In this three part series, we examine the latest advances in immunotherapy, one of the most promising strategies in cutting edge cancer research, and it’s affects on prostate cancer treatment.
|Part I||Part II||Part III|
|A Vaccine for Prostate Cancer||Who’s Who in the Immune System||Immunotherapy and Prostate Cancer|
A Vaccine for Prostate Cancer
You’ve got a lot of antibodies floating around in your blood – to every cold or virus you’ve ever had, plus all the antibodies your body has made after you got a shot to prevent the flu, measles, mumps, chicken pox, or tetanus, etc.
If results of a clinical trial are as promising as scientists believe they will be, we may soon be entering an era where every man diagnosed with prostate cancer gets a combined vaccine to help his body fight it off.
The idea is to “harness the tremendous power of the immune system to augment what your body has done your whole life, which is fight off infections,” says medical oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation. “Prostate cancers grow because the immune system misses them, or mistakes them for something normal instead of a foreign invader.”
It’s all about the flags: The immune system uses a very effective communication system that’s a lot like semaphore – using handheld flags to send messages, spelling out words by changing the position of the flags. Cells that hoist the “friend,” or “self,” flags get to sail freely; the immune system leaves them alone. But enemy invaders – viruses, infectious bacteria and other harmful pathogens – announce their nefarious intentions by flying the body’s version of the Jolly Roger, the skull and crossbones: the flag that screams, “foreign!” or “enemy!” These flags are called antigens.
Unfortunately, prostate cancer cells often trick the body by waving a false flag. They get safe passage; the threat is unrecognized by the immune system.
The goal of all immunotherapy – vaccines and checkpoint inhibitors – is to teach the immune system to recognize cancer as the enemy: to rip off the false flag and show cancer’s true evil colors. It’s similar to unmasking the creepy reptilian aliens in “V,” if you remember the TV miniseries from the 1980s.
It’s also like a toddler’s shape sorter: What’s happening in immunotherapy research right now is incredibly complicated, intimidatingly dense and confusing to understand, even for doctors. If you were to pick up an immunotherapy journal and skim through it, you might think somebody had gotten the “caps lock” stuck on the typewriter, because just about any article you might read is chock full of words like PD1 and GM-CSF and CTLA4.
Don’t let the jargon throw you. We’re going to try to cut through all the alphabet soup for you because you need to know this stuff: immunotherapy is going to be increasingly important in prostate cancer. One day, it may even be the way we cure advanced prostate cancer.
Basically, what scientists are trying to do here is very simple – something your kids, grandkids, or maybe even you learned to do at a very early age: match the target with the right block.
Yes, immunotherapy has a lot in common with a toddler’s shape sorter; except instead of finding the right place for the star, crescent moon, triangle or oval blocks, scientists are finding drugs that target extremely tiny points of vulnerability in the body’s immune system. They’re finding the chinks in our armor, and filling them very precisely to help us not only withstand the attack of cancer, but launch a counterstrike.
Provenge: Provenge (also known as sipuleucel-T) is the only immunotherapy that has been approved by the Food and Drug Administration for prostate cancer. It is usually given to men who have early metastasis after they have been on androgen deprivation therapy (ADT). (This is called castrate-resistant prostate cancer, or CRPC.)
“The vaccine is made from a man’s own cells,” says physician-scientist Charles G. Drake, M.D., Ph.D. In addition to being a renowned expert on immunotherapy, Drake is the director of genitourinary oncology and an associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at New York Presbyterian/Columbia University Medical Center.
The immune cells are collected in a process called leukapheresis – basically, blood goes out through a needle in one arm, some white blood cells, platelets and red blood cells are taken out, and the rest of the blood is pumped back into the other arm. Then, those cells are put in a culture with an engineered protein that links prostatic acid phosphatase (PAP) with what Drake calls a “special sauce” that activates the immune system. PAP is an enzyme that, like PSA, is made by prostate cells. That special sauce – think of Miracle Gro for plants, or maybe baking soda to activate the yeast in bread dough – is designed to kick-start the immune cells: it’s called GM-CSF (granulocyte-macrophage colony-stimulating factor; for more on this, keep reading).
In multiple clinical studies, Provenge has been shown to increase average survival by a few months – but don’t just look at those statistics. Provenge might be able to achieve much more than that if given earlier, in men with a “lower tumor volume” (in other words, not a lot of cancer) or less aggressive disease. It also might achieve a kind of synergy or extra momentum if it’s combined with other treatments.
“It’s a good start,” in the sense that the Mercury and Gemini space programs prepared the way for the Apollo rockets, says Simons; before astronauts walked on the moon, pioneers like John Glenn had to escape gravity and orbit the Earth. “You can’t have immunotherapy unless your body can see the foreign flags. Provenge is about using GM-CSF,” which Simons pioneered as a young faculty member at Johns Hopkins, “to activate the dendritic cells to educate the immune system. The vaccine is actually against a flag that prostate cancer cells fly, PAP.” Other vaccines in the works recognize other flags such as PSA and PSMA (a molecule on the surface of prostate cells).
In men with metastatic cancer, Provenge is able to slow down cancer, but not stop it. “This is a big clue that we could do more in at least 30 to 40 percent of patients if we had something better than the Mercury program,” says Simons. “It’s great to extend life, but what we want to do is eradicate the cancer.” That said, Provenge is “exceptionally safe,” with “the fewest side effects of anything we give to prostate cancer patients. There’s no nausea, no vomiting; you may feel like you’ve got the flu, but most of the time men don’t even feel that.”
Give it sooner? If Provenge works better when a man is healthier in general, then why not give it before there’s any evidence of metastasis? Maybe after surgery or radiation in a man who is otherwise healthy, except that his PSA is going up? “We agree with that idea so much, we started a trial” involving about 60 patients, says Chuck Drake. “Men with a rapidly rising PSA after surgery or radiation were randomized to get either a year of ADT with vaccine starting about month after the ADT began; or the vaccine first, followed by a year of ADT. Men got a better immune response when they got the vaccine first, and then the ADT.” These results were recently published in Cancer Immunology Research, with Johns Hopkins scientist Emmanuel Antonarakis as first author. This was just a small study, Drake notes, and a larger randomized trial is needed. “But our trial helped us figure out the right order – the vaccine first, and then the ADT – and that you could do it safely. A few of the men who got both the vaccine and ADT recovered their testosterone, but never got their PSA back. They have done very well.”
Like so many scientists and physicians working to help men with prostate cancer, Drake hates the side effects that go along with ADT and hopes one day that we’ll find an effective way to treat advanced cancer without taking away the male hormones. For now, he would be happy to put men on ADT for the briefest amount of time necessary, along with immunotherapy, to get their cancer into remission, perhaps continuing with “maintenance immunotherapy, potentially forever.”
However, because the main goal is to cure the cancer and save the man’s life, Drake is also looking at a different group – men who have doubled down on hormonal therapy, who are still on ADT but who have added an androgen receptor-targeting drug such as enzalutamide. There are other drugs being tested in clinical trials – one is an antiandrogen called apalutamide (also know as ARN-509) that might work well with a prostate cancer vaccine.
Other vaccines that target other flags: Other vaccines are in the works. One is based on a modified version of listeria (a bad kind of bacteria that, in its unaltered state, can give you food poisoning). Another, called PROSTVAC-VF (also called PSA-TRICOM), developed with PCF funding, uses a modified smallpox virus as its means of entry into the body and targets any cell that makes PSA. “There’s no good cell in your body making PSA once you have prostate cancer anyway,” says Simons. “If we could get your T cells to recognize and destroy everything that makes PSA, you’d be cancer free.”
PROSTVAC is being tested along with GM-CSF in a worldwide clinical trial called the Prospect Trial, involving 1,200 men with metastatic CRPC from about 200 centers. It’s designed to test whether early treatment with this vaccine improves survival. Investigators are waiting for the results, and if it performs as well as they expect, then men could start getting this vaccine in addition to Provenge. “These vaccines are so safe,” explains Simons, “that you could get more than one. When you get the hepatitis vaccine, you’re really getting four vaccines in one. You can get multiple antigens, or flags. The whooping cough vaccine has seven flags in it, and it works a lot better than if you just got one. We will be combining these prostate cancer vaccines down the road if each one shows a benefit. The great promise of all these vaccines is, if you can figure out all of the antigens you need, you might be able to vaccinate right after surgery or radiation,” and one day, men might not need ADT, or they could delay it for many years.
If the PROSTVAC trial is successful, Simons believes, “every man with prostate cancer should get vaccinated, and should get GM-CSF. Antigen-specific immunotherapy is already curing the most fatal form of lymphomas, because scientists perfected the way to make a T cell kill off that antigen. Now this is a disease where they just give a little chemo to beat down the numbers of cancer cells, and then they activate the T cells and they destroy the cancer.”
Still another vaccine, called GVAX, is being tested by Drake and Antonarakis in men with high-risk prostate cancer undergoing surgery. Here, men are getting either a short course of ADT alone, or GVAX vaccination followed by a short course of ADT. The benefit here is that a pathologist can examine the surgically removed prostate to see whether the immune system has been activated – whether there’s evidence that the immune cells have begun to attack the cancer.
Combining vaccines and checkpoint inhibitors: In another clinical trial, PCF-funded investigator Doug McNeel, M.D., Ph.D., at the University of Wisconsin, is testing a combination of a vaccine called MVI-816 that, like Provenge, targets PAP, plus a checkpoint inhibitor (see below). This particular checkpoint inhibitor, called pembrolizumab, blocks PD-1, and in early data, the combination looks encouraging: PSA levels have dropped and some men’s tumors have shrunk. The idea here is to educate the T cells – to fly the Jolly Roger on the cancer cells – and then unleash the T cells to attack them. “Immune checkpoints are natural compounds that cells make to protect themselves, and they’re the reason why we aren’t just rejected by our mothers when we’re conceived,” says Drake, “because babies in the womb are half ‘foreign’ with the father’s DNA. Once a killer T cell starts attacking something that it thinks is foreign, it won’t stop unless brakes are put on it. Checkpoint inhibitors basically take the brakes off T cells; that’s their job. Checkpoint inhibitors release the hounds.”
Can the immune system go from oblivious pacifism to DEFCON 1, with alarms sounding and the military being deployed? And if the military – the immune system’s enemy-killing T cells, or antibodies made by B cells – gets involved, is it enough to stop the cancer?
The key is to alter the balance, says Drake. “For a lot of tumors, there’s an ongoing battle with the immune system. The immune system smacks the tumor down, the tumor gets around it.”
The ultimate goal of immunotherapy is to tip the balance toward the immune system. To unleash the hounds.
Next up: Who’s who in the Immune System