The Expanding Role of Immunotherapy

Oncology, ONCOLOGY Vol 34 Issue 10,

ONCOLOGY® recently spoke with Mario Sznol, MD, professor of medicine (medical oncology) at Yale School of Medicine and Yale Cancer Center, about the rapidly expanding use of immunotherapies, the future of immuno-oncology, and the management of immune-related toxicities.

The development of therapeutic agents like immune checkpoint inhibitors (ICIs) has led to dramatically improved outcomes for patients with cancer. The approval of the first ICI, ipilimumab (Yervoy), in 20111 for metastatic melanoma signaled the beginning of a new era of cancer therapeutics, with immuno-oncology soon finding itself on par with the traditional 3 pillars of treatment: surgery, radiotherapy, and chemotherapy.

ONCOLOGY® recently spoke with Mario Sznol, MD, professor of medicine (medical oncology) at Yale School of Medicine and Yale Cancer Center, about the rapidly expanding use of immunotherapies, the future of immuno-oncology, and the management of immune-related toxicities.

Q: A tremendous amount of progress has been made with immunotherapy over the last 10 years. Could you talk about the major trends we’ve seen, and some of the developments that you’re anticipating in the near future?

Sznol: A great many of the advances we’ve made were really related to anti–PD-1. Even though anti–CTLA-4 was an active agent of melanoma, the big advance really was the use of anti–PD-1 in multiple different diseases, then anti–PD-1 and anti–CTLA-4 combinations in a number of diseases, and then taking anti–PD-1 into the adjuvant and neoadjuvant settings. So those were really the primary advances. And what’s happened over time is basically expanding the indications for anti–PD-1 now to almost every tumor type. So, the surprises have been, for example, [the use of] anti–PD-1 and chemotherapy in lung cancer, which clearly improves outcome compared with chemotherapy and even with anti–PD-1 [alone], if you extrapolate the data. The other combinations which are not as surprising, but also very interesting, are combinations of anti–PD-1 with VEGF receptor inhibitors. So now we’ve seen a combination of lapatinib (Tykerb) and pembrolizumab (Keytruda), and in endometrial cancer, the VEGF receptor inhibitors are being combined with anti–PD-1. And pembrolizumab plus axitinib (Inlyta) is now standard of care for renal cancer. And the other disease where we’ve seen major contribution of the VEGF pathway inhibitors is hepatocellular carcinoma, where atezolizumab (Tecentriq) and bevacizumab (Lynparza), are frontline standard of care. So, these sort of VEGF pathway combinations together with anti–PD-1 are really having a major impact. And we’re waiting for additional studies to come down. The CTLA-4 combinations we’ve talked about, they’re active across a number of different diseases.

Then the next question is, will any other combinations sort of rise to the top? So many clinical trials are out there. There are hints [from] some of them: For example, there was an interesting randomized phase 2 study with atezolizumab and an anti-TIGIT antibody in lung cancer, but it’s a randomized phase 2 trial. Interpreting those data is a little bit difficult. Most of the effect was really in PD-L1–high combinations. So, we’ll have to wait for the phase 3 trials to see if that turns out to be promising or not. For most of the other combinations, you see hints of activity—for example, when you look at patients with resistant/refractory disease who then get this new agent together with anti–PD-1, you see some patients are responding—but the question is, are any of those signals going to be high enough to move these into positive phase 3 trials? I don’t know; I think what we’re lacking now is just the biomarkers. It’s really possible that all these combinations are working but they’re working in small numbers of patients. Without having the biomarkers to identify those patients, we’re running phase 2 trials with lower response rates. If we run unselected trials, trials and unselected patients in phase 3, those signals may be too small to detect.

So, the field is in a transition; an enormous number of promising new agents are coming out. For example, CD-3 engagers, which are having activity in hematologic malignancies, are starting to show a little bit of activity in solid tumors. The cell therapies, like tumor-infiltrating lymphocyte (TIL) therapies, are very interesting.

Q: What are you working on right now that you’re most optimistic about?

Sznol: A number of different strategies are out there, not all of which we’re working on. But, for example, we think that an agonist anti–CD-40 antibody is going to be useful in some subset of patients. So, we’ve been involved in a multicenter trial in which anti–CD-40 has been combined with anti–PD-1, and we’ve seen a few patients who have had very interesting responses. Again, anti–CD-40 is among those agents that we know is going to be important, but the question is, in how many patients?

We’re becoming more and more interested in trying to start clinical trials with things that modulate monocytes and macrophages and change your phenotype within the tumor and microenvironment. So, my colleagues have looked at, for example, anti–CD-40 combined with a CSF-1 receptor antagonist. Whether that’s going to be the right answer or not, we don’t know. We’re about to start a trial of anti–CD-40 together with anti–PD-1 and anti–CTLA-4 in the frontline setting, and we’re very excited about that. The cell therapies, unquestionably TIL therapies, have shown activity in a subset of patients who are resistant/refractory. So, we’ve been working with biotech companies that are developing those therapies and doing those clinical trials and have seen responses in resistant/refractory patients. We think that’s going to be an important piece of this going forward. We’ve been interested in the cytokines, and we’re trying to understand how combined cytokines work together rationally with ICIs. We’ve worked with the NEKTAR-214 drug, and we’re actually looking to work with an interleukin (IL)-12 construct in the future. We’re very interested in the whole concept of co-stimulation in the tumor microenvironment, and we’re aware of an agent that provides basically CD-28 co-stimulation that’s linked to PD-L1 expression in the tumor microenvironment—almost a PD-L1–dependent CD-28 activation. So, we are looking at a bunch of different concepts.

But we are only looking at a small fraction of the big world of things that can be done. I don’t know that we have any better information, or intuition, about what’s going to end up working in these resistant/refractory patients than anybody else does. Again, it’s because when you look at the tumor microenvironment, it’s so difficult to identify in most patients exactly what’s missing. In some cases, it’s easy. If there are no T cells there, and there’s no priming, then you either have to vaccinate or you have to figure out what’s causing the exclusion of T cells from the tumor microenvironment. If you already have T cells there, and you have some idea that they’re tumor antigen–specific, and they’re not responding to anti–PD-1 alone, then the question is, what else do you need to add in order to get those things to work? Then there’s going to be a group of patients for which the tumors lose β2 microglobulin. They lose major histocompatibility complex class 1 expression that can be recognized by CDA T cells. And for those patients, you have to do something that either that activates E4 cells or activates innate immunity in order to get antitumor effects.

Q: What led to your interest and research in immunotherapy?

Sznol: I did my oncology fellowship at Mount Sinai [Hospital in New York], and Mount Sinai was one of the few institutions back in 1985 that was studying IL-2. At the time, James Collins, MD, was actually doing a trial of continuous infusion IL-2 in patients with cancer, and that was my very first exposure to immune therapies. The science was really fascinating. So, when I was looking for jobs after my fellowship, there was a job at the National Cancer Institute (NCI) as a drug monitor to oversee the development of biological agents, particularly IL-2. I took that job and stayed at the NCI for 12 years managing the development of the immunotherapy portfolios. We got to see IL-2 and all the different cytokines that were developed, peptide vaccines, all the other vaccines and cell therapies. I got a huge amount of exposure to a lot of these immunotherapeutic agents. But you know, when I left in 1999, I don’t think the picture was nearly as bright. I think at that point, anti–CTLA-4 hadn’t been discovered and had not yet entered the clinic, and the cell therapies like TIL were just starting to show a little bit of promise. But things didn’t look quite as bright and I went to industry for a little while to do something a little bit different. But after that, anti–CTLA-4 was developed, and subsequently anti–PD-1, and those are the drugs that really made a huge difference.

So, when I came back from a biotech company into academics, I still had an interest in immunotherapy. I saw that these agents had substantial promise and sort of made studying those immunotherapeutic agents the focus of our melanoma program. But even the company that I joined after the NCI was involved in a biological agent; we were using modified salmonella as a way to try and target tumors. There was a very interesting finding that the salmonella could replicate preferentially within the tumor microenvironment, and we were the scientists in the company who were actually trying to modify the bacteria to deliver cytokines and chemokines. Even back then, I really thought that there was a defect in the microenvironment, and that delivery of these agents to the microenvironment might actually make the tumors more hemogenic, based on a little bit on the work that had been done with cytokine-transfected tumor cells in the 1990s. But it turned out, at least for the bacteria that we were using, that they didn’t colonize in human tumors the same way that they did in mouse tumors. There were limitations that we could not figure out at the time. That’s what brought me back to academics.

Q: You’re cochair of the upcoming 5th Annual International Congress on Immunotherapies in Cancer. What’s the focus of that meeting and why is it so important?

Sznol: Well, I think for practicing oncologists, it’s really hard to keep up with all of the clinical applications of the ICIs. They’re now being used to treat almost every disease type, and there are 2 aspects to these clinical applications. First, how does it fit it into the paradigm of treatment for that specific disease? And second, how [do you] manage or think about managing the adverse events (AEs) that are associated with these agents? Although these agents have been out there for a while, I think people still have a relative level of discomfort with managing all of the AEs. So, this meeting will be very clinically focused on the management of AEs, with a little bit about the science behind the ICIs. In this case, mostly, we’re going to focus a little bit more on biomarkers such as mismatch repair and tumor mutation burden (TMB), and also on recent advances in the use of these agents by disease and disease types.

[We’ll have] major experts in those diseases, and investigators who really understand the use of immunotherapy in those diseases, to provide practitioners with state-of-the art use of application of those agents.

Q: With immunotherapy making its way into almost every disease type, as you mentioned, how important is it for practicing oncologists to understand how to manage those AEs?

Sznol: Well, regardless of whether you use anti–PD-1 or anti–CTLA-4 and anti–PD-1, you’re going to see some rate of immune-related AEs (irAEs)—and there’s a whole spectrum of AEs. We try to give people a brief summary of what those events are and how to manage them, and then often spend time going through patient cases, because the best way to learn how to manage these irAEs is to really go through these cases and just highlight them. You can’t go through every toxicity, but if you go through 3 or 4 of the major AEs and how you manage individual cases, we can really help people.

I’m still amazed, given that these drugs have been out there for 6 or 7 years, that there’s still some uncertainty about how to treat these patients in the clinic. We see all sorts of things that maybe don’t make a lot of sense. For example, for patients who have had severe irAEs and are on steroids, as they’re tapering the steroids, they restart the ICIs. In fact, that doesn’t make a lot of sense. You really want to complete the steroid course and make sure that the irAEs are gone before you give people additional treatment, right? So, sometimes we find that people undertreat with steroids. They give doses of steroids that are too low, or they delay the diagnosis and initiation of steroid treatment, which can cause sometimes can lead to morbidity.

And then there are AEs. For instance, some patients develop a sort of colitis that just does not respond to the initial course of steroids, and for some of them, you have to give them an anti–tumor necrosis factor (TNF) or, in some cases, even a third-line agent. And [clinicians] who give these agents but don’t [have that much experience with them] may be OK with giving the initial course of steroids, but if the patient doesn’t respond to steroids, they may not be as comfortable giving the anti-TNF infliximab (Remicade) or, in some cases, giving the third-line vedolizumab (Entyvio) to reverse the AE. So, we try to go through some of those more complicated cases so that people get a feel for it.

It’s one of those things where I can tell you that even today, as much experience as we have and as much experience as other centers have, there are patients who develop autoimmune AEs where we actually email each other—we send emails out to 5 or 6 or 7 different people—and say, “Hey, I’m seeing this. How would you manage it yourself?” So even at very experienced centers, you still have to get sort of this group experience in order to learn how to manage the more unusual AEs. That being said, we also want to give people confidence in managing these drugs, because the overall benefit-to-risk ratio is very favorable for these agents. We don’t want patients to not get these drugs because the primary oncologist feels uncomfortable with the AEs.

Q: Is managing these AEs something that can easily be done in the community?

Sznol: The most common AE is a rash, and most of those rashes are easily managed. Colitis is probably the second most common AE. Hepatitis or liver function test abnormalities are probably the third most common and the fourth most common is endocrinopathies.

With colitis, you can imagine the patient would [be inclined to say,] “I don’t want to deal with this.” But it’s actually very easy to reverse in most people. And now the fellows who are being trained are used to seeing all these [AEs], and it’s becoming second nature to them. But if you received your training in the 1980s, or the 1990s, and these agents really started to become approved around 2013 or 2014, you’re dealing with a set of AEs that you’re not used to seeing. It’s not that the private-practice doctors or community oncologists can’t do this. They can. They manage things that are worse: If somebody is neutropenic, [for instance,] that can be a much worse AE than the colitis. It’s just a matter of developing the reflexes for what to do.

The pace at which these drugs have been approved for different indications is incredible. In 2013, 2014 maybe, there was an FDA approval for lung cancer or for melanoma or maybe renal cancer. But now, it’s in every disease type: There are approvals in triple-negative breast cancer and microsatellite instability (MSI) high colon cancer, and it’s not even as simple as the disease type. For example, [certain] drugs are now approved for anybody who has MSI-high cancers. It could be one of a number of different cancers that has MSI, or it could be somebody who has a high TMB. So physicians in the community have to not only think about what line of disease and which disease, but also about diseases for which there is no indication. Take cholangiocarcinoma, for example: A subgroup of patients with cholangiocarcinoma might still be good candidates for this drug and would receive substantial benefit by using the right biomarkers for selection. So, then you have a question: How do I know which test to use in order to determine MSI high or high TMB? Where do I send it? These are the practical issues, but things are moving along very, very quickly. It’s just a very different world, and it’s really important for people to learn how to use these agents, and learn how to manage the toxicity.


1. FDA approves new immunotherapy for metastatic melanoma. Cancer Research Institute. March 25, 2011. Accessed September 9, 2020.