The Intelligence of Immunotherapy

The Intelligence of Immunotherapy

 
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Immunotherapy trains the patient’s own immune system to target and attack cancer cells. For men with prostate cancer immunotherapy can provide long-term efficacy with minimal side effects.

This episode explores the innovations in immunotherapy including the use of off-label therapy and the promise of combination therapy. Don’t miss out on these new and exciting capabilities of immunotherapy!

Dr. Scholz: [00:04] Welcome to PROSTATE PROS.  I’m Dr. Mark Scholz and this is my cohost, Liz Graves.

Liz: [00:09] This episode we’re going to talk about immunotherapy. Immunotherapy enables the immune system to target and attack cancer cells that have gone undetected. It has been a revolutionary treatment for people with aggressive cancers such as lung cancer, melanoma, non-Hodgkin’s lymphoma, and others. Let’s talk about immune therapy as a game changing treatment for prostate cancer. 

Dr. Scholz: [00:33] Treatments that enhance the immune system have been a hope for decades. Problems in the past have been that the effectiveness is just not that great.  Finally we’re starting to figure out why that’s the case. There’s new developments that help targeted awareness to awaken the immune system and there’s also new treatments overall to just stimulate the immune system in general.  We’ll cover this in our podcast today. 

Liz: [01:03] I think a lot of people have a little bit of familiarity with the immune system, but can you talk about how it works in terms of cancer? 

Dr. Scholz: [01:11] So the cancer cells, typically, are trying to hide from the immune system, the immune system, the cells that come from our bone marrow and our lymph nodes, recognize the cancer cells and then have something called natural killer cells that can attack and kill cancer cells.  But, if the cancer cells are flying below the radar and aren’t detected, they just let the cancer cells grow and proliferate. Immune therapy is designed to awaken the immune system so that it can attack the cancer cells. 

Liz: [01:42] So immune therapy is a way of kind of boosting the immune system so it can recognize these cells and then go kill them. 

Dr. Scholz: [01:50] Exactly, there’s a lot of different ways.  What we call the immune system is actually quite complex.  There are cells that do the recognizing and then there are different cells that actually do the attacking and killing of the cancer cells. 

Liz: [02:02] So let’s talk a little bit about immunotherapy in prostate cancer.  There’s one FDA approved immunotherapy for prostate cancer and that’s PROVENGE. 

DENDREON: [02:11] Prostate cancer is an immune-evasive disease.  In other words, prostate cancer cells can evade or inhibit the body’s normal immune processes.  This immune-evasive ability helps make it possible for cancer cells to grow and spread, largely unchecked.  PROVENGE is an innovative treatment. 

Dr. Scholz: [02:30] So PROVENGE uses a recognition methodology to awaken our immune systems to an awareness that prostate cancer is present.  It does that by taking some of the dendritic cells out of our bloodstream and then basically putting them in a vat and mixing them with an antigen called prostatic acid phosphatase, which is associated with prostate cancer.  This makes those cells more aware of prostatic acid phosphatase. Then when those cells are re-infused into the same patient, they go seek out prostatic acid phosphatase producing cells. That’s how they recognize the cancer cells so they can be attacked. 

Liz: [03:10] So I think that’s really cool. You’re kind of, you’re using your own immune system and then just kind of telling it what to go find and then it goes and finds it. 

Dr. Scholz: [03:21] Exactly, and the nice thing, since it’s your own immune system, it operates very quietly behind the scenes.  Side effects are really uncommon and the treatment itself is pretty convenient because it’s all administered over a six week period. 

Liz: [03:36] So PROVENGE was FDA approved in 2010 and one question that’s come up is the fact that it doesn’t really impact PSA. 

Dr. Scholz: [03:44] Yeah, that’s really created quite a bit of consternation because most of the treatments for prostate cancer, when they’re effective, will lower PSA.  PSA lowering has been seen in rare cases, but it doesn’t usually occur. Some people have used that as an argument that PROVENGE doesn’t really do much. Of course, since there aren’t many side effects either, people kind of wonder what, if any,  good is coming of all this. So the studies that led to FDA approval insisted on a group of people getting a placebo and then another group getting the real treatment and the people that got the real treatment lived a lot longer. So how could that be?  How could people live longer but not have a decline in PSA? The theories right now mostly rely on the idea of a slowing of the cancer’s progression rather than a destruction of the cancer. This has been observed in some studies where they’ve given PROVENGE to men with rising PSA after surgery, demonstrating that the rate of PSA rise was slower.  So if you take an already slow process, prostate cancer can grow and spread over a period of many years sometimes, and further retard the progression, you could see how men could easily live an extra year or two if the cancer’s progress is being inhibited. 

Liz: [05:05] So PROVENGE is only given over six weeks, but it has this ongoing effect and that’s due to the memory of the immune system. 

Dr. Scholz: [05:14] Pretty exciting because if you contrast PROVENGE with other medicines that are used for advanced metastatic prostate cancer, say chemotherapy, chemotherapy functions like a poison and as long as you keep the poison in the system, the cancer cells die or are inhibited.  But PROVENGE, because the immune system does have a memory, keeps running a year, two, or more after the treatment has been completed. There have been some discussions about giving booster doses of PROVENGE and I know of patients that have paid out of pocket for an additional PROVENGE boost a couple of years after their initial therapy.  This is unfortunately not a proven methodology, but it makes sense if you think of a reactivation of a vaccine, for example. 

Liz: [06:00] So immunotherapy sounds pretty great. It’s a short administration schedule and it works long after.  Why aren’t more men on immunotherapy for prostate cancer? 

Dr. Scholz: [06:10] One problem, of course, is it is expensive and the insurance companies will only cover it in metastatic prostate cancer that’s become resistant to Lupron.  Fortunately that’s only a minority of men with prostate cancer. There are some studies ongoing now. The company is funding investigations giving PROVENGE to men that are on active surveillance.  That’s the earliest stage of prostate cancer. They’re going to try and determine if the men who get PROVENGE, compared to those that don’t get PROVENGE, if the men that do get the PROVENGE have a longer delay to the time that they need either surgery or radiation. 

Liz: [06:48] So you mentioned trials and I think there are a lot of trials going on with immunotherapy right now.  There are some off-label immunotherapy drugs for prostate cancer. Can we talk a little bit about those?

Dr. Scholz: [06:59] Besides PROVENGE, there’s another agent that’s been looked at for prostate cancer called Leukine.  Granulocyte-macrophage colony-stimulating factor, or GM-CSF, is the generic name for it. It was originally approved to help men who have low immune systems after chemotherapy.  That agent interestingly also does lower or stabilize PSA sometimes and it’s a relatively well tolerated drug. Sometimes people have some fevers or chills with it, but, it is an interesting treatment for men that have rising PSA after surgery.  Sometimes it will stabilize disease progression and men can avoid using Lupron or radiation or other types of treatment. So Leukine unfortunately is not FDA approved for prostate cancer, so it can be a bit pricey. It requires a subcutaneous injection three or four times a week on an ongoing basis.  It can help, and it is obviously a type of immune treatment. 

Liz: [08:03] The other class of immunotherapies are the immune checkpoint inhibitors.  How are these similar or different to PROVENGE? 

Dr. Scholz: [08:11] So when we’re talking about checkpoint inhibitors, we’re talking about an agent that so to speak, takes the brakes off the immune system.  The immune system is tightly regulated because if it gets out of control it can cause rheumatoid arthritis, lupus, multiple sclerosis, all kinds of serious problems.  So when you’re fighting cancer though, you do want to take a bit of a chance and, and rev up the immune system. The best example of this was when President Carter had metastatic melanoma to the brain a few years ago.  Everyone heard that he was about to die and then they put him on a checkpoint inhibitor called KEYTRUDA and basically he’s been doing great. So that’s quite miraculous. KEYTRUDA is FDA approved for melanoma and other types of cancer.  It’s being researched intensely in prostate cancer and people are optimistic. We ourselves have used it. Merck Pharmaceuticals has been very kind to provide KEYTRUDA on a compassionate use basis to our office. We’ve treated probably close to one hundred patients and it’s a well-tolerated drug.  It does have activity in metastatic and even in some of the earlier stage prostate cancers.

Dr. John A. Thompson: [09:22] With the immune checkpoint inhibitors, we are removing the brake pedal from the immune system.  Those brake systems are there for a reason. That is to prevent our immune system from attacking itself.  So when we remove those safety mechanisms from our immune system, we encounter all kinds of side effects that could be described as autoimmune side effects.

Dr. Ernstoff: [09:44] Patients are living a lot longer with immunotherapy.  We’re now facing the chronic toxicities of these drugs and how to manage them. 

Liz: [09:53] Okay.  So KEYTRUDA is not FDA approved for prostate cancer, it is for other cancers.  Is this accessible for men with prostate cancer all over the country or do you have to be in a special place or joining clinical trials? 

Dr. Scholz: [10:08] Well, they may have to join a clinical trial or if their medical oncologist is savvy, he can call up Merck Pharmaceuticals.  The company has been very liberal and providing KEYTRUDA free of charge to patients who are in need. 

Liz: [10:23] What about men that are only seeing urologists?  Are they giving this drug? 

Dr. Scholz: [10:27] KEYTRUDA can cause a variety of side effects when the immune system becomes overactive and the complexities that are involved necessitate supervision by a medical oncologist.  So, patients with metastatic disease, with prostate cancer, should really think about consulting a medical oncologist, not only for immune therapy, but for a variety of other agents that are used in that setting and can have potential side effects that most urologists really are not equipped to handle. 

Liz: [10:59] There’s another immune checkpoint inhibitor called YERVOY and Prostate Oncology Specialists published a trial with YERVOY and PROVENGE. 

Dr. Scholz: [11:08] Yeah, it was a small trial, but it was very interesting because it’s logical that if you combine two different types of immune therapy, one that identifies the cancer cells and another one that stimulates the immune system in general, that you might have a better outcome.  So there are only nine patients in this study, but we’ve now followed up on them for almost five years and over half of them, all of these men had advanced metastatic disease, are still alive and doing pretty well. So there may be some important synergy between YERVOY, which is a checkpoint inhibitor, and PROVENGE, which is a kind of like a vaccine that helps the immune system identify the cancer cells. 

Liz: [11:57] So it seems like there’s a lot to look forward to in the upcoming years of immunotherapy and a lot of these are still in clinical trials and are still kind of getting figured out. 

Dr. Scholz: [12:07] Yeah, it’s been a big discovery when they were able to figure out how to quote, take the brakes off the immune system.  There were so many good ideas with vaccines and whatnot that never really panned out because the immune system would detect that there was some unexpected activity and then it would shut it down.  A lot of good ideas died that way. Now that the doctors have figured out what the problem is, what’s been slowing down the process, I think we’re going to see a rapid acceleration of new immune therapies.  This of course is great news, not only for prostate cancer, but for all cancers. 

Liz: [12:42] I know our office is doing some preliminary research about methods to determine, in advance, who might have side effects from immunotherapy. 

Dr. Scholz: [12:51] Yeah.  At UCLA, Joanne Weidhaas is doing research and has actually started a company looking at microRNAs in the blood, which are signaling RNAs.  Mutations in these RNAs can show who’s more likely to develop too much of a reaction when we take the brakes off the immune system. So, this is nice because bad immune reactions can be really problematic.  If we’re able to pinpoint the patients that are unlikely to get side effects, then the medicine is really very convenient and well tolerated. Patients get an infusion every three weeks and usually without much muss or fuss or unusual problems.  So far that test, which is called ImuDx (ImuDx) seems pretty accurate. The patients that are tested to be at low risk for immune related side effects have done very well when we give them KEYTRUDA. 

Liz: [14:00] So there’s a lot to look forward to in regards to immunotherapy.  But one thing I find very interesting is the immune enhancing effects of radiation.  Can we talk a little bit about that? 

Dr. Scholz: [14:12] Yeah.  It actually has a name, it’s called the abscopal effect.  That’s related to the fact that cancer cells cloak themselves.  They release substances in the immediate surrounding area around each little tumor that causes our immune system to pass by.  That protective barrier keeps the immune cells from getting in and attacking the cancer cells. Well, when you zap a spot of cancer, which may be detected on a scan, with a beam of radiation and kill that little tumor, it blasts through that protective halo and it exposes the proteins that are unique to that cancer into the bloodstream so that our immune system can sniff it out and detect it.  Once our immune system learns those little proteins are specific for the cancer, it can go search those same proteins out in other parts of the body. Giving radiation therapy therefore, can actually stimulate the immune system, which is kind of counterintuitive. People think of radiation as potentially suppressing the immune system. This could be the case if you were to radiate huge amounts of the body, but modern radiation uses these little pencil beams and so radiation could be directed just at the small tumors and thus you can get the good effect on the immune system without causing damage to the wider immune system. 

Liz: [15:42] So the type of radiation that works best with this is SBRT.  We talked about radiation on an earlier episode, so if you haven’t listened to that and you’re curious, go check it out.  It’s called Breakthroughs in Radiation.  So who would be the ideal patient for immune therapy? 

Dr. Scholz: [16:00] So since PROVENGE is only approved for men that have metastatic disease and who are resistant to Lupron, we like to identify those Lupron resistant patients as early as possible, when their PSA is as low as possible.  Studies have clearly demonstrated that when you give men immune therapy, men who have smaller amounts of cancer, are much more likely to respond to immune therapy. The problem is if the cancer gets out of control and spreads throughout the whole body, it has a strong immunosuppressive effect and immunotherapy is not likely to have as big a benefit.  So we like men that have PSAs that are very low, say less than five, who have relatively few spots that are metastatic. Our typical protocol then is to administer PROVENGE to those men. These are men that have low testosterone because they’re on Lupron and their PSA is rising, showing that they’re resistant. PROVENGE is given over about six weeks and at some point during the procedure, when they’re getting the PROVENGE, we consider either during or immediately after giving a short course of SBRT to the metastatic spot.  If there’s relatively few spots, say two or three, we would treat all three spots. If there’s more spots, we would just pick one spot to try to get the abscopal effect. After that we have discussions with our patients about their interest in the possibility of doing ancillary KEYTRUDA to try and enhance the immune effect even further. We would test these patients with that RNA, that microRNA test we mentioned called ImuDx, to determine if they’re at high risk for getting side effects from KEYTRUDA, in which case we probably would forego the KEYTRUDA.  If they have a favorable ImuDx test then adding KEYTRUDA after the PROVENGE seems like a logical thing to consider, although of course this is an off-label approach. 

Liz: [17:59] Okay. So it sounds like you’re talking about combining a bunch of these immunotherapies in the hopes that they’ll further increase longevity. 

Dr. Scholz: [18:07] If this type of therapy can be administered with relatively few side effects. It seems to us that the upside is quite big and the actual risks are quite minimal. 

Liz: [18:19] So it sounds like these patients are similar to the people you would give chemo to. How do you decide whether to give them chemotherapy or immunotherapy? 

Dr. Scholz: [18:28] Yeah, that’s absolutely true.  Chemotherapy might be an option for these patients as well.  We tend to think of chemotherapy for the type of patient that has a lot of advanced and quickly growing cancer.  Those sorts of patients, the ones with advanced quickly growing metastatic cancer, don’t respond to immune therapy as frequently, whereas chemotherapy will typically induce very good responses.   So we tend to reserve the immune therapy for men with smaller amounts of metastatic disease, men that have somewhat slower pace disease and reserve the chemotherapy for the men that have rapidly progressing cancer with high PSAs and a lot of metastatic lesions.  It is important to make clear that there have been some studies looking at trying to combine chemotherapy with immune therapy. The results have been mixed towards mostly unfavorable. It kind of makes sense because we know that chemotherapy will cyclically or temporarily suppress the immune system.  That’s kind of counter to what we’re trying to accomplish when we’re giving immune therapy to stimulate the immune system. 

Liz: [19:40] I forgot to ask, but how long are people on KEYTRUDA?  You mentioned three weeks. Does that go on for a while? Is it only three weeks? 

Dr. Scholz: [19:49] Yeah.  So the patients are given an infusion every three weeks.  But the typical approach is to continue on an every three week basis as long as the patient appears to be benefiting.  That judgment is based on how well it’s tolerated and how the PSA behaves. I would say patients could be on it as long as a year or more if it seems to be working quite well.  Well, we’ve hardly even touched on all the new stuff with immunotherapy, but we wanted to provide an introduction and we’re obviously quite hopeful for the future for immunotherapy and especially in combinations.  More and more clinical trials are exploring the use of KEYTRUDA and other immune checkpoint inhibitors in prostate cancer. We hope and believe that men with advanced prostate cancer are going to see greater longevity and a better quality of life.  Even now, immunotherapy is a good option for men who have advanced prostate cancer, and we’re going to see the popularity increase as time goes on. 

Liz: [20:59] Because immunotherapy is still developing as a treatment for prostate cancer. We’d love to revisit this and talk more about it with you.  If you have any questions you want to send or comments or anything new you’d like to send us, please email them to podcast@prostateoncology.com and we’d love to start a conversation.  Thank you for listening. Please remember to rate, review and subscribe on Apple Podcasts.

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