now researchers have learned that cancer cells exploit this regulatory component of the immune system by manufacturing immune suppressive hormones. These hormones lull the immune system to sleep, thus allowing the cancer cells to proliferate by keeping the killer T cells at bay. The regulatory cells, the Treg cells, are in a sense “kidnapped” and used as a shield to diminish our immune system’s anticancer activity. This inability of the immune system to attack cancer is not due to immune weakness; rather, it is immune suppression from increased regulatory activity instigated by the cancer cells. With this new understanding, specific pharmaceutical agents have been designed to compensate for this problem.

Yervoy is such a medication, one that is FDA approved for treating melanoma. Yervoy functions by blocking CTLA-4, a regulatory “switch” on the surface of Treg cells. When this switch is “on,” regulatory activity is increased and the immune system is suppressed. When Yervoy switches CTLA-4 “off,” the inhibitory action of the Treg cells is suppressed and the net effect is enhanced immune system activity.

Initial research evaluating Yervoy in men with prostate cancer shows promise, particularly when combined with radiation (see below). However, more recent studies suggest that another regulatory-blocking medication called Keytruda may work better.

Keytruda blocks another regulatory switch called PD-1. Preliminary studies in prostate cancer patients suggest that Keytruda may induce a greater anticancer effect than Yervoy, and cause fewer side effects to boot. If these preliminary findings with Keytruda are confirmed, combination therapy with Keytruda plus Provenge might be a good way to further enhance the anticancer activity of the immune system.

The Abscopal Effect

Radiation, directed at a metastatic tumor detected by a scan, is another potential way to stimulate the immune system through a process called the Abscopal effect. When a beam of radiation damages the tumor cells, the cells of our immune system approach the dying tumor and remove the leftover cellular debris. The Abscopal effect consists, therefore, of immune cells first identifying tumor-specific molecules on the dying tumor cells and then hunting down cancer cells in other parts of the body using those same tumor specific molecules as targets.

There are several attractive aspects to radiation-induced immune therapy: 

  1. When administered selectively and skillfully there are essentially no side effects.  
  2. The treatment is covered by all forms of insurance.
  3. The radiation is usually powerful enough to eliminate the tumor that is being targeted.
  4. It is easy to combine spot radiation with Provenge, Keytruda or both.

A Word From Verywell

Our understanding of immune therapy for prostate cancer is progressing quickly but is still in its infancy. Even so, it is exciting to realize that we already have several effective tools at our disposal. The challenge going forward is learning how these new tools can be used optimally, either by themselves or in combination with each other. Keep an open conversation with your doctor about immunotherapy options to determine if they are right for you.

Sources:

Higano, Celestia S. "Sipuleucel-T: Autologous Cellular Immunotherapy for Metastatic Castration-Resistant Prostate Cancer." In Drug Management of Prostate Cancer, pp. 321-328. Springer New York, 2010.

Kantoff, Philip W., Celestia S. Higano, Neal D. Shore, E. Roy Berger, Eric J. Small, David F. Penson, Charles H. Redfern et al. "Sipuleucel-T immunotherapy for castration-resistant prostate cancer." New England Journal of Medicine 363, no. 5 (2010): 411-422.

Lipson, Evan J., Patrick M. Forde, Hans-Joerg Hammers, Leisha A. Emens, Janis M. Taube, and Suzanne L. Topalian. "Antagonists of PD-1 and PD-L1 in cancer treatment." In Seminars in oncology, vol. 42, no. 4, pp. 587-600. WB Saunders, 2015.

Silvestri, Ida, Susanna Cattarino, Sabrina Giantulli, Cristina Nazzari, Giulia Collalti, and Alessandro Sciarra. "A perspective of immunotherapy for prostate cancer." Cancers 8, no. 7 (2016): 64.

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