Immunotherapy for Prostate Cancer, Part 1

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 and molecular biologist 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.  Level one of immunotherapy here is a prostate cancer vaccine.

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, Chuck 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 – 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).

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.”  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 or apalutamide.

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,” 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 lymphoma 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, 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.

Who’s Who in the Immune System: A Primer for You!

Making sense of some very complicated stuff only a few scientists truly understand: A guide to the immune system for the rest of us

Let’s think of the immune system as a Broadway musical. The star of the show is the T cell (actually, there are a bunch of different types of T cells, but let’s just focus on the Killer T cell, not to be confused with the “natural killer” cell; see below).

Killer T cells: These cells live up to their name: they’re precision assassins. When they are on their “A game,” they are merciless, and nothing, not even cancer, stands a chance. Killer T cells have a large and growing fan club:  “They’re my personal favorite cell in the world,” says Drake. “They’re incredible. They can go anywhere, and kill any other cell if it has the right target,” or flag.  “T cells are amazing,” agrees Simons. “They can move out of the bloodstream and go in the bone marrow, the lungs, the liver, and start attacking cancer wherever it is. They have little sensors on their surface that can recognize viruses you haven’t even been affected with yet – just because they’re foreign.”

However:   Cancer knows how to snake-charm these cells, to put them into a trance, or a straitjacket, or to put the “boot” on their tires so they can’t go anywhere – pick your metaphor, but the bottom line is that cancer temporarily takes the T cells out of commission. Cancer cells secrete a substance that puts T cells to sleep – but don’t kill them – on a large scale. If you’re a James Bond fan, think of that scene in “Goldfinger,” when planes fly over Fort Knox and cropdust entire platoons – soldiers with loaded guns at the ready – with gas that makes them drop instantly. Or that moment in “Sleeping Beauty” when the entire kingdom plunges into a 100-year slumber, waiting for the handsome prince to come save the day. One of prostate cancer’s first official functions is to deactivate the T cells with molecules that act as brakes, or checkpoints.

Checkpoint inhibitors are like the handsome prince: they allow the kingdom of T cells to wake up. There are several checkpoints, or sleeping potions. One is PD-1. Another is CTLA-4. In their proper role, checkpoints are good. “Nature doesn’t want a T cell to kill off your kidney or gastrointestinal tract,” says Simons. In an autoimmune disease, for instance, T cells are misdirected; they mistake good and decent cells for the enemy, and destroy tissue. When someone gets an organ transplant, unless the immune system is suppressed, the body will reject the foreign organ. “The reason transplants are rejected is that T cells realize that these cells are foreign, and within days or even hours destroy every last one.” Thus, the body’s checkpoints. “Nature is very sophisticated about keeping T cells from going crazy. T cells that make a mistake can be fatal.”

But cancers that successfully keep T cells from doing their job can be fatal, too, and cancer cells co-opt checkpoints so successfully that there can be a T cell sitting right next to a cancer cell and the T cell does nothing, because the cancer is sending a signal saying, “I’m normal, don’t kill me.”

Checkpoints such as PD-1 are tiny molecules sitting on individual T cells. And incredibly, there are several drugs that can deactivate them. Pembrolizumab and Nivolumab target PD-1. A drug called ipilimumab targets CTLA-4. For each checkpoint – and it’s still not clear exactly how many there are – potentially, there is some way to block it, and the Prostate Cancer Foundation is actively funding this research.

From what we know right now, it seems that a minority of men with prostate cancer respond to PD-1 blocking drugs. Only a few men with prostate cancer respond to ipilimumab. Scientists aren’t sure why. But maybe the men with prostate cancer who don’t respond to those drugs will respond to different checkpoint inhibitors.

Now, back to that Broadway musical: There don’t seem to be any bit players in the immune system. Yes, T cells are the stars, but there are plenty of potential stars waiting in the wings. These include:

Natural Killers. These sound like something Quintin Tarentino would write about, but really, they’re foot soldiers, under the command of the T cells. “T cells don’t fight alone; they bring reinforcements,” says Simons. “Natural killer cells poke a big hole in a cancer cell or a virus, but they need direction. They need to be told where the fight is. But they’re really good at killing.” Checkpoint inhibitors aimed at helping unleash natural killer cells are being developed.

Macrophages. When cancer cells die, there’s carnage. Macrophages are early responders to the crime scene, and they chew up the debris. GM-CSF activates macrophages. Physician-scientist Pam Sharma, M.D., Ph.D., of MD Anderson Cancer Center, suspects that some types of prostate cancer may be more susceptible to immunotherapy drugs that activate the macrophages, rather than, or in addition to, the T cells. But macrophages aren’t just scavengers. “They do something very important: they put cancer cell flags on the surface of cancer cells,” explains Simons, “so they’re like educator garbage men.” T cells eventually reproduce, and then die. Their offspring cells need macrophages to show them the ropes – so they can find the flag and kill whatever is flying it.

Some cancers have more macrophages than T cells. Some of these macrophages are counter-productive: not only do they not help, they may also secrete substances that make the tumors grow more quickly.

Mast cells. These are immune cells involved in the allergic response. What do they have to do with prostate cancer? Apparently something, because scientist Karen Sfanos, Ph.D., at Johns Hopkins, and colleagues just discovered that men who have more mast cells are less likely to have a recurrence of prostate cancer after radical prostatectomy.

Dendritic cells: These are the cells that stand in the wings and give the T cells stage directions, pointing out which flags are for “self” and which are for “foreign.” They encourage the T cells that target foreign invaders to get out there and do their thing – multiply, attack, kill!

B cells. If T cells are the stars, B cells are the co-stars. They make Y-shaped antibodies, which grab onto the flags on a cancer cell. Antibodies attract the macrophages to come and clear away the debris. B cells are like a Neighborhood Watch on steroids. Think of the nosy neighbor on “Bewitched,” Mrs. Gladys Kravitz, watching for suspicious activity through her binoculars, spying in the bushes, or peeping through the window. Now imagine Mrs. Kravitz on steroids – as a drone, maybe – flying around the body looking for anything that’s not supposed to be there. They don’t do the actual killing of the enemy cells, but they aim the laser at it so the T cells can see it.

“B cells are the least studied immune cells in cancer, but they’re incredibly promising,” notes Simons. “Prostate cancer generally shuts them down with checkpoints, too. But we think we have identified a checkpoint inhibitor for them, as well. It would be a very good thing to have prostate cancer cells making antibodies.” As a matter of fact, Drake’s team published a paper showing that if men taking Provenge make more and better antibodies, they seem to live longer.

Vista. “Vista may be a major switch” that really puts T cells to sleep, Simons explains. If checkpoints like PD-1 put a T cell into a trance, Vista might put it into a deep sleep – think of Juliet faking her own death in Shakespeare’s play, sleeping so deeply that her heart barely pumped and her lungs barely breathed. When cancers make Vista, T cells are exceptionally sleepy. A drug that blocks Vista might make those cells be exceptionally wide awake. An anti-Vista drug “just went into clinical trials for prostate cancer.” It might take a cocktail of antidotes – anti-PD-1, anti CTLA4, anti-Vista – to allow T cells to achieve maximum killing potential against prostate cancer.

Helper T cells. We weren’t going to talk about other T cells, but these cells help the B cells that make antibodies to do their jobs.

IDO: Indolamine amase (IDO) is the reason your mother’s body didn’t reject you in the womb. It’s a gene made in the placenta. Cancer cells stole the recipe; they make it, too, to keep your body from rejecting them.

In addition to the book, I have written about this story and much more about prostate cancer on the Prostate Cancer Foundation’s website, pcf.org. The stories I’ve written are under the categories, “Understanding Prostate Cancer,” and “For Patients.”  As Patrick Walsh and I have said for years in our books, Knowledge is power: Saving your life may start with you going to the doctor, and knowing the right questions to ask. I hope all men will put prostate cancer on their radar. Get a baseline PSA blood test in your early 40s, and if you are of African descent, or if cancer and/or prostate cancer runs in your family, you need to be screened regularly for the disease. Many doctors don’t do this, so it’s up to you to ask for it.

 ©Janet Farrar Worthington