Inmunoterapia contra el cáncer: Estudios y perspectivas en 2021

El año pasado se produjeron avances en inmunoterapia para varios tipos de cáncer, ampliando sus beneficios a más pacientes, tanto jóvenes como mayores. Los avances en tratamientos y análisis de biomarcadores permiten a los médicos personalizar más que nunca el abordaje para cada paciente, a pesar de que todavía queda mucho por hacer.

En este seminario web para pacientes y cuidadores, el Dr. Kunle Odunsi, MD, Ph.D., del Centro Oncológico Roswell Park, analiza estos importantes hitos, lo que podría surgir en este campo en 2021 y su impacto en los pacientes. El Dr. Odunsi abordará diversos temas relacionados con la inmunoterapia, a saber:

• nuevas aplicaciones de inmunoterapias con inhibidores de puntos de control
• combinaciones de inmunoterapias con otros tratamientos
• uso de biomarcadores para el emparejamiento de pacientes con inmunoterapias
• estrategias prometedoras de terapia celular, y más.

El Dr. Kunle Odunsi es director adjunto del Centro Oncológico Roswell Park, además de titular de la cátedra subvencionada Robert, Anne y Lew Wallace de inmunoterapia contra el cáncer y director ejecutivo de su Centro de inmunoterapia. Asimismo, es presidente y profesor M. Steven Piver del Departamento de Oncología Ginecológica de Roswell Park, director adjunto del Consejo Asesor Científico del CRI y, en 2018, ingresó a la Academia Nacional de Medicina.

La serie de seminarios web «La inmunoterapia y usted» es una producción del CRI presentada por nuestro redactor científico senior, Arthur N. Brodsky, Ph. D. La serie 2021 es posible gracias al generoso apoyo de Bristol Myers Squibb y Alkermes.

Consulte nuestra lista de reproducción de la serie de seminarios web La inmunoterapia y usted en YouTube o visite la página de seminarios web en nuestro sitio web para ver otros seminarios de esta serie.

WEBINAR TRANSCRIPT

Arthur Brodsky, PhD: Hello, and welcome to the Cancer Research Institute Cancer Immunotherapy and You Patient Webinar Series. I’m your host Dr. Arthur Brodsky, Senior Science Writer at the Cancer Research Institute. and during today’s webinar we’ll be focusing on cancer immunotherapy 2021 research, and a look ahead.

Over the next hour, we’ll hear from a leading cancer immunotherapy expert about what lies ahead for the field in the following year and what it means for patients. In particular, we’ll highlight new applications of checkpoint inhibitor immunotherapies, the latest in cell therapy strategies, the use of biomarkers to allow for more personalized care, and how we’re designing smarter clinical trials.

Before we begin, I’d like to quickly thank our generous sponsor Bristol-Myers Squibb, who made this webinar series possible.

And now it is my pleasure to introduce today’s expert speaker. Dr. Kunle Odunsi is the Deputy Director of the Roswell Park Comprehensive Cancer Center, among other roles there, as well as an Associate Director of the CRI Scientific Advisory Council, and a member of the National Academy of Medicine. Excitingly, in March, Dr. Odunsi will be assuming the role of Director at the University of Chicago Comprehensive Cancer Center.

On behalf of everyone at CRI, I’d like to offer you our congratulations and best wishes.

Kunle Odunsi, MD, PhD: Thank you.

Arthur Brodsky, PhD: So let’s jump right in. Obviously, COVID-19 changed everything last year. And although we have new hope thanks to vaccine development, it remains a serious ongoing crisis. So I’d like to start there. So at the moment, what do we know about how COVID-19 affects cancer patients? Does having cancer influence the risk of someone becoming infected or developing serious disease?

Kunle Odunsi, MD, PhD: Thank you, Arthur, for the introduction.

So COVID-19, this pandemic, has been a threat and remains a threat to human health worldwide. That’s my first comment. But I have to say that the scientific community has risen up to the challenge with unprecedented collaborative efforts, unprecedented new ways of thinking about how we take care of cancer patients.

There’s no doubt that COVID-19, when it affects cancer patients, it is in a disproportionate fashion in terms of the potential for significant poor outcomes. And there are two important reasons for this. Cancer by itself can affect the immune system. So that’s one reason. And the weaker your immune system, the less likely you are able to fight any infection, whether it’s COVID-19 or any other form of infection.

The second potential reason why cancer patients are more likely to have severe COVID-19 compared with other patients is because many of the cancer therapies, such as chemotherapies, also affect the immune system. And when they affect the ability of the immune system to fight infection, such as COVID-19, then, as you can imagine, the patients can be sicker and have more serious effects from COVID-19.

Arthur Brodsky, PhD: So you mentioned the effect of chemotherapy and other treatments and how they can affect the immune system. So how has the pandemic affected cancer patients who are currently receiving treatment? Do they have to postpone them, or are they still allowed to receive them?

Kunle Odunsi, MD, PhD: So when the pandemic started, there was a lot of discussion about how best to manage patients. And some of the consequences we really have not seen, we really do not know yet. But it was clear that there was a need to change how we practice.

So for example, a lot of effort went into minimizing patient exposure. So merely coming to the hospital could be a source of exposure to the virus. So there was implementation of telemedicine in our center and many other centers around the country. Obviously, there’s no substitute for a face-to-face, sitting across the table from somebody in the room.

But telemedicine substituted a lot for some of our consultation with patients. And some patients had their surgeries postponed. Some patients had their treatments postponed because nobody knew what the impact of the interaction between treatment and COVID-19 was going to be at that time.

Fortunately, there have been a lot of studies, as you can imagine. As I said earlier on, the scientific community rose up and have studied COVID-19’s impact. I mean, if you go to PubMed, which is where the scientific literature is listed, you find thousands and thousands of published articles on COVID-19 in relation to cancer, and even non-cancer related.

So the point is that it’s become clear that cancer patients have higher risk of having significant side effects because of what I explained earlier on, because of the immune system. Nevertheless, if you look at the overall totality of outcome in cancer patients, if you take thousands and thousands of cancer patients, the impact on the outcome in terms of patients dying as a result of cancer has really been minimal, at least as far as we can tell right now.

Arthur Brodsky, PhD: That’s great to hear. And as you mentioned, obviously it’s an evolving situation. We continue to learn more about it. And you alluded to it at the beginning that it’s incredible the progress we have already made. Normally, scientists, we are very thorough, and it takes years and years to develop.

Fortunately, with COVID, cancer immunotherapy kind of lent a hand with the platforms that were developed for personalized cancer vaccines were ultimately utilized for the COVID vaccine, or for at least one of the COVID vaccines. So fortunately, now we have multiple vaccines that have been shown to prevent infection by this new SARS-CoV-2 coronavirus.

With respect to these vaccines, are there any special considerations for cancer patients? Like would someone currently undergoing immunotherapy or another treatment still be able to receive the vaccine?

Kunle Odunsi, MD, PhD: Yeah, absolutely, I think there are special considerations for cancer patients. And the first important point to make is that many of the– actually, all of the clinical trials that tested the COVID-19 vaccine did not include cancer patients. So we have very little information about the impact of the vaccine on cancer patients. So that’s the first thing. However, I think it’s important to know that there is no reason to expect that cancer patients will have potentially more untoward side effects compared with the general healthy population.

The striking thing about COVID-19 is the link between age and severity of disease. So if someone is older and they are doing well on their cancer therapies– in fact, if you look at the CDC guidelines, the CDC hasn’t said don’t take the vaccine. But you have to be aware that we don’t fully know how cancer patients are going to react to the vaccine. So I think it’s reasonable to speak to your physician about the risk-benefit of taking the vaccine and make an informed choice.

But there are some general principles. Number one, if you are a cancer survivor where you are doing well, there’s no reason to expect that you will not do well with the vaccine. I think you would do well with the vaccine if you are a cancer survivor.

If you are a cancer patient actively undergoing therapy, I think, again, depending on how you schedule your treatment, just like any other vaccine. I mean, cancer patients getting chemo or radiation get the flu vaccine every year as well, but it needs to be timed. There are certain times where– it needs to be at a time when your immune system is not down as a result of your treatment so that you can get maximum benefit from the vaccine.

With regards to immunotherapies, that’s even another question. We just said that cancer patients were not included in those trials. So we don’t know whether patients who are getting immunotherapies are going to do well or not with the vaccine. But the general thought is that there is no reason why they cannot take the vaccine, again providing that you give it at a time when you think the side effects are likely to be minimal.

So there are a lot of unknowns, but overall the vaccine is safe in several of the clinical trials. And I think each person will need to discuss with their treating physician the risk-benefit of taking the vaccine.

Arthur Brodsky, PhD: I think that’s very solid advice. As you well know, even with COVID-19, as you just mentioned, cancer doesn’t stop, and these patients still have to deal with that. And so with respect to cancer, and immunotherapy specifically, the checkpoint inhibitors have really dramatically changed how we treat a lot of advanced cancers over the last decade.

So what new applications of checkpoint immunotherapies are you hopeful about in 2021, especially with respect to combinations for new cancer types, as well as the use of checkpoint immunotherapies earlier in treatment, either as first line or as maintenance therapies?

Kunle Odunsi, MD, PhD: Yeah, checkpoint inhibitors have been a major breakthrough, as we all know, for cancer therapies, thanks to the work of my colleague and friend Jim Allison and others, who really pioneered the field. Nevertheless, the proportion of patients who are responding to single agent checkpoint inhibitors– while it’s promising in the majority of cases, proportion of patients who are not responding, we think that proportion is still too high.

So in an effort to improve on the proportion of patients who are responding, there’s a need for combination. So there are a lot of ongoing clinical trials testing different combinations. I have to say checkpoint inhibitor therapy is almost applicable to any form of cancer. But not every cancer responds very well. I’ll give an example of ovarian cancers, where the response rates have been modest.

So how do we enhance the response rate? Combinations is one strategy. And there are different types of ongoing clinical trials testing different combinations– combinations, for example, in ovarian cancer with PARP inhibitors, combinations with chemotherapy, combinations with bevacizumab, for example, which is called an angiogenesis inhibitor. So there are all these types of combinations, which I think are going to come to the fore as we await those results. And some of those results are going to be available in 2021.

In the case of trying to improve the efficacy, I have to also point out that there are different types of immune checkpoints. The one that is most popular is the PD-1 checkpoint. So drugs like pembrolizumab, nivolumab, durvalumab, and so on, they are targeting the PD-1 pathway, the PD-1 immune checkpoint.

There are other immune checkpoints. There is the CTLA-4 immune checkpoint. There is another one called LAG-3 immune checkpoint. There is TIM-3 immune checkpoint, and the list goes on and on. So you can imagine, if you are targeting a single checkpoint in the immune system, there is still additional opportunity to target additional immune checkpoints.

So again, those clinical trials are ongoing where we are seeing a combination of immune checkpoints, hoping for synergy by blocking more than one immune checkpoint. Blocking two, three immune checkpoints, you probably will be able to enhance the efficacy of immune checkpoint therapies.

Arthur Brodsky, PhD: Gotcha. Yeah, that makes a lot of sense. It reminds me– I’ve heard Jim Allison speak on several occasions about the immune system. It has, obviously, so many different pathways and signals that it sends to maintain equilibrium, but its job is to maintain that equilibrium. It can boost the activity when it needs to do something, and then it goes back down to a baseline.

And so to your point of why targeting only one checkpoint at a time doesn’t necessarily work, that’s more because the immune system and cancer have ways to avoid that. And so the rationale with combination therapies, that would be more to kind of prevent these escapes?

Kunle Odunsi, MD, PhD: Yeah. The immune system is this very complex, elegant system that has a lot of redundancies. So if one checkpoint fails, the other one kicks in. So you can imagine cancer cells. Cancer has figured out a way to hijack this normal mechanism by which the immune system prevents immune system from attacking itself.

So if you block one immune checkpoint, we and others have shown that sometimes there is compensatory up-regulation of the other immune checkpoints. So what you’re trying to achieve by blocking immune checkpoints, you may not necessarily accomplish.

So I think those combinations of blocking multiple immune checkpoints, combinations with other strategies– I talked about combination with chemotherapy, for example– combinations with other targeted therapies are likely to improve the response rates in many cancer types where currently we don’t see a sufficient number of patients responding.

But let me also point out that the more you combine– and this is a very important point to make. The more you combine drugs, for example, if you give a patient one chemotherapy, versus two chemos, versus three, or you combine two immune checkpoints, the more the likelihood of having side effects from those treatments. So we have to be careful. As we go on to combine, we need to pay attention to make sure we are not causing too much side effects in our patients.

So the patient-reported outcomes from all of these clinical trials are going to be really critical for us to understand how are patients are reacting. What are the side effects? And some side effects are early side effects, some are late side effects. So all of this will need to be factored in in deciding how to move forward.

Arthur Brodsky, PhD: Great. And yeah, like we discussed, so far, as in every new type of treatment, they’re first tested on the very advanced cases for which the patients don’t really have any other options. And I think it’s approved for over a dozen major types of advanced cancer now. But again, in some of them– I believe lung, and kidney, and bladder, and a few others– it’s now approved as a first line treatment. So patients can receive that without having to go through chemotherapy or something else first. Although in some cases, like you mentioned, it’s combined with chemotherapy at the start.

Do you expect that maybe some of these combinations might also be able to help patients in the first line and then the maintenance phase, where maybe they are treated with a chemotherapy or have their tumor surgically resected at first, and then they receive the immunotherapy after to keep it in check?

Kunle Odunsi, MD, PhD: Yes, that’s a great question. And in fact, there are many clinical trials now testing exactly that question. So I’ll go back to ovarian cancer because that’s what I do.

So in ovarian cancer, there are now several clinical trials in the frontline setting where we’re combining immunotherapy, immune checkpoint inhibitors with standard therapies, not only combined in the active treatment phase but also in the maintenance phase with the idea that the immune system can help. Even if it doesn’t eliminate the cancer cells, it can at least maintain a state of equilibrium where the cancer is kept in check. It’s not growing. And the patient can have a good quality of life if the cancer is not growing.

So I think, more and more, we are seeing efforts to bring those immunotherapy trials to frontline settings. And sometimes they want to include them in maintenance, whereby the patient has either no evidence of disease, or patient has minimal residual disease. And you are trying to maintain the immune system to remain active against the cancer.

Arthur Brodsky, PhD: Gotcha. So now I want to turn to another type of immunotherapy, which is the cell therapies, probably the most notable of which is CAR T-cell therapies. And last year, a third CAR T cell immunotherapy was approved for patients with blood cancers, which include leukemia and lymphoma. And for various reasons, cell therapies– we know that they work much better in these liquid cancers, compared to solid cancers of the brain or breast, liver, lung, ovaries. And these are the ones that cause the vast majority of cancer-related deaths.

Now, obviously the field has been working very hard over the last several years to develop cell therapies, both CAR T-cell based therapies and others, to help people with these cancers. So might 2021 be the year that we see a leap forward in cell therapies for solid cancers?

Kunle Odunsi, MD, PhD: The short answer is, there is hope that 2021 will bring significant advances in cell therapy for solid tumors.

So if you think about it, the tumor microenvironment, in other words, where the tumor sits, in liquid cancers is the blood. If a patient has leukemia, lymphoma, it’s the blood. And when you give cell therapies, you are infusing into the blood. So the cells immediately can recognize and attack the cancer cells within the blood environment.

In solid tumors, such as ovarian cancer, the tumor is sitting in the abdomen. So you are giving the T-cell a lot of work to do. Number one, it has to be able to travel efficiently to the tumor site. And then, when it gets there, it needs to be able to do its job.

So what we have found is that some of the tumors use another interesting mechanism, which is to disrupt the type of blood vessels supply to the solid tumor. So you can imagine that you have your best T-cells in the world. You’re trying to attack breast, ovarian, or prostate, or any type of solid tumor. Even just to get in there and do its job is a challenge. So you have to overcome that.

And then when it gets in there, many solid tumors have put up barriers, a lot of different types of barriers whereby they are actively fighting back– fighting back these T-cells, these immune cells that are coming in. So you’ve got to identify, what are those barriers? How is the cancer fighting back? And how can I overcome those barriers?

So over the last few years, there has been significant progress in what we call genetic engineering techniques so as to make those T-cells, either the CAR T cells or other forms of T cells, to make them to be able to endure whatever the cancer is throwing at them. So there are ways to engineer the cells and make them to be able to be durable so that, even if the cancer is trying to fight back and throw substances at them, they can still standing to be able to do their job.

So we are seeing more and more of those types of designs of cells, cell therapies, where the cell is not just going there by itself. The cells sometimes even secrete. It’s engineered to produce some drugs into the tumor. So I expect some significant breakthroughs based on those developing technologies.

Is it going to get to the point of FDA approval? That’s uncertain. But clearly, there’s going to be significant progress in 2021.

Arthur Brodsky, PhD: That’s great to hear. And so our common theme, I guess, between the checkpoint inhibitors and all the cell therapies is the immune system’s complexity and cancer’s complexity. And so it’s not as easy as just having that one magic bullet that goes in. Again, you reference the amazing genetic engineering capabilities that we have now, and how we can give these cells all sorts of new skills and also enable them to resist cancer’s efforts to kind of shut them off and keep them out.

So just like checkpoint inhibitors are being combined with other treatments, are these cell therapies also being explored in combination with other treatments that might be able to make them more effective?

Kunle Odunsi, MD, PhD: Short answer is yes. As you know, again, cancer has so many different ways of making whatever you throw– just like if you give chemotherapy, many times the cancer becomes resistant to chemotherapy, and it no longer works. So the same thing with immunotherapy. It’s similar.

So when you’re giving your cells, the T-cells, again remember, they get to the tumor microenvironment, the cancer cells can now begin to turn on those immune checkpoints on the cells that you have given to the patient. So some of the ongoing clinical trials combine cell therapy with immune checkpoint inhibition, again, in order to further enhance the ability of those cells to be able to function.

Because once the cancer cells make the new cells that you are giving– once it makes them to express the immune checkpoints, which is a hallmark of what we call exhausted T cells, that is T cells that are not able to function, then game is over because the cancer cells are going to ignore the T cells. So you’ve got to always think of a way to make the cancer cells to be functional, to be active, to be able to persist within the tumor microenvironment.

And I think adding immune checkpoints is one such strategy. And there are ongoing clinical trials of combinations of cell therapy with immune checkpoints, and even some cell therapies where there is engineering to deliver immune checkpoints by these cells that you are putting in.

Arthur Brodsky, PhD: Great. And so now I want to turn to biomarkers, which can be a number of things, but essentially just pieces of information that tell doctors something about the biology of a patient’s overall health, their immune health, or their tumor. Last year, we saw a few biomarker-based immunotherapy approvals, including for tumors that have high expression of PD-L1 as well as for those with high numbers of mutations, which is known as high TMB.

So while these are helpful, they’re not perfect. And in the past, you’ve mentioned the need to go beyond these biomarkers in order to give doctors the tools they need to truly tailor their therapeutic strategies to individuals. So what is the state of biomarker science in cancer immunotherapy at the moment? And what are some things that you hope we’ll learn in the coming year?

Kunle Odunsi, MD, PhD: I think to identify effective biomarkers, it’s going to be important to conduct clinical trials where we are taking biospecimens– not just from blood, where we’re taking biospecimens as we give these new immunotherapies, checking the patient’s blood samples, and secondly taking biopsies. Because the tumor environment, the cancer site, is where all of the battle is taking place– the battle between the immune cells and the cancer. So we need to understand what’s going on.

And I’m pleased to see that many of the trials that we’re doing over the last few years are incorporating ability to take biospecimens. And we’re learning a lot from those trials. I’ll give examples from ovarian cancer. We don’t fully have the perfect biomarkers. Actually, there’s no FDA approved biomarker for ovarian cancer immunotherapy.

But there are biomarkers that have been approved for treatment of ovarian cancer patients using a class of drugs called PARP inhibitors. So it turns out that those biomarkers may indirectly identify patients who may also respond to immunotherapy, to immune checkpoint inhibition. They are not perfect, but there is some signal, there’s some evidence that those biomarkers approved for PARP inhibitors may indirectly also identify some markers for responses to immunotherapy. So that is an active area of investigation.

But I think what is going to be important going forward is not to focus on a few panels of genes or a few panels of biomarkers, but to be very expansive, extensive as we are doing biomarker studies. Because technology has advanced so much we can understand a whole gene expression profile of a tumor within a matter of a few days. And so by incorporating all of those types of technologies in our clinical trials, that will accelerate the pace by which we discover biomarkers.

I’ll give an example of a technology that is totally mind-blowing. It’s called single-cell RNA sequencing, where even if you take a tumor, you are not just taking a chunk of tumor to look at gene expression. You’re actually cell by cell analyzing the cells within the tumor to understand the changes that are happening in the presence or absence of immune cells, of immunotherapy.

So I think the technologies are going to help us going forward. There are a lot of things that are cooking right now as part of those clinical trials. And I’m hopeful that, in 2021, we will see more biomarkers come to the fore.

Arthur Brodsky, PhD: I hope so as well. You mentioned the relationship between cancer and the immune system is so complex, and it’s hard to really get a picture of what’s actually going on by just looking at one marker or one pathway. So it definitely makes sense that we’d want to not only look at higher resolution, as you mentioned with the single-cell sequencing, but also look at a variety of biomarkers that might indicate the immune system’s health and the cancer’s activity.

And with all of this, obviously, is clinical trials. And it’s really hard to overstate the importance of clinical trials in cancer research. Every approved treatment, including every immunotherapy, first had to prove its effectiveness in clinical trials.

But over the last decade, as you well know, because immunotherapy works differently than chemotherapy or radiation therapy, we’ve had to redefine how patients are evaluated in clinical trials. It’s not just enough to see if their tumor has shrunk or not. We’re also trying to analyze their immune activity and see how the treatments affect a variety of biological pathways and the panel markers, as you just mentioned. And that will be very important if we’re going to gain deeper insights into the mechanisms behind why some patients respond but not others.

So to that end, how are trials now being designed more rationally in order to ensure that we’re able to learn as much as possible from each patient and accelerate our efforts to develop effective biomarkers, combination strategies, and ultimately, cures for all cancers?

Kunle Odunsi, MD, PhD: Yeah. So the first point I would like to make with regards to clinical trials is the fact that the way we design clinical trials nowadays is so different from 20, 25, even 30 years ago. It used to be the case that clinical trials were designed for patients who have failed all types of therapies, and essentially you are just trying to–

Arthur Brodsky, PhD: A last resort almost.

Kunle Odunsi, MD, PhD: Right. You’re just trying to find the dose, and toxicity, and so on and so forth. That is no longer the case. There has been a significant paradigm shift, even with phase I clinical trials. Many of our phase I clinical trials, even though they are labeled phase I, they in fact have therapeutic intent, whereby the goal is to try and cure the cancer, or at least to put a patient in remission.

So the first point is that, especially with immunotherapy, many of the trials are designed not just to look for safety, toxicity, which are very important– in fact, they are so important– but also are designed to look for signal of efficacy. So the way clinical trials are designed nowadays– the way we design clinical trials is that, even from phase I, to accumulate as much knowledge as possible.

I talked about biopsies, trying to get biospecimens, blood, and tumor biopsies while on the trial so that we can understand if it works. What is the mechanism? How is it working so well? If it doesn’t work so well, why is it not working so well? And therefore, what can we do in the future to further augment the efficacy of that particular trial? So the biomarker, or biospecimen, tumor biopsy link is so, so critical now more than ever, especially because we have technologies to be able to interrogate the tumor to the fullest possible extent. So that’s number one.

Number two– again, we still go with phase I, phase II, phase III clinical trials, but phase I trials nowadays, especially once you see a signal of efficacy, phase I trials could be expanded very rapidly so that you can accelerate the pace at which FDA approval can be obtained. So it used to be the case that Phase I trials were usually very small trials. But now you can see Phase I trials, or Phase I/II trials that extend into hundreds of patients. And that has allowed the FDA to be able to look at data and potentially grant approval for the use of those drugs so it becomes widely available to our patient population.

So clinical trial designs are taking a different shape, number one, in terms of the intent behind them. Number two, the type of design, to identify biomarkers on select patients who are most likely to benefit the most. And number three, in terms of the size of phase I clinical trials, in many instances, the sizes have become larger so that you can rapidly generate sufficient data to begin to talk to the FDA about potential approval.

Arthur Brodsky, PhD: Yeah. I think, relating to your thing about how phase I’s have really changed, I know it’s not necessarily the norm now, but there’s even been some approvals that have come out of phase 1 trials recently, right?

Kunle Odunsi, MD, PhD: Absolutely. So some trials were designed so that they were large enough to generate sufficient data for approval, and some trials were phase I/II. So I’ll give an example.

The trial on the approval of checkpoint inhibitors for patients with MSI-high tumor, for example–

Arthur Brodsky, PhD: Sorry, Dr. Odunsi, could I just stop you real quick? Would you mind just defining MSI-high for our audience real quick?

Kunle Odunsi, MD, PhD: Oh, this is a genetic abnormality that you can find in some tumors. It’s frequent in uterine cancers. It’s frequent in colon cancers, a few ovarian cancers, and some other types of cancers. So when this abnormality occurs– it’s called microsatellite instability. When it occurs in tumors, those tumors tend to be more sensitive to immune checkpoint inhibitors.

So here we’re using a biomarker, regardless of cancer type, whether it’s cancer of the lungs, ovary, uterus. FDA was able to give approval based on the biomarker, rather than based on approval for a cancer type. That actually was unprecedented in the history of FDA approvals.

So this is why this whole area of identifying biomarkers is so crucial, because if we find a biomarker, let’s say in ovarian, maybe it will help a patient with colon cancer, or with kidney cancer. So it’s very crucial to continue to search for all of these appropriate biomarkers.

Arthur Brodsky, PhD: Yeah, it really is fascinating and amazing. You mentioned that approval for all types of cancers, as long as they have this biological feature, which, for essentially all of history, we just treated cancers based on where they arose. I don’t know if it’s necessarily our fault. We didn’t have that much knowledge or technology at the time. But it is really promising to see how far we’ve come.

So at this point, I don’t have any more questions. I just wanted to open the floor to you. And leave us with your general vision for what you think we might be able to expect over the next year, and what you hope we might be able to see over the next year in cancer immunotherapy.

Kunle Odunsi, MD, PhD: I think cancer immunotherapies are advancing at a very rapid phase. And it’s almost like the more you dig, the more you find avenues to improve on existing platforms. The most important advance over the last 25, 30 years in cancer therapy is the use of immune checkpoint inhibitors. It’s probably the most important, significant change that has impacted millions of lives.

So the question is, what is the next frontier? And we’ve talked about cell therapy. So I think that’s going to be an important next frontier to help cancer patients. But we continue to look for targets of immune recognition. So there is an effort by many groups, including ours, to identify additional targets, additional ways by which we can manipulate the immune system so it becomes even more effective.

This requires in-depth analysis, of biospecimens especially, from patients undergoing clinical trials. It requires a number of laboratory experiments so that we can take this new information and select the best combinations, optimal combinations that will maximize the impact of the immune system in attacking and defeating cancer. So I am very optimistic that what we’ve seen so far is really just the tip of the iceberg. I think there’s more to come in terms of how best to deploy the immune system.

Arthur Brodsky, PhD: Awesome. And I apologize. I actually jumped the gun a little bit, and we actually did have some audience questions. So I’d–

Kunle Odunsi, MD, PhD: OK.

Arthur Brodsky, PhD: –go through those now. The first is, how is CRISPR being used in the development of new immunotherapies?

Kunle Odunsi, MD, PhD: So CRISPR is a technology that allows you to edit genes. It’s a gene editing technology. If you recall, I said in the beginning that there are novel, new genetic engineering approaches where you can engineer cells. So CRISPR could be useful in those areas.

So for example, there was a clinical trial published, I think in the last year or one and a half years ago, by Dr. Carl June from University of Pennsylvania, where he was able to use CRISPR to edit out what you don’t need in a cell in the T cells that he used for cell therapy. So CRISPR can be used to genetically engineer, to make the T cell behave the way you want.

And so it’s a very promising technology, but it’s early days yet. There haven’t been a lot of clinical trials, but I can assure you that they are coming.

Arthur Brodsky, PhD: That’s great to hear. And then now, one of our audience members wants to know, how is immunotherapy being developed for rare cancers? And I guess what dovetails with this is, would that approval earlier that we were talking about that’s for all cancers, this would presumably apply to rare cancers as well?

Kunle Odunsi, MD, PhD: Yes. So when you approve based on a biomarker, it applies to all cancers, whether they are rare cancers or not. Unfortunately, rare cancers sometimes are difficult to study just because they are rare. Difficult to study.

So if you remember, when you are doing these clinical trials, you need to test a sufficient number of patients before you can make confident conclusions.

Arthur Brodsky, PhD: Mm-hmm.

Kunle Odunsi, MD, PhD: So that’s why rare cancers are difficult. I mean, I remember some studies that we did as part of the gynecology/oncology group that took us 10, 12 years to complete because we were focused on some rare cancers. We don’t have 10 or 12 years to wait for these results. We need results now.

Consequently, I think, again, it goes back to advances in technology, where we can deploy knowledge of biomarkers to say, even if this is a rare cancer, it has this genetic feature. It has this molecular feature. Therefore, it should respond to this or that type of immunotherapy.

Arthur Brodsky, PhD: And now with what you mentioned, that it’s harder to form those conclusions because you need enough patients to make sure that your data is statistically significant not just a red herring, how does that work for clinical trials? Are there usually patients with rare cancers– I guess going back to how we’re trying to treat in a disease-agnostic way, not dependent on where it is. So are there more trials nowadays, you’d say, where they group patients with different types of cancers, including the rare cancers, together?

Kunle Odunsi, MD, PhD: Yes. So there are trials where you have– these are solid tumor trials where they just put everybody together. But typically, those trials are conducted in the earliest phase, maybe Phase I/II. And then, because typically FDA is looking for one disease type, again until recently, and so you then branch out. And you focus on if you wanted to test lung cancer patients, or ovarian, or kidney. Then you expanded cohort of a specific disease type.

For rare cancers, obviously that’s difficult. But again, if you build in biomarkers, you can go back to rare cancers and use the biomarkers to select those patients for therapies.

Arthur Brodsky, PhD: Yeah, that makes sense. If you find out that lung cancers have activity in pathways XYZ and don’t have activity in pathway A, you could presumably extrapolate that to apply to the rare cancers. And obviously, you need to test it still, but it could save a lot of time, and energy, and effort and, hopefully, get those treatments to the patients sooner.

Kunle Odunsi, MD, PhD: Absolutely. Yep.

Arthur Brodsky, PhD: Great. So that is all the time that we have for today. Thank you so much, Dr. Odunsi, for sharing your expertise and insights with us. 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.

Here you can read and watch stories shared by others who have received  immunotherapy across a wide variety of cancer types. You can register for one of our immunotherapy patient summits, browse our entire library of past webinars featuring the world’s leading immunotherapy experts, like Dr. Odunsi. You can access information on other resources, including treatment, emotional support, and financial assistance. And you can get help to find an immunotherapy clinical trial that might be right for you.

Finally, I’d like to thank our generous sponsor Bristol-Myers Squibb one last time for making this webinar series possible.

And thank you all for your attention today. I hope you found today’s webinar very interesting and informative. And again, you can watch this and all of our other webinars on our website at cancerresearch.org/webinars to learn more about the immunotherapy options in a number of cancer types.

Dr. Odunsi, I just want to thank you so much again for taking the time to share your expertise with us today regarding the future of cancer immunotherapy, as well as the amazing work that you continue to do for patients. We wish you the best of luck.

Kunle Odunsi, MD, PhD: Thank you.