A lot of news about this already. But I think this is worth a read by anyone interested in more details. Don't forget most of the data are in melanoma.
For people investing in bio stocks, we can be a little hard on drug candidates because we have been taught that most candidates fail, especially in cancer. And with so many claims of excellence in mice or small number of people and sometimes by dubious companies, we need to be a little disconnected. We may have ways to go but good science here and good luck to us. It may help a lot of people, a few of them, us.
----------------------------------
Prostate Cancer: From Inoperable to Cancer Free
Mayo investigators studying immunotherapy for aggressive prostate cancer have found a combination therapy that has dramatically reduced tumor size to make surgery possible. The findings are preliminary — only two cases thus far — but the results are significant for future research.
Learning you have prostate cancer is bad enough, but then to be told that your condition is inoperable can be devastating. That’s where Rodger Nelson found himself. He and his wife Carol were wintering in California. Doctors there made the diagnosis, but it wasn’t until he decided to return home to Minnesota for treatment that he was told an experimental therapy was his best option.
“I arrived Tuesday and was told my surgery was scheduled for Friday,” says Nelson. “But when the final test came back late on Thursday, I was told the surgery was cancelled.” MRIs had shown the tumor had grown beyond the prostate and was encroaching on the stomach. That’s when urologist and surgeon Michael Blute, M.D., referred his patient to urologist and immunologist Eugene Kwon, M.D., who was conducting a clinical trial on prostate cancer.
Dr. Kwon had been working on the foundations of this study for over ten years, when he did the initial laboratory and modeling studies when he was on staff at the National Institutes of Health. He was a practicing surgeon at Loyola Medical Center recruited to Mayo Clinic by Dr. Blute and then developed collaborations with him and others.
“The goal of the study was to see if we could modestly improve upon current treatments for advanced prostate cancer,” Dr. Kwon explains. “The candidates for this study were people who didn’t have a lot of other options. However we were startled to see responses that far exceeded any of our expectations.”
Though many men experience prostate cancer when older, the cancer usually doesn’t progress quickly enough to be life threatening. However, a significant subset are aggressive forms of prostate cancer. These are aggressive, virulent and deadly, advancing so quickly, that diagnosis often comes too late for any effective therapy. They are the second largest killer of men with cancer. Currently all treatments for the aggressive forms are palliative, not curative.
Study coordinator Diane Mann, R.N., M.S.N., says that hearing a diagnosis of advanced prostate cancer can be disheartening. “Many of these patients are told by their urologist to get their personal business in order because they likely have only months to live. Learning about our clinical trial offers them some hope.”
“We heard Dr. Kwon’s presentation,” says Nelson, “my family, my wife and my children. And we decided to join his study.” Nelson was injected with an experimental drug called MDX-010. One dose, administered by IV, takes about 3 hours, including observation. Nelson describes it as painless. He was also placed on hormones to reduce his testosterone levels. Then he went home to Alexandria, Minn.
Fructuoso Solano-Revuelta
In Vera Cruz, Mexico, Fructuoso Solano-Revuelta, owner of a wholesale food supply company, found himself in a similar situation — with a cancerous tumor the size of a golf ball that had grown from the prostate into the bladder. In March 2008, he phoned Mayo Clinic’s office in Mexico City. “When I heard I had prostate cancer I took the first airplane to the best clinic in the world.” His feelings stemmed from Mayo’s previous treatment of his father and the fact that his physician brother had trained in orthopedics at Mayo.
Tricking the Immune System
Before receiving the MDX-010, both men underwent a hormone therapy called androgen ablation. It’s a combination of a pill that blocks testosterone and an injection tells the brain to order the testicles to stop producing it. This removal of testosterone from the system usually shrinks the tumor to some degree.
When Dr. Kwon was a surgeon at Loyola Medical Center in Chicago, he observed that during androgen ablation prostate tissues are swamped with immune cells — T cells — due to cell injury or death, as they are dependent on testosterone (Mercader et al, Proc Natl Acad Sci USA 2001, 98:14565-70). At the same time, a second observation was made by Dr. Kwon’s collaborator, J.P. Allison, M.D. (then at UC Berkeley, now at Sloan Kettering Cancer Center). He found the first off-switch for T cells. It’s called the CTLA-4 (cytotoxiclymphocyte-4) receptor (Leach et al, Science. 1996, 271:1734-6).
Cancer has a propensity for turning off T cells. Dr. Allison hypothesized that if you block the off-switch, T cells will stay turned on and create a prolonged immune response. Dr. Kwon, then at NIH, demonstrated that CTLA-4 blockage could be used to treat aggressive forms of prostate cancer in mice (Proc Natl Acad Sci USA, 1997, 94:8099-103). There was one limitation to that concept — the worry that by simply leaving all the T cells on there may not be enough response aimed at the tumor. Dr. Kwon called Dr. Allison and designed the trial together. The idea: use androgen ablation or hormone therapy to ignite an immune approach — a pilot light — and then, after a short interval of hormone therapy, introduce an anti-CTLA-4 antibody that acts like gasoline to this pilot light and overwhelms the cancer cells. MDX-010 (now called Ipilimumab) is the clinical antibody being tested in the Mayo trial.
Patients Influencing Research
Several weeks went by. Rodger Nelson noted that his PSA scores were dropping about 50 points a month. At the end of four weeks Fructuoso Solano-Revuelta saw his go from a high of 74.4 to 1.2. “Within the next month it was undetectable. The MRI in June showed the tumor was quite a bit smaller,” he explained. “Then in September the radiologist who performed the MRI was quite surprised. He asked if I had undergone radiation therapy. I said no.”
On Nelson’s MRI the shadows representing the tumor extending from the prostate and into the abdominal area had disappeared. His PSA was also undetectable. The discussion with Nelson and his wife, Carol, returned to the issue of surgery. The physicians wanted to wait.
“I never thought surgery should be totally off the table in my husband’s case,” says Carol Nelson, a retired registered nurse. “I always thought the answer was more than just this therapy. It wasn’t easy to tell a Mayo physician that, but they really listen to patients here.” Dr. Kwon and Dr. Blute left the room to talk and returned to suggest they vote on the idea of surgery.
“There were four people in that room and I was the only one who didn’t vote for surgery,” says Rodger Nelson. “I quickly came around.”
In this way, according to Dr. Kwon, a patient and his family influenced the direction of Mayo research. “We left the room to consult with each other,” says Dr. Kwon, “because history had taught us that surgical treatment of advanced forms of cancer like this were disappointing and oftentimes unadvisable. It was Carol Nelson who pressed us to entertain a surgical approach. Dr. Blute and I realized we were in uncharted waters. This was something new.”
“Were it not for Carol Nelson’s tenacious nature we would not have gone off study. You have to handle the voices of the researchers, the surgeons and the patients and their families. We remained flexible. This was a significant collaboration.” By ultimately opting for surgery, Rodger Nelson left the clinical trial, opening the way for discovery. Within a few days Solano-Revuelta’s check up revealed similar findings.
Image of prostate after therapy and before surgery.
“I realized something unusual had happened when Dr. Kwon saw the results. He ran off to find Dr. Blute — and then the two of them came running down the hall. They were surprised and happy and they were saying ‘Incredible’ and ‘This is a fantastic result!’ I heard Dr. Kwon say, ‘This is like the first pilot breaking the sound barrier.’” Like Nelson, surgery was also scheduled for Solano-Revuelta.
With Nelson, Dr. Blute spent more time in the OR than planned. “I was cutting away scar tissue, while trying to find cancer cells. The pathologist was checking samples as we proceeded and sent word back asking if we had the right patient. He had a hard time finding any cancer. I had never seen anything like this before. The pathologists were floored.” The same story played out for Solano-Revuelta. In that case there were two phone calls from pathology, one asking if he was operating on the correct patient.
Michael Blute, M.D., describes what he found in surgery following the treatment.
Both investigators are quick to point out that the outcomes in these two patients need to be validated in further studies. Plans are already underway for extended trials at Mayo Clinic to determine the dosage to optimize this therapy and explain how this combined treatment actually works.
“It’s important for us to understand the mechanism of favorable response in these patients,” says Dr. Blute. “This could have significant implications for other forms of cancer, including hormone-sensitive forms, such as breast and ovarian cancer.
Dr. Kwon agrees, praising highly collaborative interactions as essential for important discoveries. He credits Dr. Blute for his knowledge and his grasp of how study findings and experience in the OR can be synergistic in moving scientific approaches to useful clinical treatments. He also does not underplay the significance even though publication of the findings will await more data.
“This is one the holy grails of prostate cancer. This is what we’ve been seeking for years. Now we’ve got to build on this.”
Both patients return regularly to Mayo Clinic for follow up. Both are free of cancer, feel fine and have returned to their businesses.
“You know, I am 71,” says Solano-Revuelta, “but I have the spirit of a 25-year-old.” |
