The Rise of Immunotherapy: Considerations to Ensure Optimal Management With Matthew Hadfield, DO

Oncology Data Advisor: Welcome to Oncology Data Advisor. Today, we're having a Fellows Forum interview, and I'm joined by Dr. Matt Hadfield. Thanks so much for coming on today.

Matthew Hadfield, DO: Thank you so much for having me.

Oncology Data Advisor: To start off, would you like to share a little bit about yourself and what you do and your work?

Dr. Hadfield: Yes, I am a third-year Hematology/Oncology Fellow at Brown University in the Legoretta Cancer Center in Providence, Rhode Island. I predominantly do research in early-phase clinical trials. These are clinical trials that are often first-in-human studies, with an emphasis on novel immunotherapy medications as well as immunotherapeutic combinations to overcome resistance and focus predominantly on solid tumors. Throughout my fellowship and even residency, I've developed a really profound interest in immunotherapy toxicities, which I think is something that is very relevant to not only practicing oncologists and hematologists, but all practitioners of medicine. Those are my big areas of research and interest.

Oncology Data Advisor: Awesome. To delve into your research a little bit, what exactly is immunotherapy, and how does it differ from chemotherapy or targeted therapies?

Dr. Hadfield: Immunotherapy has really changed the landscape of how we treat cancer. The concept that we could harness the body's immune system against cancer goes back all the way to the turn of the 20th century with something called Coley toxins. Physicians back then would notice that patients who had co-infections with sarcoma would actually do better in terms of regression of their tumors, which led to this hypothesis that the immune system played some type of role in controlling cancer growth and proliferation.

In the 80s and the 90s, we used something called interferon pretty frequently, which essentially stimulated innate immune responses. It was horrible; it really led to lots of systemic toxicities. People felt like they had the flu all the time. It was not easy to tolerate, and in addition to not being easy to tolerate, it also had very poor responses in terms of treating cancer, particularly melanoma.

Then Jim Allison, who won the Nobel Prize back in 2018, spent most of his career working on something called cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4), which is an immune checkpoint. Basically, the immune system is wonderful when it works the way it's supposed to, but we have these brakes built in place called checkpoints that stop the immune system from becoming too overactivated and too proliferative. It essentially stops autoimmunity. What Jim Allison, as well as his collaborators in Japan, discovered was that these immune checkpoints could be blocked and then allow the immune system to then turn T cells against cancer and treat it as a treatment modality.

The first approved immune checkpoint inhibitor was ipilimumab in 2011 for metastatic melanoma. Just to give a little context to how bleak melanoma was prior to that, we used to give, as I mentioned, interferon and dacarbazine, and the overall survival back then for patients was less than a year. With ipilimumab alone, the overall survival increased to just shy of three years. Then with the combination of two immune checkpoint inhibitors, nivolumab and ipilimumab—nivolumab targets another immune checkpoint called programmed cell death protein 1 (PD-1)—the overall survival is now over five years, which is remarkable considering where we came from.

Immune checkpoint inhibitors turn the body's immune system against the cancer, whereas chemotherapy is drugs that just indiscriminately kill rapidly dividing cells. Then targeted therapy, which is the third box that we think about in terms of cancer treatments, is therapies that target specific proteins or genomic alterations that are driving the cancer. Immunotherapy has now had dozens of FDA indications across multiple solid tumors and hematological malignancies. It has become an absolutely remarkable advancement in the field of oncology and has provided durable benefits to multitudes of patients.

Oncology Data Advisor: Awesome. It's really remarkable to hear about those results, so thanks so much for such a comprehensive overview of them. I know that a lot of your research, as well, focuses on the management of immunotherapy- related adverse events. What exactly are these, and how do they differ from known toxicity from chemotherapy?

Dr. Hadfield: I think that's a really important question right now as we start to give more immunotherapy across the board to lots of different types of cancer. When we think about chemotherapy, it's drugs that are designed to kill rapidly dividing cells, and it has a very predictable pattern of toxicities. For instance, when you give chemotherapy, you can expect things like nausea, vomiting, hair loss, gastrointestinal (GI) side effects, and cytopenias like anemia and thrombocytopenia, which all are very predictable when you think about giving a drug that attacks rapidly dividing cells. Obviously, every chemotherapy has its own side effect profile, but immunotherapy is a completely different box altogether.

When you give an immune checkpoint inhibitor, what you're doing is you're taking the brakes, so to speak, off the immune system. When you do that, you can induce an autoimmune reaction in a patient. In patients who have received dual checkpoint inhibitors, the incidence of grade 3 and grade 4 side effects is over 50%. It's a significant amount of patients who develop these types of toxicities. Most commonly, you could have inflammation from T-cell application in your lungs, which would be considered pneumonitis, or colitis or dermatological reactions. Those are the most common, but it really is remarkable that immunotherapy can cause autoimmune adverse events in any organ system of your body. There are rare cases of things like autoimmune thrombocytopenia, autoimmune uveitis—all sorts of strange side effects.

It really is important not only for oncologists who manage these patients to be very aware that these toxicities exist and to have a high clinical suspicion for diagnosing them, but also to know that the timing of these types of toxicities is incredibly variable. When you give chemotherapy, you can expect that someone's going to have side effects within seven to 14 days, and then they'll slowly get better. That's why we design chemotherapy regimens and cycles. Immunotherapy can cause adverse events several months after last receiving the drug. It's a really important thing for not only oncologists to keep in mind, but also general practice physicians, emergency room physicians, and subspecialists. Everyone has to have a high clinical knowledge because the pattern and incidence of these types of toxicities is incredibly variable.

Oncology Data Advisor: What is the current understanding and approach toward how immune-related adverse events are diagnosed and managed, and how do you personally go about approaching this in your practice?

Dr. Hadfield: The way we diagnose immunotherapy toxicities is through a clinical diagnosis. At the current time, we don't have any biomarkers to predict or diagnose immunotherapy-related adverse events or toxicities. It's an incredibly important void in the field of oncology right now, that we don't know who's going to develop these toxicities. There's been some very interesting research done at the Harvard Cancer Center and Massachusetts General Hospital (MGH) recently that showed that certain human leukocyte antigen (HLA) subtypes can predispose to toxicities. But even in those studies, among people who had this predisposition, not all of them developed the toxicities. There's still a lot of room to research this further and figure it out.

Really, the way we diagnose immunotherapy toxicities is clinical. For instance, for pneumonitis, if someone who's been treated with immunotherapy presents to the emergency department or the outpatient clinic and they're having shortness of breath, you go through a typical differential diagnosis for shortness of breath. For cancer patient who has infectious etiology such as pneumonia or pulmonary embolism, immunotherapy toxicity becomes something of a diagnosis of exclusion.

It can be very challenging, and it can very much overlap with things like pneumonia imaging, for instance, or very nonspecific pneumonitis. Sometimes pneumonitis can look like consolidation, like a bacterial pneumonia, and sometimes it can look like patchy infiltrates. Sometimes radiographic findings can be pretty subtle. If you have a patient who has significant hypoxia, this is something where with any new symptom or any new physical exam finding any change in vital signs, we always have to think about the differential diagnosis—could this be related to immunotherapy?

In terms of management, that's a really important aspect of this as well, because if you think about immunotherapy toxicities, the whole concept is that we're taking the immune system and we're turning it against the cancer. When patients develop these types of immunotherapy-related adverse events, then we have to use immunosuppressive medications to then stop the patient from having symptoms and reduce morbidity and mortality. But by doing that, we're reducing the efficacy of the intended treatment. This was actually shown in melanoma, again. The MGH group published results about a year ago that showed that patients treated with high-dose steroids for immunotherapy-related adverse events did have worse overall survival, which is intuitive when we think about the fact that we're activating the immune system and then dampening it with an immunosuppressive medication.

Typically, once we have a high clinical suspicion for an immunotherapy-related adverse event such as pneumonitis, we start high-dose steroids and then taper those based on clinical response. That's true for most adverse events. For endocrinopathies, if someone has autoimmune thyroiditis or adrenal insufficiency, we do not treat with steroids. We just treat with hormone replacement therapy because the role of steroids is not helpful. You know you're not going to save those organs in that situation. Same thing with type I diabetes that results from immune checkpoint inhibitors. You just treat as any other type I diabetes; you wouldn't treat that with steroids. It can be very nuanced in terms of the management.

One thing that's really important, and hopefully we'll see more of this in the future, is steroid-sparing treatments, things like interleukin-6 (IL-6) inhibitors or tumor necrosis factor (TNF) alpha inhibitors or intravenous immunoglobulin (IVIG). Things of that nature could either augment the treatment with steroids or could potentially replace steroids altogether, because we know that giving high-dose steroids can reduce the efficacy of treatment. We know that the efficacy is worth treatment. It's a rapidly evolving field, and unfortunately we don't have tons of biomarkers at this point. We don't have good predictors. It's a challenging area and field to manage.

Oncology Data Advisor: Thanks so much. That was, again, a really comprehensive overview of all the different nuances and considerations that go into this. With all these complexities, what do you think the future of immunotherapy-related adverse events will look like in regard to how these will be diagnosed and managed as time goes on?

Dr. Hadfield: I think there are several things that hopefully will evolve over the next five to 10 years. I think one of the big things will be predictive biomarkers. There's been a lot of research into this over the last 10 years, as I mentioned, such as HLA subtyping. Could we find subsets of patients that are at least at a higher risk or lower risk so that we can stratify them? This is going to become more pertinent as we progress with these treatments, because if you think about patients who are treated in the metastatic setting, you have limited options, and unfortunately sometimes, a terminal diagnosis for their cancer. Toxicity is something where you have to weigh the risks and benefits as these therapies trickle down more into the neoadjuvant setting.

As we give them to patients who are going to potentially have curative-intent treatments either with surgery or radiation, and you think that someone could develop a grade three or grade four adverse event that could take away their potential lifesaving, life-prolonging therapy, we really need better biomarkers to predict who's going to respond, or not only respond, but also develop immunotherapy toxicities. There have been a few interesting studies looking at cytokine profiling—for single cytokines, whether or not baseline elevations of IL-6 predict for immunotherapy toxicities, or multiple for cytokines together, predicting whether or not elevations with a composite score could predict whether or not someone's going to have a toxicity. So far, those haven't really panned out.

I'm hopeful that we will be better at figuring out A) who's going to develop these toxicities based on some type of predefined risk stratification score, and B) use that information to then stratify whether the risk is too high for them to get an immune checkpoint inhibitor. Should they receive just one instead of two, or are they really in such a high risk of toxicity that they shouldn't get an immune checkpoint inhibitor at all? Those are some of the big things in terms of determining who's going to and who's not going to get immune-related adverse events.

In terms of treatment, unfortunately, we're very heavily reliant on high-dose steroids. There's a real risk for patients who develop some type of immune toxicity like pneumonitis, for instance, to be on steroids for prolonged periods of time, many weeks and months before they can be weaned off altogether. I think that has a whole lot of issues in itself, such as people being on high-dose steroids who can't be tapered off. There are metabolic side effects being on high-dose steroids. There's the reduced efficacy that I mentioned from having high-dose steroids to treat immune checkpoint inhibitors. There are just a lot of issues with that.

Hopefully, in the future, we will uncouple ourselves from being completely reliant on high-dose steroids and we'll be able to use things like IL-6, IL-12, and TNF alpha, to treat, but I also think there's potential that in the future we will combine those upfront. When someone starts an immune checkpoint inhibitor, they will get something like a TNF alpha or an IL-6 inhibitor at the same time that will hopefully mitigate and prophylax against developing a toxicity. Hopefully, at that point, we'll have predictive biomarkers or something that could help tell who's going to be at higher risk and could benefit from that type of treatment.

There's a lot to figure out, unfortunately, but it's becoming more and more pertinent every day. More and more FDA indications have led to many more patients being treated with these types of therapies than five years ago. There are lots of patients who are going to be seen in the emergency department, primary care physician offices, and things like that, who are going to be developing or showing signs of these adverse events. The clinical suspicion will have to be very high for a lot of different practitioners. There are multiple new checkpoints, such as lymphocyte activation gene 3 (LAG3) is now approved in melanoma and being studied in lung cancer, so there's going to be a lot more of this in the future.

Oncology Data Advisor: Awesome. That'll definitely be exciting to see all the ways that the field progresses in the next few years even. To wrap up, any parting words you'd like to share about immunotherapy or adverse events to raise awareness about them?

Dr. Hadfield: The big thing that I would just hope people take away is that immunotherapy-related adverse events should always be on the differential diagnosis for any cancer patient who's treated with these therapies. It really does go beyond the scope of just oncologists. There's a really interesting study that's a little dated now, but it was done at MGH—MGH has done a lot of work in this area, so they get cited an awful lot. They polled different oncologists at their center as well as subspecialists about their comfortability with managing immunotherapy-related adverse events. Basically, the gist of the study was that a significant amount of both didn't feel comfortable managing a toxicity.

If the person prescribing immune checkpoint inhibitors doesn't feel comfortable managing the toxicity, and the subspecialist such as the pulmonologist who is managing pneumonitis doesn't feel comfortable, someone has to own it. It really does go beyond just the scope of oncologists. It's a medical problem that everyone has to think about, and it's going to become much more relevant for everybody in the very near future. It's something that everyone's going to see in any subspecialty, as well as primary care and hospitalists. I think everyone should have some baseline understanding of these types of toxicities and always have them on their differential when these patients are admitted to the hospital or seen in the clinic.

Oncology Data Advisor: Definitely. Well, thanks so much for coming on today to talk about all this and help spread awareness of what clinicians should be on the lookout for. This was definitely a really informative session.

Dr. Hadfield: Thank you so much for having me.

About Dr. Hadfield

Matthew Hadfield, DO, is a Hematology/Oncology Fellow at Brown University/Legoretta Cancer Center in Providence, Rhode Island. Prior to fellowship, he completed his Internal Medicine Residency at the University of Connecticut in 2021. Dr. Hadfield's research focuses on melanoma and early-phase clinical trials. To date, he has published numerous peer-reviewed articles and studies, and he has presented his research at multiple national and international meetings. His main areas of interest include early-phase drug development, novel immunotherapeutic combinations to overcome therapeutic resistance, and predictive biomarkers for immunotherapy toxicities.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.