Checkpoint Inhibitors

Miracle Drugs for Some, But Not Yet All

Checkpoint inhibitors have one mission: to unleash the immune system.  They wake up the sleeping T cells, and in some people with cancer, they have done this spectacularly well. But right now, they don’t help more than a fraction of patients. In other words, for every extraordinary responder – a man whose metastases in the liver and brain simply melt away, whose PSA drops from the thousands to undetectable – there are six or seven men who don’t get any better.

Doctors and scientists desperately want to change this.

A brilliant scientist and investigator named Jim Allison, with initial funding from the Prostate Cancer Foundation, was the first to discover molecules on T cells called checkpoints. He figured out that these molecules were putting T cells into an induced coma, stopping them from carrying out their mission as assassins of cancer cells, and he worked to develop the first checkpoint-inhibiting drug, ipilimumab, which has had great success in treating some cancers, particularly melanoma.  In fact, he just shared the  2018 Nobel Prize in Physiology or Medicine for this work.

Why don’t checkpoint inhibitors work better in prostate cancer? Chuck Drake, M.D., Ph.D., director of genitourinary oncology and the associate director for clinical research at the Herbert Irving Comprehensive Cancer Center at New York Presbyterian/Columbia University Medical Center, explains: “When a T cell moves into tissue, it installs a brake.” It doesn’t necessarily apply the brake; it just has one ready to go.

I wish these brakes had convenient names, like “Bob,” or “Annette.”  But they don’t; they have pesky initials and numbers, so just hang in there and power through.  This is important:  One of those brakes is a molecule called PD-1, which sits right on the surface of the T cell. “Many tumors have T cells inside them, but they’re not working, because they have PD-1 on their surface.” The T cell with the PD-1 is just sitting there. But cancer cells make sure that cell isn’t going to move by adding a molecule called PD-L1. “That’s the foot on the brake. PD-L1 binds to the PD-1 on the T cell.” Imagine a car with several unpaid parking tickets under the windshield wiper; now imagine a traffic cop coming along and putting a parking boot on the car’s front tire. That car isn’t going anywhere.

So we’ve got our superhero in a stupor, like Superman staggering around or unconscious because Lex Luthor put a big chunk of Kryptonite in the room. But wait! Checkpoint inhibitors are coming to the rescue! “If you block either PD-1 or PD-L1 with a drug, a monoclonal antibody, you can wake up the T cell, take off the boot,” T cells can come roaring in and “do what they were designed to do, which is kill specific cells, including tumor cells.” And this is happening with checkpoint inhibitors in kidney cancer, bladder cancer, melanoma, and lung cancer.

Why not so much in prostate cancer? It may have something to do with the number of mutations on the prostate cancer cell. “Some melanomas have over 500 mutations; squamous cell lung cancer can have 200 to 500 mutations; garden variety lung cancer has 150 mutations, kidney cancer has about 70,” says Drake. “But prostate cancer only has about 30 mutations.”

Basically, the more mutations a cancer cell has, the more freakish it looks to the immune system, and the easier it is to recognize as an enemy. Think about any villain in Batman – the Joker, with his green hair and white pancake makeup, for instance. The villainous disguises are really helpful to crime fighters, because they say, “This guy’s dangerous.” But prostate cancers, even the very worst ones, are more like James Bond villains; they don’t look that much different from anybody else.

Timing may be a key factor, too.   Drake recalls a study he took part in when he was at Johns Hopkins, of a PD-1 blocker called nivolumab, which has worked well in other cancers. The patients were men with late-stage prostate cancer who had been through ADT and chemotherapy. “We had zero responses in 17 patients.” He recalled some anecdotal evidence from another trial, where a man who was on enzalutamide got Provenge , “his PSA went down to nearly undetectable, and his response lasted a very long time.”

In talking with Julie Graff, the lead investigator on a recent trial where Drake was a co-investigator, “we said, why don’t we try this same thing with pembrolizumab,” another PD-1 blocker. “We wanted to have patients who initially responded to enzalutamide but were progressing, and we didn’t stop the enzalutamide, but added on the pembro. Maybe there’s something funky about tumors progressing on enzalutamide that allows the immune system to recognize them. Whatever it is, maybe it’s better to stay on the enzalutamide and just add the PD-1 blocker.”  This strategy worked in a few men who were “exceptional responders.”

This study, published in Oncotarget, showed in just a few men with the most devastating prostate cancer – cancer that has metastasized, cancer that has invaded the bones, cancer that got better for a while on hormonal therapy but came back with a vengeance when the hormonal therapy stopped working – what might actually be cures.  It’s high time!  Why shouldn’t this happen in prostate cancer, number of mutations aside?  What is it, exactly, that has been happening in those other cancers:  Tumors that should have killed people with lung cancer, melanoma, kidney or bladder cancer have melted away instead, because checkpoint inhibitors allowed the T cells to recognize the cancer that’s been growing – invisibility-cloaked in plain sight – right beside them.  The results with pembrolizumab were so dramatic, and so unexpected, that the investigators decided to publish the early results.

Oncologist Julie Graff, M.D., at the Knight Cancer Institute of Oregon Health & Science University, explains:   “PD-1 inhibitors on their own have not seemed to have much of an effect on prostate cancer.”  But Graff, Drake and colleagues saw two exceptions to the rule, two men with “castrate-resistant prostate cancer” (their hormonal therapy stopped working) who responded exceptionally well to immunotherapy:  their PSA went away, and their cancer appeared to be undetectable.   “We wondered whether enzalutamide, which targets the androgen receptor, might stimulate the immune system to make the PD-1 inhibitor work better.”

The team designed a study of 28 men who are taking enzalutamide but whose cancer is still progressing.  The men continued to take enzalutamide as they received four doses of  pembrolizumab. The first 10 patients were enrolled from March 2015 to January 2016.  Their ages ranged from 61 to 80, and their PSA ranged from a little over 4 ng/ml to nearly 2,503.  Here’s what happened to them:  in three men, the disease did not change; it did not get noticeably better, but it didn’t get noticeably worse, either.  Four men did not have any evidence of a benefit, and one of these men died of his cancer.  So that’s seven men; what about the other three?  Their response blew the investigators away:  Their PSA – including the man with the PSA of nearly 2,503 – dropped to the undetectable range of less than 0.1 ng/ml.  Two of these men had been on narcotics for pain, and stopped taking them.  One man’s liver metastases went away.  “These three men had a complete response,” says Graff.  “Their tumors shrank radiographically” – meaning that they couldn’t be seen in imaging – “in the lab” – their PSA falling to nearly nothing – “and clinically,” with the need for pain medication going away.  “None has had a recurrence.”

With Emmanuel Antonarakis, M.D. of Johns Hopkins, Drake is looking at ipilimumab, which blocks a different checkpoint called CTLA-4.   “It turns out that within tumors there’s another population of bad guy lymphocytes (white blood cells), called regulatory T cells. These cells have a number of ways to turn off the immune response.”  In addition to blocking CTLA 4, ipilimumab interferes with the function of these regulatory T cells. Which begs the question: “What if you help the killer T cells by blocking PD-1, and at the same time block CTLA4?”  Blocking two checkpoints at once!  “In animal models, this works brilliantly,” says Drake. “The first data with melanoma were just magical; tumors shrank in four to six weeks.” Antonarakis and Drake “took turns petitioning the drug company” to do a clinical trial in prostate cancer for several years, with no luck. Then Antonarakis and Hopkins colleague Jun Luo, Ph.D., published an important paper in the New England Journal of Medicine showing that men who have a particular variant androgen receptor, called ARV7, don’t respond to enzalutamide and abiraterone. “We said, “If we can’t try this with everybody with prostate cancer, can we at least give it to guys who have the mutation? What if we took ARV7 patients and treated them with both anti-PD-1 and –CTLA 4 (blocks CTLA-4?),” says Drake.  “Emmanuel wrote the trial,” which just finished, and was published in Oncotarget.  “That’s the first clinical trial ever to combine anti PD-1 and anti-CTLA-4 in prostate cancer. It’s very promising.”  It’s also the first study to look at a specific, very bad, form of prostate cancer.  Let’s look at that study:

Combination Immunotherapy Combats AR-V7+ Prostate Cancer:  In this Hopkins-led study of men with very aggressive prostate cancer, this combo of two immunotherapy drugs has made a significant difference – shrinking tumors partially or completely – and two of 15 men have shown exceptional responses.

Once again, no one is suggesting that these drugs would produce the same promising results in all men with aggressive prostate cancer.   But this is an exciting example of precision oncology– finding the right drug (or combination of drugs) to work for the right patient and the right cancer.  The idea is that one drug might just help a few people; but another drug might help a few different people, and if we just keep chipping away at it, eventually we’ll help everybody, one subgroup of patients at a time.

The 15 men in the study had AR-V7-positive prostate cancer; AR-V7 is an aggressive variant of the androgen receptor, first discovered at Hopkins several years ago by Jun Luo and Antonarakis (this can be diagnosed by a blood test, available at Hopkins and through a company called EPIC Sciences).  They were given a combination of ipilimumab and nivolumab.  This specific form of prostate cancer, “can lead to fatal disease in only six to nine months and has inadequate treatment options,” says Antonarakis.

Patients received treatment by IV infusion:  3 mg per kilogram of nivolumab plus 1 mg per kilogram of ipilimumab every three weeks for four doses, followed by a maintenance regimen of 3 mg per kilogram of nivolumab alone every two weeks thereafter. The patients were enrolled between December 2016 and October 2017.

Two of the 15 men (13 percent) experienced a significant drop in PSA – by at least 50 percent.  “More encouragingly,” notes Antonarakis, “one-quarter of patients achieved an objective response, meaning that their tumors shrank partially or completely with combination immunotherapy.  These responses were durable and typically lasted more than nine to twelve months.”  But here’s the most exciting part:  “At least two of these patients remain alive for more than 18 months, which is much longer than expected for patients with AR-V7+ prostate cancer.”  Which means that Antonarakis and Luo don’t even know how long the response will last, because it’s still happening.

Genetic mutations affect response, too:  The men in this study were already different from many patients with advanced prostate cancer because of their AR-V7 variant.   Were there other differences that might help predict which men will respond best to this double checkpoint inhibitor approach?  Yes:  the specific genetic mutations are very important.

“Interestingly, six of 15 patients (40 percent) harbored damaging mutations in at least one DNA-repair gene,” notes Luo.  These mutations were either germline (inherited) or somatic (mutations that just developed spontaneously as the cancer advanced).  “In these six men, we detected gene mutations of BRCA2(3 men), ATM(2 men), and ERCC4(one man).

The job of DNA repair genes is to fix mistakes that occur in the DNA as cells divide – to keep a mistake from being repeated over and over again.  “Remarkably,” notes Antonarakis, “most of the benefit from ipilimumab plus nivolumab appeared to occur in patients who had one of these gene mutations, particularly in two men with BRCA2 mutations.”  If this proves true in larger studies, “it will have profound implications for other diseases such as breast and ovarian cancers, where these genes are more frequently mutated.”  An estimated 20 percent of men with metastatic prostate cancer have mutations in BRCA2or related DNA-repair genes. “This study suggests that these gene mutations may be even more common in men with the AR-V7+ form of prostate cancer, perhaps as high as 40 percent.”

The study also showed that the combination of nivolumab plus ipilimumab was safe and tolerable in men with AR-V7+ advanced prostate cancer.  “We did see some important side effects including colitis, pneumonitis and hepatitis – all caused by an over-activated immune system. These side effects were managed with prompt administration of steroids, which often resulted in reversal of these conditions.”

Encouraged by these preliminary findings, Antonarakis and his team are now expanding the study to include more patients.  This larger study is currently open to enrollment (https://clinicaltrials.gov/ct2/show/NCT02601014?cond=NCT02601014&rank=1), and is actively seeking participants.  If you are interested, please call Mrs. Rana Sullivan at (410) 614-6337.

So where do we go from here? Medical oncologist and molecular biologist Jonathan Simons, M.D., CEO of the Prostate Cancer Foundation, quotes Winston Churchill: “Now this is not the end. It is not even the beginning of the end. But it is, perhaps, the end of the beginning.” In other words, it’s just getting good. “We are learning so much about the immune system.”

There may be a dozen or more potential checkpoints to block. “We only have drugs for about half, and we have a lot more being investigated.” It may be that for the T cells to eradicate prostate cancer, it will require one or more checkpoint inhibitors, plus one or more vaccines. “When we’ve really got a checkpoint inhibitor that allows these T cells to wake up, PSAs will fall, tumors will melt away. When one of these works, man does it work!”

Immunotherapy-induced changes in how we kill cancer are happening so fast, it’s hard to keep up. In lung cancer, for instance, 30 percent of patients now get a checkpoint inhibitor, nivolumumab, before they get chemotherapy, and about half don’t even need standard chemotherapy.   “We don’t even know what some of the antigens are,” says Simons. “We’ve got to make this work for every patient.”

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

1 reply

Trackbacks & Pingbacks

  1. […] particular genes, called DNA-repair genes, are tiny quality control specialists; they’re the spell […]

Leave a Reply

Want to join the discussion?
Feel free to contribute!