Immunotherapy Side Effects: What Patients Need to Know

Immunotherapy—a class of treatments that utilize the body’s immune system—has begun to revolutionize the landscape of cancer care. Due to the incredible power of the immune system, immunotherapy has been able to provide remarkable benefits for patients with a number of cancer type, including those for which there were previously no effective options. However, sometimes activating the immune system against cancer may lead to side effects and even autoimmune responses against healthy tissues.

In this webinar for patients and caregivers, Jeffrey S. Weber, MD, PhD, of NYU Langone Health discusses our current understanding of the side effects that may result from immunotherapy as well as current strategies that are being explored to minimize these potentially harmful side effects and improve the patient experience.

Dr. Jeffrey S. Weber is the deputy director of NYU Langone Health’s Perlmutter Cancer Center, where he works with a multidisciplinary team of medical and surgical oncologists, dermatologists, and pathologists to treat patients with melanomas ranging from the most common to the most complex.

Dr. Weber works at the forefront of the immunotherapy field, and his clinical and research interesting involve novel immune-based strategies to treat patients with melanoma as well as manage the side effects of these treatments. As part of these efforts, he remains involved in a variety of clinical trials, including those evaluating melanoma vaccines, cellular immunotherapies, among other new approaches against melanoma. He is also the principal investigator of several ongoing studies funded by the National Cancer Institute, including trials in clinical drug development and managing the autoimmune side effects of immunotherapy for melanoma. In the past, he has served as the principal investigator and director of Moffitt Cancer Center’s Specialized Programs of Research Excellence (SPORE) grant for skin cancer and melanoma research from the National Cancer Institute. He also serves as the codirector of the Melanoma Research Program, where he oversees work in experimental therapeutics, and currently sit on the scientific advisory boards of cancer-related biotechnology companies and numerous cancer institutions and foundations.

The "Cancer Immunotherapy and You" webinar series is produced by the Cancer Research Institute and is hosted by our science writer, Arthur Brodsky, PhD The 2020 series is made possible with generous support from Bristol-Myers Squibb, ALkermes, and Foundation Medicine.
 
Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.

WEBINAR TRANSCRIPT

Arthur Brodsky, PhD: Hello, and welcome to the Cancer Research Institute Cancer Immunotherapy and You patient webinar series. Today is Friday, July 17^th, and the title of today's webinar is Immunotherapy Side Effects: What Patients Need to Know. Before we begin, I'd like to thank our generous sponsors who have made this webinar series possible. Bristol-Myers Squibb with additional support from Alkermes and Foundation Medicine.

My name is Arthur Brodsky, and I am the senior science writer at the Cancer Research Institute, a nonprofit organization established 67 years ago with a mission to save more lives by funding research that aims to harness the immune system's power to conquer all cancers. Now, it is my pleasure to introduce today's expert. Dr. Jeffrey S. Weber is the deputy director of the Perlmutter Cancer Center, as well as the co-director of the Melanoma Research Program at NYU Langone Health.

Dr. Weber, thank you so much for joining us today. As I mentioned, we'll be focusing on the side effects of immunotherapy, especially the checkpoint immunotherapies that target the PD-1/PD-L1 pathway. And these are the most widely-used types of immunotherapy. And six of them have already been approved by the FDA for various types of cancer. So first, what are some of the common side effects of these checkpoint immunotherapies. And how serious can they get?

Jeffrey Weber, MD, PhD: Well, the most common side effects of the checkpoint inhibitors break down into skin, GI, liver, and endocrine. And rashes, itching would be the most common by far. The next most common would be GI side effects, things like bloating, diarrhea, nausea. After that would come what we call the endocrine side effects, which can be low pituitary output, low thyroid output, low testosterone. But most commonly, thyroid and pituitary.

And finally, liver abnormalities, that is toxicity to the liver causing abnormalities of the liver functions that we measure in the blood. And these can range– most of them, thank goodness, are not serious. They are what we call grade 1 and grade 2, which are not severely impacting on one's quality of life. But if they're not paid attention to or if you're one of the unlucky ones with the so-called high grade side effects, these can be life-threatening. And they have to be taken very seriously.

Arthur Brodsky, PhD: Gotcha. And also, it sounds like we're still learning more of the full range. Are there are there also, in addition to these ones that can commonly occur, are there some rarer ones that patients might also need to be aware of?

Jeffrey Weber, MD, PhD: Yes. When I talk to patients about what the potential side effects are of these drugs, I will go into the side effects that encompass the vast majority of them. And then we'll talk about the one-off stuff. And the one-off stuff is the stuff that tends to keep us up late at night, things like the neurologic toxicities, the paralysis of the lower extremities, otherwise known as Guillain-Barre syndrome. The paralysis of the eye muscles and the diaphragm, otherwise known as myasthenia gravis. Or severe neuropathies with numbness and tingling.

Those are big deals. We also see really rare things, like a case that I saw this morning, of aseptic meningitis, where you have all the symptoms of what seems like meningitis, headaches, stiff neck, white blood cells in the cerebral spinal fluid, and it turns out it has nothing to do with infection, and it's just the drug. Or the patient who gets disoriented and turns out to have encephalitis or inflammation of the brain. So those are neurologic.

Then there are the pneumonitides, that is inflammation of the lungs. And when that happens, you can get symptoms that mimic pneumonia. I mean, you can have a cough spitting up blood, green or yellow sputum. And for all the world, it looks like an infectious pneumonia. But it's not an infection. It's the drugs.

And distinguishing those two is not so easy. And it takes, shall we say, a lot of experience. Finally, the very rare inflammation of the heart tissue or myocarditis. That's, thank goodness, extremely unusual. But that can lead to congestive heart failure and early on in the development of the drugs that led to the deaths of some patients. So those are the three really rare, unusual, but potentially life-threatening side effects that we worry about and that keeps me up late at night.

Arthur Brodsky, PhD: Now, with respect to these side effects, I guess both the common and the rare ones, are there ways that– do doctors have ways to manage them?

Jeffrey Weber, MD, PhD: Virtually all of these side effects are manageable. Virtually all of them are reversible. There are some irreversible ones. The endocrinopathies may not be reversible. There may be the extremely rare development of inflammation of the islets of Langerhans in the pancreas, which is where our insulin comes from. And when that happens, we don't have any insulin, we get diabetes. And I've seen two patients in my career, out of the well over 1,500 patients I've treated, where they develop diabetes mellitus and they required insulin.

And that's a devastating complication. That didn't go away. That was irreversible. But the vast majority, other than the endocrine-related side effects, the vast majority of the side effects will go away with steroids or other immune-suppressive substances.

Arthur Brodsky, PhD: Gotcha. Now, obviously, the diabetes would be a very severe side effect. That would, obviously, impact the patient's daily life. But for the average patient, and I guess the common side effects that occur, how do these influence a patient's life? Would they disrupt some of their normal activities, potentially?

Jeffrey Weber, MD, PhD: Again, I'd say– for example, for a pembrolizumab or nivolumab single agent PD-1 blockade, or cemiplimab, 90% of patients do really well, have no serious side effects. And only about 10% of patients will have some significant or serious side effects that would be so severe that they'd have to stop their treatment. So I tell people, 90% of the patients are going to do great. But 10% of those patients will have lifestyle-altering side effects that at least temporarily are going to impact on their quality of life.

They may get hospitalized. They may need to take medicines. They will, perhaps, need to stop the drug they're on. The gentleman who had the aseptic meningitis ended up in the hospital. That's definitely put a crimp in his lifestyle. And he'll probably go home on Sunday on some steroids. And then the steroids will make him sleepless.

But in a couple of weeks he'll be fully recovered, back to normal, and he'll be perfectly fine. So again, the vast majority of these things go away completely. I had one lady who developed paralysis of her lower extremities and was in the hospital for three weeks. Three months later, she was back to normal. She's a realtor. And she went back to work driving, walking, every normal activity. She feels perfectly normal.

But there can be serious side effects. So I will not downplay that potential. The good news is virtually all of them will reverse and go back to normal. And even the ones that don't reverse, let's say you develop low thyroid, you can take thyroid medicine by mouth and lead a perfectly normal life, have no limitations whatsoever. But you will need to take Synthroid every day, potentially for the rest of your life.

Arthur Brodsky, PhD: Wow. So as you just mentioned, most patients will be okay on these, or at least not be too severely impacted. But with them running the gamut from not being affected to very serious, what kind of side effects or symptoms would require a patient to contact their care team and let them know about them?

Jeffrey Weber, MD, PhD: Well again, when I start patients out, and each time I see them during the first 12 weeks, by rote repetition, I will emphasize the reasons why we want to hear from them. Anybody who gets a fever of 100.4 or more, especially in the COVID era, I need to hear from them to decide what this most likely is. Anyone with nausea or vomiting that doesn't just go way over a 20, 30 minute span, I need to know. Any diarrhea more than once in a day.

Anybody can have diarrhea once in a day. But more than once in a day, two or more, I need to know about it. Any blood in the stool, any profound fatigue or paralysis or weakness or numbness of an arm or leg, I need to know. Those are the things we tell people.

And most of our patients are very compliant. The ones who run into problems are the folks who decide they don't want to call or don't wish to call. And the classic is the lady who called me one day, this is back when I was in Los Angeles. It was a Friday night at 8:30. I was eating with my family at our favorite Mexican restaurant in Glendale. And I got a phone call, and it was her husband. And he reported that his wife had had 20 diarrheas that day and was incapacitated and couldn't get out of bed other than to go to the bathroom.

I said, oh my god, this has been going on this evening, and it just started? He said, oh no, she's been having diarrhea for a week. I said, why didn't you call? Well, I figured I could handle it. I said, are you a physician? He said, oh no, I'm a dentist. I said, well I guess you didn't handle it very well.

So I said, put your wife on, please. And she reported to the ER and was hospitalized for 30 days in the local emergency room in Oregon. She was quite a bit of distance from LA. She should have called a week before. So it's the delay that's the damage. And the key is good communication between the treating team, your nurse, nurse practitioners, physicians, and the patient. So the care team has to be in the loop. And there has to be good communication. And if there is, these are safe drugs.

Arthur Brodsky, PhD: So as we've– you mentioned that was several years ago while you were still in California. As we've learned more about how these immunotherapies work and the potential side effects that can arise, has that helped foster better communication between patients and their care team?

Jeffrey Weber, MD, PhD: I think that over the years, people have done a much better job of understanding how to give these drugs. There's been a learning curve. Go back to 2005 when I was in Los Angeles. So by the way, this is 15 years ago, that case. So go back 15 years, those drugs are only used in specialty institutions, academic centers, by very few people. Today, they're widely used in the community.

And I think docs have picked up on the need for good communication. And they understand how these drugs need to be used. So there's been a learning curve. And I think they're infinitely safer today than they were in the past.

Arthur Brodsky, PhD: That's great to hear. So you discussed a little bit earlier about how long some of these side effects can last, even unfortunately, some that can lead to, in rare cases, permanent changes. How soon after a patient is treated can side effects arise?

Jeffrey Weber, MD, PhD: Well, usually it's not an immediate thing. I mean, there's always the one-off case where you get a dose of cemiplimab, and the next day you have severe diarrhea. But that's pretty rare. Usually, it's 5 to 10 days after the treatment that patients will begin to see things happen. And the good news is it's not going to happen immediately. The likelihood of there being an infusion reaction with these drugs is pretty low.

In combination, sometimes you see infusion reactions, like when you give Avastin and atezolizumab or something like that. You may see a slightly increased rate of infusion reactions. But mostly, when you're giving these drugs alone, or like ipi plus nivo, infusion reactions are very rare. It's days to a week or so later that you begin to see these side effects.

Arthur Brodsky, PhD: Gotcha. And so, as you mentioned, most of the patients will have mild or not bad side effects. But obviously, it's important to be able to tell which patient– or would be very helpful to tell which patients might have these. So at the current moment, are there any ways that doctors can predict in advance who might be more likely to suffer from these more serious side effects?

Jeffrey Weber, MD, PhD: Boy, that is the holy grail. Right now, we have no idea in advance. If you look at a patient, there is no way to look at someone and say, ‘aha!’, you're the one really at risk for colitis. I will say, someone with a pre-existing autoimmune disease would be at risk of a flare. Every patient I've treated with an autoimmune disease like scleroderma, or similar such diseases, ankylosing spondylitis, has had a flare.

And usually, they're not life-threatening. They're manageable. And we managed to get them through their treatment with usually a single agent PD-1 blocking antibody. But other than someone with an existing autoimmune disease, and those are not common, there's no way to tell.

And we have an entire specialized Center of Excellence grant from the NIH worth 11 million bucks to try to figure some of this out. And we have some pretty good leads. And I predict by the time our so-called SPORE grant runs its course in another three and half years, we'll have some excellent candidate biomarkers to predict in advance who's going to be the most likely to have side effects.

So the idea is you select those patients, and you preventively treat them with immunosuppressants right up front or at the first dose or second dose and that will help you prevent the side effects. As opposed to what we do now, which is you wait till they happen, wham, then you treat them. It's therapeutic. It's not prophylactic.

Arthur Brodsky, PhD: Gotcha. Speaking of ways that could possibly prevent it, until that we have those insights that we might be able to better predict who might experience them, in general, are there any ways right now that patients might be able to prepare or protect themselves against possible side effects?

Jeffrey Weber, MD, PhD: Well, there are not a lot of things you can do. People say, ‘oh, well, what should I eat?’ And my feeling is you should eat a healthy diet, a balanced diet. I tell people no alcohol, because alcohol is hepatotoxic and so are these drugs. I tell people no spicy foods, because they inflame the GI tract. And the last thing you want is to be inflaming the GI tract at a time when you're taking a drug or drugs that could also inflame the GI tract.

But other than that, if you're having diarrhea, you probably want to trim the roughage and go with a high protein diet. But really, there's no magic or magical diet, I wish there were, that will minimize the risk of a rash or liver toxicity or neurologic toxicity. It's really an amazingly random phenomenon, as far as we can see, as to who develops the side effects.

At the end of the day, I predict that we will measure autoimmune antibodies, which all of us have, to some degree. But virtually none of us ever get autoimmune disease, because we control it. But you'll have some autoimmune antibody tests and some immune T cell test at baseline– pardon me– that will help us predict who's going to be the ones most likely to get the side effects.

And again, you'll do a clinical trial in your selected population, selected by your biomarkers, and you'll randomly allocate half of them to get preventive immunosuppression, half of them not. And the half that won't, I am virtually positive will have some risk of the side effects that's high. And we hope the group that gets the immunosuppression has fewer side effects but doesn't decrease the risk of benefit or the chance benefit. That's the kind of trial that we will do as part of our SPORE if we can define, say, a profile of autoimmune antibodies at baseline in our patients that seem to be associated, in our analysis, with the development of these immune-related adverse events.

Arthur Brodsky, PhD: Gotcha. I understand. So now, I want to get something that's kind of at the heart of immunotherapy and immunotherapy side effects, which is, all these side effects that you're mentioning, or most of these side effects that you've mentioned, result from an overactive immune response, or an immune response that's directed at the wrong cells or wrong tissue. But at the same time, the goal of immunotherapy is to boost the immune system and have it attack the cancer more aggressively. Is there any connection between if side effects occur, or if they do or don't occur, and how likely– or the connection to whether a patient's likely to respond, whether their cancer is likely to respond to the therapy?

Jeffrey Weber, MD, PhD: Excellent question. Excellent question. And there's been a lot of work put into that over the last 5 to 10 years. And the answer is, in most cancers, there is some association between developing those side effects and clinical benefit. It's particularly weak in melanoma. And it's got contradictory data in melanoma. In lung cancer, bladder cancer, it's probably somewhat more straightforward.

But there is a connection, which doesn't mean if you don't get side effects, you won't get benefit. It just means there's an association between the two. So getting side effects is not a guarantee of benefit. No side effects is not a guarantee of no benefit. But yes, I think we all agree that there is a connection between those two. And in animal models, you can break the connection, meaning you can treat with a TNF-blocking antibody.

And you'll spare the benefit, you'll still have benefit, but you'll decrease some of the side effects in experiments done by several of my colleagues. So you don't have to have a direct connection between benefit and side effects, meaning if you suppress the side effects, you won't suppress the benefit. And that's the hope for future clinical trials.

Arthur Brodsky, PhD: That certainly would be ideal. Now, with respect to that connection, are there any specific side effects? Or is it the severity of the side effects? Or could you talk a little about more– about the specifics of that connection?

Jeffrey Weber, MD, PhD: So be a little more specific. You mean–

Arthur Brodsky, PhD: I guess, is it like–

Jeffrey Weber, MD, PhD: It's just incidence of any side effects–

Arthur Brodsky, PhD: Okay.

Jeffrey Weber, MD, PhD: –that seems to be associated with benefit. So it's not just the bad side effects, not just the lower-level side effects, it's when you look at it as a whole, that's where the connection is.

Arthur Brodsky, PhD: Okay.

Jeffrey Weber, MD, PhD: Now, melanoma, in melanoma in particular, there's this profound association, which is well-known, between developing vitiligo, which is a side effect of the treatment with these immune drugs, and causing an autoimmune depigmentation, you lose pigment, and benefit. And that's well-known for all immunotherapy, IL-2, interferon, as well as the checkpoint inhibitors. And that clearly is an autoimmune side effect directed against the pigment cells, which kind of makes sense. That's why you get vitiligo. You kill off your pigment cells, and of course the melanoma is tumor of pigment cells. So naturally, you're going to boost the immunity against those pigment cell tumor cells.

Arthur Brodsky, PhD: That does make sense. So earlier you mentioned that we can– and just now, you mentioned we can treat with something else, the anti TNF blockade and other types of immunosuppressants, that could possibly make it so the drugs still work, but they don't have– but it potentially minimizes the side effects. But with respect to the drugs themselves and just immunotherapy in general, how are these immunotherapies being developed to become safer in and amongst themselves?

Jeffrey Weber, MD, PhD: Well, I don't think the immunotherapies themselves are developed to be safer. Although, there are some exceptions to that rule. And the exceptions are that there are now antibodies against things like CTLA-4 and PD-1 that are engineered to have a blocking molecule placed on them. And that blocking molecule is only released in the tumor microenvironment when the engineered antibody is in the presence of something called a protease.

So the tumor-specific protease clips off this little blocking molecule and allows the antibody to function to unleash immunity. But outside the tumor it wouldn't happen, because the protease isn't present. So that's a very interesting strategy. And it's been evaluated in early phase studies. And we don't quite have answers yet, but it's a very interesting idea.

In addition, indirectly, there are many antibodies being developed that just don't appear to have the side effects of drugs like CTLA-4 blocking antibodies and PD-1 blocking antibodies. And as those drugs come along, hopefully we'll be able to generate the same benefit, as you see, with say, combination immunotherapy with fewer side effects. But they're not developed just for the side effects, they're developed because they're good drugs. Thank goodness they do appear to have fewer side effects.

Arthur Brodsky, PhD: Gotcha. So now, I'm moving, I guess in a slightly more personal direction. A patient that's receiving these checkpoint immunotherapies, could that potentially affect their ability to be intimate with a partner or even their fertility by any chance?

Jeffrey Weber, MD, PhD: Well, if you have an endocrinopathy, it definitely can affect your fertility. If you have hypothyroidism, I can guarantee it's going to affect your sex drive or hypopituitarism. But once you go on to hormonal therapy, it should return to normal. I mean, there's no inherent damage to the reproductive system.

And interestingly, it's one of the few parts of the body where it is extremely rare to have an immune-related side effect that relates directly to the reproductive system. Frankly, a patient with cancer, in general, the last thing on their mind in sexual activity, in my opinion, from what I've discussed with patients. I mean, someone who's ill is just not thinking about that.

But let's say someone's on adjuvant therapy. They're feeling well. They're free of disease. There's no reason directly why the therapy should impact on their sexual activity unless there's an endocrinopathy. And if there is an endocrinopathy, that's fixable with replacement therapy. And the other point is, given that we don't know what the effect of a pregnancy from, let's say, a male donor, obviously, who's making the sperm. When they're on immunotherapy we don't know what the effects on the sperm are. Nor do we know what the effects are on the egg from the female recipient.

So someone who's either a woman who wants to get pregnant who's on immunotherapy, or a man who wants to impregnate his partner while he's on immunotherapy, I think it's a bad idea. And I tell people to wait at least six months after finishing before and thinking about having children. Obviously, you want that drug to be out of their bodies.

In the handful of patients that I've had in my experience, usually people on trials who have managed to either become pregnant or impregnate somebody else when they were on immunotherapy, the kids have turned out fine. But god only knows, if I were in that position, I would not want to take the chance. I would play it absolutely safe. And if there's going to be sexual activity while you're on these treatments, you've got to practice appropriate birth control. It's just not worth the risk.

Arthur Brodsky, PhD: What about– I think it's still kind of within the scope of this. But what about a woman who is already pregnant? With, again, immunotherapy, because a fetus is technically a foreign tissue, do we know anything about how– or is it even out of the question to prescribe a woman who's pregnant with these?

Jeffrey Weber, MD, PhD: Wow, that's a good one. I have personally never treated a woman who is pregnant, with immunotherapy. Certainly, you would not treat an adjuvant patient who is pregnant, because you don't have a guaranteed benefit

Arthur Brodsky, PhD: Just to be safe.

Jeffrey Weber, MD, PhD: In metastatic treatment, you would wait till the third trimester to treat. If they were in the first trimester, they have to decide about termination. In the middle trimester, boy, that's a real problem. Thank god I've never had to deal with that. That would be a tough one. But I personally have no experience with that, nor I think is there much published about that.

Arthur Brodsky, PhD: Gotcha. So for patients who want to learn more about the potential side effects of immunotherapy, are there places that patients can speak with someone who has had immunotherapy to ask questions about their experience?

Jeffrey Weber, MD, PhD: Well, the CRI itself, like a number of other such organizations, has some resources to read and watch videos about cancer patients’ experiences with immunotherapy. It's called the CRI ImmunoCommunity. They also have advocates. And you can connect and speak with them about their personal experiences.

There are a number of other resources that are available out there. There's this thing called Imerman Angels, which can connect you to people one on one. Within, for example, our institution, we have some patient advocates who are really nice folks, always willing to share their experiences with patients who are considering going on immunotherapy.

And there's something called Cancer Care, I think that's probably through the American Cancer Society, that'll connect you to a social worker to find psychosocial support and other practical support services. And of course, almost all academic centers and all good practices will be able to connect you to someone, whether it be a patient advocate with experience or a social worker who will help people work their way through the issues.

Arthur Brodsky, PhD: So I think one of the take-home messages would be that there are places and people for patients to reach out to, that they don't need to necessarily navigate this journey on their own.

Jeffrey Weber, MD, PhD: Absolutely. And it's always an inspiring thing that patients, many of whom who have been through some bad experiences with toxicity, are more than willing to share their experiences with others. I mean, it's a very selfless thing to do. They don't have to do it. Nobody's requiring it.

But every institution I've been at over the last 20 years since I've been doing this, there's always been a nice cadre of people who've been more than willing to work with patients, who are patient advocates who've been through this and share their experiences. So that's an inspiring thing in my view.

Arthur Brodsky, PhD: Definitely. And thank you so much for sharing all of your insights today, Dr. Weber. For more of our webinars and additional resources that we have for patients and caregivers as part of CRI's answer to cancer educational programs, we encourage you to check out our website at cancerresearch.org/patients.

Jeffrey Weber, MD, PhD: Great.

Arthur Brodsky, PhD: Here, you can read and watch stories shared by others who have received immunotherapy treatments across a wide variety of cancer types. You can register for our virtual immunotherapy patient summit, browse our entire library of past webinars, featuring the world's leading immunotherapy experts, such as Dr. Weber. You can access information on resources including treatment, emotional support, and financial assistance, and find help locating an immunotherapy clinical trial.

Finally, I'd like to thank our sponsors one last time for making this webinar series possible. Bristol-Myers Squibb with additional support from Alkermes and Foundation Medicine. And thank you for your attention today. And I also want to give a special shout out to the CRI ImmunoCommunity, and especially ImmunoAdvocates for help formulating these questions.

And again, you can watch this and all of our other webinars at cancerresearch.org/webinars to learn more about the immunotherapy options and a number of cancer types. Dr. Weber, I just want to thank you so much again for taking the time to speak with us today and for the amazing work that you are doing to improve care for people with cancer.

Jeffrey Weber, MD, PhD: Thank you. And take care.