Imaging in Immunotherapy: Using PET Scans to Guide Cancer Treatment

Imagine a safe, non-invasive method that would allow doctors to predict if patients will respond to certain immunotherapies. If oncologists could measure certain factors (such as the presence of T cells or the expression of PD-L1 within tumors) before treatment, they could design better treatment regimens for patients. If oncologists could measure these factors during treatment, they could determine if or how patients are responding. 

In this webinar for patients and caregivers, Kim A. Margolin, MD, discusses antibody-based imaging strategies that help doctors visualize patients’ tumors and immune cells in real-time via PET scans. 

Kim A. Margolin, MD, is a clinical professor in the department of medical oncology and therapeutics research at the City of Hope National Medical Center, where she serves as a principal investigator on a phase 2 trial that is using novel, immune-based imaging in patients with metastatic cancer who are being treated with immunotherapy and chemotherapy.
 
Dr. Margolin is triple board-certified in internal medicine with subspecialties in medical oncology and hematology, and is a fellow of the American College of Physicians. She has been the Chair of the Cancer Education Committee and a member of the Nominating Committee of the American Society of Clinical Oncology (ASCO) and previously served as a member of the Oncologic Drug Advisory Committee (ODAC) of the FDA.
 
Dr. Margolin is also an active member of several foundation and federal grant review committees, including the Melanoma Research Alliance, Department of Defense, and Melanoma Research Foundation. Among her 180 peer-reviewed articles, 60 invited reviews or editorials, and 16 book chapters, her most recent work has been in the area of melanoma metastatic to the brain and immunotherapy strategies for melanoma and other skin cancers.
 
Previously, Dr. Margolin earned her undergraduate degree summa cum laude from University of California, Los Angeles, graduating Phi Beta Kappa, then went on to receive her medical degree from Stanford University School of Medicine. After internal medicine residency at Yale-New Haven Hospital in New Haven, CT, Dr. Margolin began her fellowship in hematology/oncology at the University of California, San Diego School of Medicine and completed the fellowship in medical oncology and hematology and bone marrow transplantation at City of Hope. She remained on the City of Hope faculty in both departments for 25 years prior to her recruitment to Seattle.

This webinar is a special edition of CRI's "Cancer Immunotherapy and You" webinar series is produced by the Cancer Research Institute and is hosted by our science writer, Arthur Brodsky, PhD This webinar is made possible with generous support from ImaginAb.

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.

TRANSCRIPT

Brian Brewer: Welcome to the Cancer Research Institute Cancer Immunotherapy and You webinar series for patients and caregivers. Today is Tuesday, April 21, 2020, and the title for today's webinar is "Imaging in Immunotherapy: Using PET Scans to Guide Cancer Treatment". Before we begin, I'd like to thank our very generous friends at ImaginAb, who have made today's webinar possible.

My name is Brian Brewer, and I'm director of marketing and communications at the Cancer Research Institute. The Cancer Research Institute is a non-profit organization established 67 years ago with the mission to save more lives by funding research that aims to harness the immune system's power to fight all cancers.

Now it's my pleasure to introduce today's expert. Dr. Kim Margolin is a clinical professor in the Department of Medical Oncology and Therapeutics Research at the City of Hope National Medical Center. She is currently a lead investigator on a phase 2 clinical trial using novel, immune-based imaging in patients with metastatic cancer who are being treated with immunotherapy and chemotherapy. Dr. Margolin, thank you so much for joining us today.

Kim Margolin, MD: Thank you for inviting me. So I will be now going through a number of slides that will be directed at the use of PET-based imaging for various purposes in cancer immunotherapy, with a little bit of background shown in this slide, that's entitled "The Immunotherapy Revolution".

So as we know, novel immune-based therapies– mostly immune checkpoint inhibitors, but a number of other novel agent designs, as well, in the recent past– have helped against many types of cancer, but they don't work for everyone. And it's very important for matters of cost, quality of life, and really, the quintessential risk-to-benefit aspect of treating cancer with immunotherapy, or any other kind of therapy, that we have ways to predict which patients are most likely to benefit from the current immunotherapies. So one clue is that patients with the so-called killer T cells or effector cells or cytotoxic T lymphocytes in their tumors are more likely to respond to checkpoint immunotherapy, and indeed, other immunotherapies, than those who do not have such killer T cells or cytotoxic T cells infiltrating into their tumors.

How can we tell who will respond to immunotherapy? Well, there are many, many lines of investigation that have been directed towards answering that question. And as yet, there are no simple designs for doing a blood test or even a tumor biopsy and being able to say, this person has a 90%, this has a 50%, this has a 20% chance of responding to a given immunotherapy. It's complicated. And the interactions are between the host, the patient with cancer, the treatment that you're giving, and the biology of the tumor.

Traditionally, biopsies have been used to analyze the disease. But we don't routinely use biopsies over and over again to assess whether a patient is responding. We tend to use physical examinations and traditional scanning, such as CT scanning, sometimes MRI. We now have a technique called positron emission tomography, or PET, which is based on a radioactively labeled substance that has some particular characteristic of visualizing tumor or visualizing some component of tumor– or in the case that we're going to be talking about, killer T cells or cytotoxic T cells that may be going to or present in the tumor– as ways to detect the likelihood that a patient will respond to a given treatment. And those scans can be repeated over and over, and they can be correlated with biopsies if necessary, and they can also be correlated with other types of scanning so that you can get a complementary look at what's happening in the patient and in the patient's cancer.

So PET scans can be used not only in the traditional fashion, to look for the amount of metabolic tissue is present in a tumor, which is the classic FDG or fluoroglucose PET scan. But we can also label a number of different tracers with something radioactive and set the camera in such a way that one can really track the appearance of such things as cells going into a tumor or other aspects of cancer cells that are much more specific. For example, in prostate cancer, there's a type of PET scan that can trace specifically where those tumor cells go in a fashion that's more specific than, for example, an FDG PET scan would be for melanoma or lung cancer, where it's simply the metabolism of the tumor cell that's being detected.

In this particular case there are several companies, but the one that we'll be talking about today is ImaginAb, who has developed a very favorable and optimally used form of a fragment of an antibody that is against these CD8 cells. These are the cytotoxic T cells that attack tumors if everything else is all lined up properly. And the way that this PET tracer works is that it allows the detection of CD8 cells wherever they are. But if they're congregating in tumor, in large quantities in a tumor, then you've got enough of these cells in one place that you can actually visualize them on the PET camera, which would not be the case if you're just detecting them floating around in the blood, where their concentration would be far too dilute to be able to pick up. So you can really detect a signal over the noise with these effector T cells, these CD8 T cells that are going into the tumor.

What we don't know at this point, of course, is how many of the CD8 cells need to be in a tumor in order to predict that that tumor is going to be killed by the CD8 cells. And importantly, only a particular fraction of those CD8 cells will be specific to the antigens of the tumor. And that may in fact be an important factor in determining how useful these types of PET scans are for predicting the likelihood of a response to therapy, as well as subsequently tracking the response itself. For example, if a lot of CD8 cells can be detected in the tumor, but a different kind of scan actually shows that the tumor is smaller than it was when it started, when the therapy was started, then of course, that's generally a very good sign.

And so here, on this slide, you can see this fraction of an antibody that has been engineered to optimally traffic to the tumor, and not to other tissues, where we don't particularly want these isotopes to be emitting the radioactivity. Although the amount of radioactivity for these tracers is extremely small. And so, this is the CD8-targeting, engineered, antibody fragment here. This is the CD8 on the so-called killer T cell or cytotoxic T cell. And this is some other aspects of its mechanism for recognizing tumor antigens, which I think was more clear in this slide.

This is the T cell receptor, where a tiny fragment of a tumor antigen is expressed on the tumor and can be recognized by this T cell receptor. So here, you see this CD8-targeting, engineered, antibody fragment, which at this point is simply circulating through the blood, because these are administered intravenously. And then, as you can see, through the antibody, a fraction of this engineered structure will recognize the CD8 portion of this antigen, recognizing an effector machinery on the cytotoxic T cell.

And bang, signal. So signal is shown when– I mean, the signal is already there. So these antibody fragments are already labeled with– in this particular case, it's a zirconium-89 label. And the signal is not turned on, per se, by the interaction of this structure, this construct, with the CD8 determinant on the T cell. But the point of this, I think, is to illustrate that if you get enough of these engineered antibody structures on the CD8 molecule of these cytotoxic T cells, and they are congregating in the tumor or anywhere else– for example, they may be congregating in the spleen or in a lymph node– then you should see a strong enough signal that it will shine over the background noise, which should be trivial for the scanning isotope. And in fact, that's how it works.

As you can see from this picture, using these PET scans to analyze immune activity, you can see that as one would expect– so this scan has probably been done a few days after the initial injection, because after the initial injection, what you'll generally see is something going to the liver and the spleen, and sometimes, a bit of the lungs. And then you get a little bit of something in the intestine.

But here, after you wait for some of those organs that are sort of non-specifically taking up any kind of an antibody structure, you will see that if you look closely, that the tumor nodules have also become so-called hot or illuminated by this isotope. And you can see in this particular case, it– I don't know what the case is, but interestingly, I predict that it could be something where a tumor started in the leg and may have gone initially to the inguinal lymph node, and then sort of marches up the iliac nodes and up the retroperitoneal nodes up into this area near the liver. So that's just an example.

Now, you know, how clean or how dirty these scans look will depend in large part on characteristics of the isotope and the antibody structure. So I can't tell you, for example, whether some of these so-called hot spots are real, or if they're simple inflammatory, or if they're purely artifact. And only time and experience will allow us to understand that better.

There are a number of other clinical applications of engineered antibody fragments which are also of great interest. So in addition to enabling the detection of these cytotoxic or killer T cells within tumors, or in their draining lymph nodes, the platform can also be used to aid in the analysis of other important molecules that may determine immune outcomes. So for example, cancer cells, as well as other cells in the immune tumor microenvironment, may express PD-L1, which is a ligand– L stands for ligand– for the PD-1 molecule– PD stands for "programmed death". Sometimes, these T cells have been stimulated overly actively and repetitively by their antigen, which is here on the cancer cell.

Right here, you see the T cell receptor, as we saw on the other slide. And this is the major histocompatibility complex determinant here on the cancer cell. And this tiny little triangle here is a tiny peptide or a very small piece of a protein that's an antigen. All it takes is a very, very short little fragment to endow this interaction with an enormous amount of specificity. But if the cancer cell expresses PD-L1, or if other cells in the tumor microenvironment also express PD-L1, and if this so-called exhausted or used up or overly stimulated killer cell starts to express PD-1, then sort of a stop sign will occur, in which the normal machinery in the T cell involved in activation or cytotoxicity, or killing, against a cancer cell will actually be lost. And in fact, the tumor– sorry. The T cell may undergo programmed cell death or apoptosis.

So what happens in the case of these protein interactions is that many of these immune checkpoint antibodies that we've been talking about interrupt this precise interaction between PD-L1 and PD-1. Of course, the story is not nearly as simple as that. But it's a good schematic. And we can– there have been a number of engineered antibody endeavors that are directed at assessing the expression of PD-L1 or PD-1 in this setting, and also predicting whether an effective immune response will occur, or whether it will be an ineffective, futile immune response that will leave the tumor unabated.

Other kinds of determinants on cancer cells or T cells can also be studied with these various engineering strategies. And they're all ongoing at this point.

In addition to those immune determining molecules, such as we talked about, are also, again, antibodies– sorry. Tumor-associated antigens. I glossed briefly over the concept of the prostate cancer specific PET scanning, although it shows up here. The PS– prostate membrane antigen, prostate-specific membrane antigen. And HER2, which is an important antigen, predominantly on breast cancer cells, but there are many other cancer types that can express HER2, in much lower quantities than does the HER2-positive breast cancer. And then CA19.9 is another determinant which is used for pancreatic cancer and other GI cancers.

So I would say, stay tuned for a number of other types of engineered antibody fragments that can be labeled with these PET tracers that can then be used to either, as standalone or to complement other kinds of scans, that will allow the best, more of a functional than a purely structural, dissection of what's happening at the level of the tumor, and ability to either predict before treatment or to trace or track during treatment the possibility of an effective response to a particular intervention.

So I think we talked about the first two bullets. PD-L1 expression, PD-1 expression. These cancer-associated markers. And then finally, there are other immune cells and immune cell-related markers. Every time you turn around, there's a new one that's been described or a new function of one that's already known. And they may be present. It wasn't shown here on these pictures, which would have been rendered far too busy, but dendritic cells have determinants. This is the classic nature's antigen-presenting cell that really teaches the T cell what to do.

And then, often, T cells teach B cells or other T cells. Natural killer cells may turn out to be a very important component of our immune system, particularly in the initial antigen-independent control, until the T cell gets going. And then, macrophages have a number of roles. They may be related in some ways to the dendritic cell, but they have both stimulatory and suppressive effects in the tumor microenvironment, some of which may turn out to be readily traceable with these PET-based systems, where you may be able to distinguish between a macrophage that is promoting an anti-cancer tumor immune response versus one that is doing just the opposite and suppressing the immune response in the tumor.

So with that, I'll just kind of conclude that the future of imaging in immunotherapy could help in our understanding of a variety of immune-related processes in cancer. And it's certainly going to be– comparison with serial biopsies– a safer and easier way to monitor patients and to gain an understanding of the biology of their disease and its treatment. These modalities may inform future clinical decision-making, both for newly diagnosed individuals or for patients whose cancers are treatment resistant. Again, as I mentioned, monitoring treatment responses in patients who are on immunotherapy– what I call the dynamic use of these agents– and then ultimately guide the hypotheses behind the development of the next generation of immunotherapies and of imaging modalities.

Brian Brewer: Thank you so much. That is so, so interesting. I wondered, you know, in the very beginning, you talked about other or current, existing scans, so biopsies, and PET scans– I mean, CT scans. Will this replace that? Or do you see this all being used together in the arsenal for the oncologist?

Kim Margolin, MD: Well, I think initially, given that all of these scanning techniques are investigational, I think that they will complement both other radiologic types of analysis, particularly CT scans and FDG PET scans, as well as occasional MRI or other ultrasounds. Because we first need the proof of the concept that tracing CD8 cells or tracing some of these other markers for tumor into the tumor actually has a correlate in both predicting the likelihood of response, based on what the initial appearance of the milieu inside the cancer cell may be, and maybe the tumor-associated lymph nodes. And then being able to say, OK, if the density of the CD8 infiltrate is over a certain level, that you'll have to quantitate based on the SUV, as it were, some kind of estimate of the brightness. That would portend a certain level of likelihood that the patient is going to benefit from the therapy.

Once those kinds of things are validated with, you know, numerous cases and properly designed trials, then it may move into the position of being able to supplant or replace some of the scans, and maybe ultimately, all of them. Maybe we'll be doing that instead of biopsies at some point. Because it may be– well, I don't know about the CD8 per se, but if we have other scans– or it–

Maybe someday, we'll have some kind of a multi-channel scanner, such as we do with the immunohistochemistry of tumors, where we can literally use several different fluors or several different materials that fluorescence at different wavelengths. And we can sort of overlay these beautiful pictures that allow us to assess which cells are in the tumor, and how close they are to each other, and how they may be interacting functionally. Maybe someday we'll be able to do something like that with these PET scans, where we can look at the antigen and we can look at the CD8 cell and we can look at the PD-L1 expression all at the same time, and be able to really get a sense of the complex tumor milieu, and what we can say about how it's going to behave in response to treatment.

Brian Brewer: How far away do you think we are from wider adoption of something like this in the clinic?

Kim Margolin, MD: These days, predictions about how far we are away from anything, I don't know. I would say a couple years. You know, it's going to take a while to accumulate these data and to really corroborate them. You know, when you're only looking at one factor– so we know, for example, from all the biopsy work, that CD8 cells in the tumor versus around the tumor versus nowhere in the neighborhood– those are kind of the three levels– are one of many factors that predict certain tumors' responsiveness to certain therapies. The tumor mutation burden, the expression of PD-L1, and other aspects of the immune milieu are also important. And mutations in the tumor cells, their tumor-associated macrophages, type 1, type 2 cells, all of those things are contributing. And it's likely that the equation won't be the same for multiple tumors. One tumor may depend more on one factor. Another may depend more another factor.

Brian Brewer: Do you– do you see this being applied to also track regulatory T cells? Is there any harm in saying, wow, OK, now, we can really see what the mixture of–

Kim Margolin, MD: Oh, yeah.

Brian Brewer: T cells is in that tumor?

Kim Margolin, MD: I'm sure if we can– I'm sure if we can track CD8 cells, we can also track certain kinds of CD4 cells, which contain the regulatory T cell population. And of course, none of these had– none of these cell types is unique and always the same. CD4 cells in particular are very plastic. And even Tregs can vary in their functions. And B cells and so forth. There are a number of other cells that will exert important actions.

Brian Brewer: And of course, I have to ask, what about micro metastases? Can those be tracked down, perhaps, with radiolabeled antibodies?

Kim Margolin, MD: Yeah, I don't– I don't think that we're even ready to talk about that quite yet. You'd have to have– I think you'd have to have some kind of an amplification step, kind of like the old style autoradiography, where you had to pre-expose the film and amplify the signal so that you could see it. Patients often ask, well, doc, wouldn't it be better to do a PET scan than a CT to detect– you know, whether you have a tumor? Doesn't it pick up really small amounts of tumor? The answer to that is actually, no. You have to have a PET scan– depending on the avidity of the tumor.

Melanoma, the field in which I mainly work, is particularly FDG-avid. And so it may be that much smaller lesions will pick up enough of the FDG to show up on a traditional PET scan, whereas other tumors that are far less FDG-avid are not going to do that. And you need a bigger tumor to just get enough isotope there.

Just as I was saying earlier, you need enough of those CD8 cells congregating in one spot to pick up the signal. And we don't know how many CD8 cells you need per whatever geographic unit you want to measure in order to be associated with a favorable response. So there's a lot we don't know.

Brian Brewer: Right. You– so you mentioned how it works, where it's radiolabeled, and it attaches to the CD8 receptor on a T cell. Are there more than one CD8 receptor on T cells? Like, can you have 10, 20 of these antibodies?

Kim Margolin, MD: I'm sure there are. I don't know exactly how many there are in a given T cell.

Brian Brewer: Wow, OK. Great mystery of the field. Let's see. We have another question. Oh. Yeah. Actually, do you think– let's just– let's just focus. I know you're looking at a lot of different factors in order to validate this, but right now, it's in a phase– you're in a phase 2 study, correct?

Kim Margolin, MD: Basically, it's a phase 2 study, because– I mean, it's hard to use traditional phase nomenclature to designate these studies, because they're not therapeutic. This one's called phase 2. They call it baseline and on therapy, BOT, because they're talking about when you do the biopsies, the validated biopsies. And it's phase two because the patients are actually getting a treatment while they're doing these scans. So they're getting standard of care therapy with immune checkpoint antibodies. And then we are basically corroborating the appearance of those are zirconium⁸⁹ CD8 scan with the disease assessments that we would do traditionally as part of our standard of care.

Brian Brewer: And has it so far affected your treatment decision for any one of your patients?

Kim Margolin, MD: No, because that's not what's supposed to be happening. We're supposed to be purely doing what we would do as part of our standard of care. And then this is a parallel path. And then at the end of the day, when we've treated the 40 or 75 patients in the study, we will go back and see what– because if you– the thing is, in any kind of a phase 2, if you start looking early at the results, and then you start changing your practice based on ongoing results, that becomes a bias in itself and that may alter the results of the study. So you shouldn't do that.

Brian Brewer: Scientific method. There we are. Well, that's all the time we have. I don't know if there's any last bits of advice you'd like to give the patients and caregivers who are watching this. It sounds like it's still– the technology you're using is still a little far off from the community oncology office. Unlikely that they'll encounter this there. So how would you set their expectations about either this or what kind of technology they are likely to encounter?

Kim Margolin, MD: I think that, to be optimistic, I think we should say that we have some very exciting methodologies that are in development. They're looking very promising. And that the only way we can learn enough about these to hasten their appearance in the clinic and their use in the proper setting is to enroll patients in these trials. So patients should be encouraged to enroll in trials for first line, second line, every line therapy, not just wait til later on. As it says at the bottom of every page of the National Comprehensive Cancer Network guidelines, the best therapy for any kind of malignancy is enrollment in a clinical trial. And that's really, truly the case.

Brian Brewer: Wow. Thank you so much. That's all the time we have for today's webinar. And just wanted to let folks know that if you want to watch this or other webinars in our series, you can do so at cancerresearch.org/patients.

This webinar series is part of our broader Answer to Cancer Patient Education Programming. These include our immunotherapy clinical trial finder, which Dr. Margolin just referenced. If you are looking for a clinical trial or looking for options for yourself or a loved one, we do provide a free service. And you can speak to someone on the phone, and they can help you navigate what can be a very confusing process. We also have other resources, as well as a community of patients treated with immunotherapy who have shared their stories, either in video or written form. So you'll learn an awful lot there. And then there's more, of course. Again, that's cancerresearch.org/patients.

Once again, I'd like to thank our generous friends at ImaginAb for making today's webinar possible. And I'd also like to thank BioRender, which has provided some of the imagery that you saw in today's webinar. And with that once again, Dr. Margolin, thank you so much. And we'll be sure to look forward to the outcome of this exciting trial in the future.

Kim Margolin, MD: Thank you very much for inviting me to participate in this webinar.

Brian Brewer: Goodbye, all.

Kim Margolin, MD: Bye.