The body’s immune system has incredible power. When it turns on something it recognizes as an enemy, its effects can be brutal; just ask anyone suffering from an autoimmune disease.
Wouldn’t it be nice if we could somehow harness these cell-killing abilities and use them against cancer? A great idea – and one that, until recently, has proven elusive. For decades, immunotherapy (using the body’s immune system to fight cancer) achieved results that were mostly lackluster. Instead of unleashing a ferocious beast to fight cancer, scientists unleashed something more akin to a cranky hamster.
Cancer yawned, then went back to causing trouble.
Then some new heroes appeared on the scene. Called immune checkpoint inhibitors, these immunotherapy drugs have been life-saving in people with melanoma, lung cancer, Hodgkin’s lymphoma, and other cancers.
Much of the groundwork for this new approach was funded by the Prostate Cancer Foundation – even though, traditionally, prostate cancer has been one of the cancers least impressed by immunotherapy.
Maybe that’s about to change.
Before we can talk about that, however, we need to take a brief look at some of the evil stuff cancer does to trick the body’s immune system.
Think of the most devious, insidious villain ever. That’s cancer, and one of the first sneaky things it does is to dupe our immune system’s greatest warriors, the T cells.
T cells are white blood cells, or lymphocytes, and they stand guard 24-7 – letting friendly cells pass by safely, and killing anything that looks faulty or appears to be an enemy.
How do the T cells tell the good guys from the bad guys? They have an intelligence network that signals when a cell is dangerous; in this network are checkpoint proteins. Think of a fancy nightclub with a bouncer standing outside: The bouncer is the T cell, and the clipboard he’s holding – like a VIP list – consists of checkpoint proteins, saying who gets to pass freely and who doesn’t. Even if other molecules are telling the T cells that a cell is dangerous, it’s what the checkpoint proteins say that seems to matter most. If they say, “It’s okay, he’s with me,” then that cell gets a free pass.
So, cancer has its own version of an invisibility cloak: It disguises itself with molecules that appear to be healthy. The T cell sees the cancer cell, frisks it by checking certain proteins on its surface, finds nothing unusual. The cancer says, “There’s nothing to see here” – think of Obi-wan Kenobi’s Jedi mind trick as he says, “These aren’t the droids you’re looking for” – and the T cell moves on. More cell sneakiness is discussed here.
Ideally, immune checkpoint proteins are supposed to latch onto healthy tissues to protect them from the wrath of T cells. Basically, checkpoint proteins are “get out of jail free” cards, and when cancer wears them it can hide in plain sight, evading an immune attack.
Checkpoint inhibitors, on the other hand, counteract these normal proteins on cancer cells; they also deactivate similar proteins on T cells that respond to them. Here’s an example. One checkpoint protein is called PD-L1 (for “Programmed Death Ligand 1”). Its receptor on the T cell is called PD-1. Say a cancer is really getting some momentum. It starts making PD-L1, and the T cells, fooled into thinking everything is normal, go away.
But checkpoint inhibitors show the T cells what’s really happening – like Dorothy discovering that there’s a “man behind the curtain” who’s the real Wizard of Oz. They take the blinders off; or, as some scientists describe it, they take the brakes off the T cells.
Other immune-boosting drugs work in a different way: they hit the gas pedal on T cells, boosting their momentum. It may be that a combination of these drugs might work even better. Three checkpoint-inhibiting drugs have been approved as cancer-fighting treatments by the FDA so far: ipilimumab, pembrolizumab, and nivolumab. All of these drugs have shown spectacular results in some patients.
Now, what does all this have to do with radiation therapy and prostate cancer? Something pretty exciting.
Adam Dicker, M.D., Ph.D., Chairman of the Department of Radiation Oncology at Thomas Jefferson University’s Sidney Kimmel Cancer Center, and medical oncologist Larry Fong, M.D., Professor and Co-Leader of the Cancer Immunotherapy Program at UCSF’s Helen Diller Family Comprehensive Cancer Center, suspect that a short course of external-beam radiation therapy will make immunotherapy – at long last – more effective in prostate cancer.
With a grant from the Prostate Cancer Foundation, they will be conducting a series of phase 1 trials in men with locally advanced prostate cancer who are planning to have surgery. The beauty of this is that they can compare the biopsy samples with the entire prostate after surgery, and look to see if the cancer has taken a hit.
Radiation does some pretty ruthless things to prostate cancer. It breaks the DNA strand, which causes cancer cells to die. “As cells die and break down, they release antigens – little flags on their surface – that the T cells recognize,” explains oncologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation. What happens next is like what happens to sharks when there’s blood in the water: “When prostate cancer cells die, the T cells pick up the scent – and come to kill any remaining cancer cells. These protein flags are not on the surfaces of normal cells, so they are left untouched,” which means that collateral damage to healthy tissue is minimal. “The T cells then go out on a search-and-destroy mission for other cancer cells. They keep on hunting.” This “antigen shedding” happens when you have an infection, too. “Many scientists think that immunotherapy for prostate cancer is going to require a combination – trying to kill enough prostate cancer cells with radiation, so the T cells can mop it up, and then go out on a hunt” for any stragglers.
In the study by Dicker and Fong, one group of men will receive an injection of ipilimumab directly in the prostate, and then will receive radiation – not enough to kill the cancer, but enough, they hope, to spike the number of T cells in the prostate. Another group will be receiving a different agent, a PD-1 inhibitor, infused in to the bloodstream, plus radiation. And a third group will receive both the injection in the prostate as well as the PD-1 inhibitor and radiation.
If this type of therapy is as promising as the investigators hope, they may expand it to include men who have oligometastatic prostate cancer – cancer that appears to be confined within the prostate, except for a tiny bit of cancer that has spread elsewhere. “The approach that we’re taking is one that has been successful in other forms of cancer,” says Dicker. “It just so happens that in prostate cancer, for reasons that no one fully understands, unlike lung, head and neck, bladder, colorectal cancer, or melanoma, the checkpoint inhibitors to date have not had much success. How can we make prostate cancer respond like a melanoma? Here we’re using radiation to enhance immunotherapy, and we can do this because the technology has improved dramatically.”
Terms to know from this article:
Immunotherapy is a type of treatment that boosts or restores the immune system to fight cancer, infections and other diseases. There a several different agents used for immunotherapy; Provenge is one example.
A doctor who specializes in treating cancer. Some oncologists specialize in a particular type of cancer treatment. For example, a radiation oncologist specializes in treating cancer with radiation.
The removal of cells or tissues for examination under a microscope. When only a sample of tissue is removed, the procedure is called an incisional biopsy or core biopsy. When an entire lump or suspicious area is removed, the procedure is called an excisional biopsy. When a sample of tissue or fluid is removed with a needle, the procedure is called a needle biopsy or fine-needle aspiration.
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