| Breaking News - March 2004
Immunotherapy: A New Weapon in Fighting Prostate Cancer
A recent New York Times Magazine article has listed it as one of the "New Ideas of 2003"; BusinessWeek (May 19, 2003) asked, "Can This Vaccine Prevent Cancer?" and the Food and Drug Administration (FDA) granted fast-track status to accelerate the development process of this drug called, Provenge.
All of this attention is not just media hype, but is a focus on a new approach to addressing androgen independent prostate cancer, which is the most lethal stage of the disease. For many patients, a successful therapy here literally is a life-saving intervention. While it does not have an universal effect on all AIPC patients, the results to date have been extremely encouraging. More importantly, the trials are still on-going and more data will better substantiate the viability and hope for treatment.
We have asked one of the Principal Investigators of this drug, Dr. John Corman of Virginia Mason Medical Center in Seattle, to detail the results of some of his research and to give us a greater understanding of the protocol.
VS: Dr. Corman, the article in New York Times Magazine characterized the drug as a vaccine. When I think of a vaccine, it calls to mind that which was developed for polio, a viral-based disease. Are we implying here that cancer is in some way a virus?
JC: No, the word vaccine has a much broader implications than treating a virus. In this instance, the word vaccine implies altering the host's (patient's) immune system to enable it to impact cancer
VS: In trying to understand how the immune system is engaged in fighting the disease, take a moment to talk about disease progression from post-primary treatment failure through hormone and then chemo refractory failure.
JC: We, and others, have demonstrated that in normal, healthy 18-year-old men, the body's immune system has the capacity to recognize prostate cancer specific markers and to mount an immune response to these markers in a laboratory model. The theory is that variations occur in the immune system that may make the host (patient) more susceptible to prostate cancer. As a patient becomes immunosuppressed (which occurs following years of systemic therapy [hormonal treatments, chemotherapy]) the body's ability to recruit the immune system to impact the disease is similarly impaired.
VS: Following on this, how does the drug strengthen the immune system and then retard or destroy the progression of AIPC?
JC: Provenge recruits the immune system against specific targets; in this case, prostate cancer specific targets.
VS: Looking at the trials done, give us the profile or acceptance criteria for those individuals who were selected to participate in your research.
JC: There are two actively accruing trials of which I am aware. The first involves AIPC patients with documented, but asymptomatic metastatic disease. The second is for patients who have biochemically recurrent prostate cancer after primary treatment. Ed. Note: see criteria here for participation and locations for both metastatic, AIPC patients and non-metastatic androgen dependent patients
VS: A recent article in the Wall Street Journal (1/26/04 "Review and Outlook") talked about the response rate for Provenge with patients having a Gleason score of 7 or less being better than those with 8 and above. Please discuss this implication given that many men have a Gleason score of 7 at initial diagnosis/staging. Does this mean that an initial Gleason staging of 7 or above should be treated systemically as a primary therapy?
JC: This study was performed in patients with androgen independent metastatic disease. The results of the study indicate that in this patient population, there appears to be a delay in disease progression, a delay in the development of pain, and, most importantly, a survival advantage in those patients with Gleason Grade 7 or less. Nothing in this study suggests that Grade 8 and above tumors should be treated systemically as the primary therapy, although a significant amount of clinical and basic science research is being dedicated to that field at this time.
VS: Many people believe that clinical trials are just a way to use people as "guinea pigs" in medical experiments; yet, we know, that in a clinical trial the participant is always assured of receiving the best current standard of care as well as the experimental protocol. With the participants in this study at a "near death" disease stage, how were you able to address these concerns?
JC: The most essential aspect of this or any other clinical trial is informed consent. We spend hours reviewing with patients the potential risks and benefits involved in any trial. The consent process is comprehensive and must be approved by research advisory boards and patient review boards. Only after patients have a clear and comprehensive understanding of the program, alternative treatment options and standard medical care are they permitted to participate in the program. We caution patients against a long list of potential, however unlikely, side effects. In clinical practice, what we have seen are flu-like symptoms for a few days following infusion.
VS: The interesting concept about immunotherapy is that it is not hormone therapy or chemotherapy; help us to understand what it does in either stabilizing or killing cancer cells.
JC: Essentially, the goal of immunotherapy is to enhance the patient's immune system. I explain to patients that this therapy is somewhat analogous to providing a "search and rescue dog" with a sample of a missing person's scent. We provide the immune system with a clear marker of the patient's prostate cancer. When the immune system recognizes that marker, it musters T-cells (immune cells) to search the patient's body for other cells that bear that marker. In this case, those other cells will be prostate cancer cells. When the cells are discovered, they can be destroyed by the immune system.
Ed. Note: see this page for an enhanced description of the immune system and cell interaction
VS: Given that no two cancers are exactly the same, how does this marker work?
JC: The marker in question is common to most low and intermediate grade prostate cancers.
VS: Will it be equally effective in all patients manifesting the same or similar disease staging?
JC: That has yet to be seen; because prostate cancer is heterogeneous, we would expect different responses in individual patients.
VS: Do these T-cells have a definitive life span or will they naturally regenerate once the drug is introduced to continue to attack the prostate cancer cells?
JC: The idea is that, once stimulated, the immune system will maintain a higher level of surveillance against a specific target, in this case prostate cancer.
VS: Researchers for many years have felt that dendritic cells were key targets in fighting prostate cancer; how does this drug utilize them in managing the disease?
JC: Dendritic cells are potent antigen presenting cells (APC). In order for the immune system to recognize the cancer marker, it must be presented to the immune system by an APC. The dendritic cells themselves do not kill cancer. They are, however, the first key step in the cancer-killing cascade. Provenge is an APC in conjunction with a specific antigen.
Ed. Note: see graphic explanation of process
VS: There has been approval of a vaccine, Leukine by the FDA for the treatment of skin and kidney cancer and some early trials using it to treat advanced stage prostate cancer. How does Provenge differ from Leukine in addressing the disease?
JC: Leukine is a granulocyte-macrophage colony-stimulating factor (GM-CSF) whose primary use is in the recovery of neutrophils (cells that fight infection) in patients who have received chemotherapy for leukemia. Its mechanism of action is far less specific than Provenge, which targets immune cells that are specific for prostate cancer. Leukine is a general stimulant for several different types of immune cells (not specifically directed against prostate cancer). Similar GM-CSF based compounds have been used for prostate cancer in the past. I'm not aware of any study that has shown a survival advantage in patients with AIPC receiving GM-CSF based therapy alone.
VS: A study reported in the November 1, 2003 issue of Clinical Cancer Research detailed work done in promoting immune response in advanced melanoma patients. The key conclusion noted that mature dendritic cells were superior to immature dendritic cells in inducing immune response for improved clinical results. Does your research show the same requisite response in type of cells?
JC: The Provenge study has not addressed the issue of immature versus mature APC's. The dendritic cells used in Provenge are obtained from the patient's peripheral blood and are mature APCs. The key concept to understand is that the cells used in the preparation of the vaccine are the patient's own dendritic cells. The cells that are removed during leukapheresis (the process of separating immune cells from the rest of the blood products) are the same cells that are stimulated in the laboratory and ultimately reinfused into the same donor patient.
VS: How many individuals have participated in your study (Ed. Note: this was one of many trials done throughout the US) and what are your results noted to date?
JC: At my institution we have treated over 25 patients on trial with Provenge. Because the trial is placebo controlled, I do not know how many of my patients received placebo versus Provenge itself. The importance of the Provenge data, however, is that no previous Phase III study has demonstrated a survival advantage in the treatment of AIPC. Several studies have shown a PSA response (decline in PSA level), but to have a statistically survival benefit in patients with advanced disease is remarkable. In point of fact, no other trial in this patient group has ever shown a survival advantage. In this study the finding of an 8-month survival advantage is, indeed, remarkable. Just as notable, however, is that the study is ongoing and therefore we may see an even more profound benefit as time goes on. The point is, the 8-month number is a starting point, not an end point.
VS: With all of the participants being androgen independent and with statistically less than a year left to live, what can you say about the human side of your work and what is the prognosis for them and others in similar clinical situations?
JC: The average survival of a patient with AIPC is less than 18 months. While it is extremely exciting that a product has been developed that, at least initially, appears to offer a survival advantage, one has to remember that patients are facing advanced, progressive disease.
It is important to help patients and their families maximize the quality of their lives as they face progressive cancer. This is best done through consultation with institutions that care for prostate cancer patients in a multi-disciplinary (involving specialists from urology, radiation and medical oncology) model. There patients can continue to receive medical therapy while also obtaining advice from experts in social services, physical therapy, sexual health and counseling.
From a personal standpoint, seeing patients struggle with end-stage disease is a continual reaffirmation of the necessity of developing exciting, novel agents that offer great hope.
VS: We've discussed the criteria for participating in these trials (Ed. Note: locations of the trials can be found HERE), how should patients and their doctors go about deciding on whether or not participation can be beneficial?
JC: Speak with health care providers with expertise in the field. Ideally, seek care and consultation from institutions that offer the entire spectrum of prostate therapies. Typically, again, this is best facilitated in multidisciplinary clinics, which are available in most major U.S. cities. Insist on second opinions from the onset of diagnosis. Ask Questions. Get Educated! There is no "Magic Bullet"; appropriate care requires a thoughtful, intelligent, individualized approach.
VS: Thank you again, Dr. Corman, for this information and for the promise of a better life for those affected by the disease.
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