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Blood Tests and Immunotherapy: New Approaches to Diagnosing and Treating Cancer Patients

Blood-based tests offer incredible potential in cancer immunotherapy. By monitoring a variety of factors, especially at the genetic and genomic levels, these tests can give doctors deep insights into a person’s cancer and their immune health.

In this webinar, Elsa Anagnostou, M.D., Ph.D., a Cancer Research Institute (CRI) Clinical Accelerator Clinical Investigator at Johns Hopkins Medicine, explains the science behind these blood tests—also known as liquid biopsies—and highlight the ways they’re being explored in clinical trials.

Among other work, one application that Anagnostou is investigating in a CRI study is whether or not blood tests for circulating tumor DNA (ctDNA) could allow for earlier detection of immunotherapy responses in people compared to current imaging technologies. If so, it could provide doctors with more timely information that enables them to adapt their approaches more effectively. In addition, these tests may also allow for earlier diagnosis, and identify biomarkers that guide doctors as far as which strategies are most likely to work for which individuals.

Dr. Elsa Anagnostou directs both the Thoracic Oncology Biorepository and the Molecular Oncology laboratory at Johns Hopkins, and is an assistant professor of oncology at the Sidney Kimmel Cancer Center.

The “Cancer Immunotherapy and You” webinar series is produced by the Cancer Research Institute and is hosted by our senior science writer, Arthur N. Brodsky, Ph.D. The 2021 series is made possible with generous support from Bristol Myers Squibb and Alkermes.

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.

Bristol Myers Squibb

Alkermes

WEBINAR TRANSCRIPT

Arthur Brodsky, Ph.D.: Hello, everyone, 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 “Blood tests and Immunotherapy: New Approaches to Diagnosing and Treating Cancer Patients.

Over the next hour, we'll hear from a leading cancer immunotherapy expert about these important emerging technologies and their potential applications in cancer immunotherapy. In particular, we'll look at how they compare to current approaches and the potential advantages that they offer when it comes to earlier detection of immunotherapy responses, predicting which therapies will work best for which patients, diagnosing cancer earlier, and designing personalized immunotherapies for patients. Before we begin, I'd like to quickly thank our generous sponsors, Bristol Myers Squibb and Alkermes, who made this webinar series possible.

And now, it is my pleasure to introduce Dr. Elsa Anagnostou, who is the director of the Thoracic Oncology Biorepository and the co-leader of the Molecular Tumor Board at Johns Hopkins Medicine, as well as an assistant professor of oncology at Johns Hopkins’ Sidney Kimmel Comprehensive Cancer Center. She also leads the Molecular Oncology Laboratory at Hopkins, where she seeks to understand the genomic factors of response and resistance to immunotherapy by using cutting-edge tools to analyze tumor and immune evolution. To that end, she's currently leading a CRI-funded trial that's exploring whether blood tests might enable doctors to detect immunotherapy responses in patients earlier, which we'll discuss soon.

So thank you for joining us, Dr. Anagnostou.

Elsa Anagnostou, M.D., Ph.D.: Thank you, Arthur, for the very kind introduction. And I would like to thank the Cancer Research Institute for sponsoring this webinar on the clinical utility of blood-based testing in the context of immunotherapy. So let's get started.

Arthur Brodsky, Ph.D.: Glad to have you. And I just want to let our audience know before we begin that there are live closed captions and subtitles available with today's webinar that you'll be able to find on the bottom right of your Zoom window, where it says CCs. And there are settings in there also, if you need to make them bigger or anything. So let's start by defining what we're talking about. What are blood-based tests, otherwise known as liquid biopsies, and what kind of important stuff is in the blood that we want to measure when it comes to cancer and the immune system?

Elsa Anagnostou, M.D., Ph.D.: So molecular profiling of biofluids, blood being one of them, has gained momentum. And these approaches are collectively described as liquid biopsies. Liquid biopsies for cancer, for the most part, fall under three main categories, depending on the source of the tumor-derived material. And these are circulating tumor DNA, circulating tumor cells, and tumor-derived exosomes. So let me tell you a little bit more.

Tumors routinely shed intact whole cells called circulating tumor cells, or CTCs. They also shed small packages that contain tumor material. These are called exosomes. They also shed cell-free DNA, all this into the bloodstream, which can then be, quote unquote, biopsied by means of liquid biopsy, compared to a traditional tissue biopsy. And this liquid biopsy can be analyzed to provide valuable information such as changes in the genetic material associated with the patient's cancer.

And specifically related to immunotherapy, as the individual's immune system is activated to fight cancer cells, changes in levels of specific immune cell types in the blood, this may be reflective of an effective anti-tumor immune response. And for instance, the neutrophil to lymphocyte ratio has gained some interest as a biomarker for immunotherapy. That can be easily calculated from a standard complete blood count by regular blood draw. However, these approaches on the immune cell types are not supported by a large body of data, and more work remains to be done to prove their clinical utility.

More recently, the concept of liquid biopsies has practically become synonymous with analysis of circulating tumor DNA. And that's what would be the focus of our discussion today. So let me start by describing what circulating DNA is. Cell-free DNA, or cfDNA, is released into the bloodstream from dying cells. And a small fraction of this shredded cell-free DNA is tumor-derived, called circulating tumor DNA, or ctDNA. ctDNA can be extracted from blood, can be amplified, sequenced, and bioinformatically analyzed, and ultimately interrogated for the presence of changes in the sequence or structure of DNA known as mutations.

Arthur Brodsky, Ph.D.: Gotcha. So as you alluded to, all this information can tell doctors a lot about someone's cancer and the mutations that it has, which can, in some ways, kind of shed light on the tumor's identity, if you will. Before-- as you mentioned, doctors had to take samples of the physical tumors themselves to learn about this genomic information. So what are the potential advantages of being able to do this, to get this information with a simple blood draw instead?

Elsa Anagnostou, M.D., Ph.D.: Let's start by talking about the history of liquid biopsies and their current use in clinical cancer care. Liquid biopsies were introduced as a complementary approach to tissue biopsies in cancer patients. And currently, in clinical practice, they're used to determine whether patients with advanced cancers may be candidates for targeted therapies. And there are currently FDA-approved liquid biopsy tests that are used to detect genetic abnormalities in circulating tumor DNA for multiple cancer types. And while genetic testing of tissue biopsies, as we said, Arthur, remains the gold standard, liquid biopsies are easily obtained by a simple blood draw, and typically have a faster turnaround time. And while liquid biopsies may not always be as comprehensive as tissue testing, they sufficiently capture the genetic footprint, if you will, of cancers, especially in later stages.

So liquid biopsies actually offer a significant step forward because they're less invasive, they typically have lower cost compared to tissue analysis, and importantly, they provide real-time insights into tumor status, into cancer status. And compared to what I call snapshot tissue testing, liquid biopsies allow for minimally invasive monitoring of response to therapy and a more accurate representation of tumor heterogeneity and changes in cancer biology during therapy, and under selective pressure any type of therapeutic. And of course, with emerging improvements in technology and development of ultrasensitive next-generation sequencing methods and expedited turnaround time, liquid biopsies are now utilized more broadly, with the general feeling being that they may overcome the limitations of traditional tissue biopsies.

And again, the important advantage here is that liquid biopsies can be obtained repeatedly. Over time, during therapy, monitor cancer's response more, or pick up additional alterations that are related to resistance to therapy. And importantly, we've seen this in the context of both targeted therapy and immunotherapy. In the vast majority of cases, emergence of resistance mutations or resistance mechanisms is detected months, or even more, before we see appreciable changes on imaging. And there is a multitude of research studies now that support the clinical utility of liquid biopsies at almost every stage, practically, of the management of patients with cancer, including diagnosis, detection of residual disease, response monitoring, and identification of resistance.

Arthur Brodsky, Ph.D.: That's great to hear, and it sounds like it offers benefits not only to the doctors, but the patients, as well. It's kind of a win-win. Before we go on, you mentioned tumor heterogeneity, and I was wondering if we could just back up for a second, if you wouldn't mind just explaining to our audience what you mean by that.

Elsa Anagnostou, M.D., Ph.D.: Yeah, absolutely. So sometimes when we obtain a tissue biopsy, this is subject to sampling bias. And we are analyzing a very small piece of the tumor, and we are making, potentially, a therapeutic decision based on the molecular analysis of the small piece of the tumor, which may not actually be representative of the whole tumor. Now, the benefit of actually using blood-based approaches is that blood is the pool, is the reservoir where tumor cells from multiple sites may shed DNA. And then by analysis of tumor DNA identified in the circulation, we may be able to capture what we call tumor heterogeneity, which is, practically, different parts of the tumor not being exactly identical in terms of their molecular profile.

Arthur Brodsky, Ph.D.: Great, thank you. So now with respect to immunotherapy in particular, what might be some of the advantages of these liquid biopsies, the blood-based tests?

Elsa Anagnostou, M.D., Ph.D.: So as I said, liquid biopsies provide a less invasive means to track cancer status. And there's actually a lot of excitement in the cancer immunotherapy field because, in contrast to traditional biopsies, which, again, provide a snapshot of the tumor characteristics, liquid biopsies may generate a more complete picture of lung cancer, as we just discussed. And what I want to emphasize here is the following. Immunotherapy poses a challenge to the well-established concept of assessing clinical response based on radiographic imaging. Conventional imaging, say CTs, and imaging-based response criteria may underestimate the benefit from immunotherapy and the unique timing and patterns of response on immunotherapy.

And in addition, in looking at the landscape of immunotherapy clinical trials-- and the Cancer Research Institute iAtlas Initiative is actually a fantastic platform to visualize the space of IO clinical trials-- it's pretty obvious that we are nearing trial fatigue, with thousands of trials. And that truly highlights the unmet need-- the urgent need, I would say-- for molecular real-time biomarkers to guide therapy. And liquid biopsies are an emerging, very powerful tool to help navigate through the available therapies and available clinical trials in the IO space.

Now of course, there is a growing body of evidence that again supports the clinical utility of ctDNA, now in the context of immunotherapy. We and others have observed distinct patterns of ctDNA dynamic changes during therapy that are ultimately reflective of clinical outcome. And these are as follows: individuals with a significant drop or clearance of circulating tumor DNA tend to achieve long-term clinical benefit from immunotherapy, but in contrast, in individuals that do not respond to therapy-- and we call that kind of resistance-- ctDNA levels have limited fluctuations or actually display a rise after therapy initiation.

Arthur Brodsky, Ph.D.: Wow. And so speaking of clinical trials, right now, you're leading a Cancer Research Institute trial that's determining if these blood tests could enable quicker detection of immunotherapy responses in patients compared to the traditional scans, the CTs that you mentioned. And specifically, you're measuring the circulating DNA of patients who have metastatic lung cancer that expresses-- that has high levels of the marker PD-L1, which is what a lot of the checkpoint immunotherapy targets. So in this context, why would it be helpful to detect these immunotherapy responses sooner in these patients?

Elsa Anagnostou, M.D., Ph.D.: This is a very important point. And I would like to add here, that liquid biopsy is captured clinical outcome and response to primary resistance to immunotherapy sooner, as you said, but also in a more accurate manner, compared to imaging. And that again, is extremely important with an increasing number of studies, suggesting that blood-based tests can change the way cancer patients will be treated by helping to evaluate therapeutic responses quicker, in a more accurate manner, and avoid unneeded toxicity, and a treatment that may actually be ineffective.

And as I mentioned before, accurately assessing who may be benefiting from immunotherapy by imaging is challenging, as the change that we see in tumor size on imaging may actually not reflect the anti-cancer effect, because of immunotherapy. So we truly need objective biomarkers that accurately capture tumor burden, to inform us whether a patient is responding to therapy.

And again, this is very important, because it opens the therapeutic window of opportunity, in which changes in liquid biopsies may allow patients with primary resistance to be rapidly identified, and redirected to get another therapy that may be more effective. And it's also crucial in order to avoid toxicity, and also from a cost effectiveness standpoint.

So you can imagine that oncologists may gain a new more reliable, less costly, less invasive means to help them reliably identify much earlier in the patient's disease course, whether treatment with immunotherapy may be effective, or another intervention or a therapeutic option may offer a better alternative. So with support from some of the Cancer Research Institute, we have incorporated liquid biopsies in a clinical trial for lung cancer patients on immunotherapy.

This is primarily run through the Canadian Network, CCTG. And in this trial, changes of ctDNA are used to determine ctDNA response, which we term molecular response, and identify patients that may continue on an effective therapy, or switch to another treatment regimen. And in particular, we're asking the following question: which treatment naive PD-L1 positive advanced lung cancer patients, as you mentioned Arthur, can be treated with pembrolizumab alone, or go on intensified therapy, such as pembrolizumab and chemotherapy.

And such clinical trial design in general, allows for rapid identification of patients that are less likely to respond, who can then receive potentially more efficacious therapies. And again, I cannot stress this point enough, avoid treatment related toxicity, and financial toxicity.

Arthur Brodsky, Ph.D.: And I just want to follow up on that real quick, because you mentioned something at the beginning that I just want to make sure our audience, that that was clear to our audience, where the imaging doesn't necessarily always accurately reflect. The imaging sees if the tumor gets bigger or smaller, but sometimes, I think what you're referring to, I just want to confirm that you're referring to the phenomenon of pseudoprogression, where sometimes, even if the immunotherapy is working and it's stimulating the immune system, it sometimes can make the tumor bigger at first, because it swells up.

And before, years ago, it took a minute I guess to recognize that just because it was getting bigger, doesn't mean the treatment is not working. So that could be an additional thing where you-- the doctors may not think a treatment's working, and so they subject the patients to another treatment when it really was working. Is that what you're referring to?

Elsa Anagnostou, M.D., Ph.D.: That's correct. And pseudoprogression, I think it's the extreme of how bad imaging is actually in determining response. And so there is this, as you're saying, while this well-described phenomenon mainly in melanoma, we don't see it in all tumor types. It is relatively rare in lung cancer, where what you see is this flare on imaging.

And practically, this is not because the tumor is progressing and spreading, but this is because there is this huge recruitment of the good cells, the fighters of the immune system that come to the tumor site, and actually do what they're supposed to do, which is destroy the cancer cells. So this is one potential field for error for clinical utility, for liquid biopsies.

But what I also want to stress out is that imaging is unreliable in general in the setting of immunotherapy. And for the most part, we see that in patients that have stable disease to therapy. But in these patients, if one looks at liquid biopsies and trends of mutations over time, patients can actually be classified into molecular responders or molecular nonresponders, and this is reflective of their long-term clinical outcome, although they're all grouped together as stable disease by imaging.

Arthur Brodsky, Ph.D.: Great. So now sticking with-- I'm going to focus on the CRI trial that you are leading. What specific ctDNA markers are you measuring and tracking in this study? And how do you know that they're from cancer? Because as you mentioned earlier, there's all sorts of DNA in the blood. And then also, after you explain what these markers are, what exactly constitutes a response as far as influencing the clinical decisions that the doctors would then make?

Elsa Anagnostou, M.D., Ph.D.: So in this trial, this ctDNA informed clinical trial, we are tracking levels of mutated circulating tumor DNA as a proxy for tumor burden. So we're tracking mutations and levels of mutations. And in the trial's first stage, we will identify whether testing blood for evidence of tumor DNA can identify which patients will benefit better than imaging, related to what we were just discussing about how bad imaging is in determining responses.

And in the trial's second stage, we will prospectively examine whether these patterns can effectively guide therapy for patients with lung cancer. And in the second stage ctDNA analysis, again, levels of mutations and molecular response assessments based on levels of mutations, these will be used to determine whether a patient should receive immunotherapy alone, or we escalate to immunotherapy and chemotherapy.

You're bringing up a very important question on how-- well, several important questions, starting with the original variant. So actually, let's go through so how do we know what is the origin of mutations detected by liquid biopsies? In other words, is everything detected and recorded by plasma NGS tumor derived? Does it come from the tumor?

And one has to remember that the majority of cell-free DNA in plasma is released from blood cells, not tumor cells. And therefore, any blood-based next-generation sequencing approach has the potential to detect mutations that come from blood cells. This is a phenomenon we call clonal hematopoiesis. And these can actually be misclassified as tumor-specific.

To overcome this issue, one would have to perform sequencing of both plasma cell-free DNA, and the cells in the blood, white blood cell DNA, from the same individual and the same blood draw, in order to determine the origins of mutations and cell-free DNA. And that's exactly what we're doing for the ctDNA trial that we have been talking about.

And then of course, comes the very important, the million dollar question that you asked, which is, what is molecular response? So significant drop, or clearance of ctDNA has been shown in a pretty consistent manner to predict response to immunotherapy, especially in the lung cancer space. And one concept, I just want to point this out that, as a field we may agree upon, it's not a single molecular response. But it is that of molecular progression, where there is no change, or there is actually an increase in ctDNA levels.

And one approach would be to identify and intervene on these high-risk patients that do not clear ctDNA, or in which ctDNA does not drop. For example, early lack of response on single agent immunotherapy may warrant addition of chemotherapy, as in our trial, or a second immune checkpoint inhibitor. And I would like to take the opportunity here and highlight an important initiative that focuses on getting answers to these exact questions, origin of mutations, what is a ctDNA response, what is the clinical utility of ctDNA dynamics as a predictive biomarker for cancer.

So Friends of Cancer Research have launched the CT monitor project, which is an effort to pool published and unpublished cohorts with serial measurements of ctDNA, in order to understand the clinical utility of ctDNA in the context of immunotherapy, and other cancer therapies. And more to come from them on this subject.

Arthur Brodsky, Ph.D.: Great. And before we go on, I just wanted to let our audience know that you all can submit questions either through the chat box, or the Q&A box at the bottom of your screens. So now, I want to turn to the patient involvement, and the education, and the empowerment side of this equation.

What else do patients and doctors learn from these blood tests, from this trial, and in general? And more importantly, how do doctors communicate this information to patients? And what information is actually given to the patients?

Elsa Anagnostou, M.D., Ph.D.: So there is a wealth of information that can be derived from liquid biopsies, and looking broadly at circulating tumor DNA, and that has to do with tumor mutation, how many mutations are identified, as well as the specific potentially targetable alterations that may be therapeutically leveraged. And all this is communicated to the patients by their physicians. And other than this kind of pre-treatment molecular profile, changes of these characteristics in ctDNA can also be very helpful to patients, and their treating physicians, and help them navigate through different therapeutic options.

I want to stress out how important it is-- and I think you alluded to that, to carefully interpret liquid biopsy results, and then communicate that in a meaningful way with our patients. We talked about the challenges related to detection of mutations that do not originate from tumor cells, but are found in the plasma. That's a very important point to understand. And distinguishing these mutations in cancer-derived DNA from mutated DNA carried by non-cancerous blood cells, this is a newly appreciated—

Arthur Brodsky, Ph.D.: And just to clarify, these blood cell mutations are a normal part of immune cell development, correct?

Elsa Anagnostou, M.D., Ph.D.: This is typically normal what we see in the context of aging. So as we age, we tend to accumulate these mutations in blood cells. It becomes complicated for cancer patients, especially if they have received radiation or chemotherapy, because these approaches can actually prime the development of what we call clonal hematopoiesis mutation.

So it's a real problem, understanding what is the origin of what it is we're seeing in a liquid biopsy next-generation sequencing report. It's a true challenge. And you can imagine that these blood-derived mutations can actually confound the actual calling of ctDNA molecular response, right? So if you're not tracking the right variants, the right mutations, you would probably not make the right determination whether the patient molecularly is responding.

And another thing to consider and communicate with our patients here is, what does a negative liquid biopsy mean? What does it really mean? A negative liquid biopsy-- and just to be clear what I'm referring to here, is no mutations detected in the liquid biopsy assay. That has to be interpreted with respect to the sensitivity of the assay that was used, and the cancer type and stage of the patient. And we know that some cancers, for example, shed more than others. And there is obviously incremental increase in ctDNA levels with more advanced stage. So a negative liquid biopsy does not prove that there is no circulating tumor DNA. It actually, what it says is the following: ctDNA is undetectable with a particular assay, in a particular individual, in a particular time and point in their disease and treatment course.

And I cannot stress enough how important it is what you said, which is the careful interpretation and communication of liquid biopsy findings. And this can also be done by molecular tumor boards. And these are tumor boards which leverage multidisciplinary clinical and cancer genomics expertise to actually dissect DNA next-generation sequencing.

I'm leading such an effort at John Hopkins. And there are several other institutions that have implemented such approaches in their clinical workflows. So continued education of the medical community, our patients, and patient advocates is key.

Arthur Brodsky, Ph.D.: Great. So now, you touched on it briefly, but most of this time we've been talking about patients who have already been treated, and then trying to detect responses, or lack thereof, after they've already been treated. But what about using them in advance to kind of guide the treatment, as you kind of touched on a little bit. Could these identify genomic biomarkers that could then guide treatment?

I guess I'm thinking specifically of the genomic biomarkers that have already been approved by the FDA, such as the high microsatellite instability, otherwise known as MSI high, or high tumor mutational burden, high TMB. Could these blood tests kind of identify biomarkers that might indicate whether a patient is going to respond to immunotherapy, or is more likely to respond to immunotherapy?

Elsa Anagnostou, M.D., Ph.D.: Absolutely. We don't have an FDA approved indication yet. And again, the approved indications, the liquid biopsy as of now, is plasma-based genotyping, the guide targeted therapy. But in the immunotherapy setting, liquid biopsies can be informative in determining the tumor mutational burden, and microsatellite status.

And these features, as you said, are linked with responses to checkpoint blockade. OK. Let's talk a little bit about what tumor mutation burden, or TMB is, and what microsatellite instability, just for context. So tumor mutation burden, it's a measure of the number of mutations carried by tumor cells. And it's practically a measure of tumor foreignness to the immune system. And it's considered an emerging biomarker response to immunotherapy.

However, tumor mutation burden assessment and values can be confounding by sampling bias that we discussed earlier on. And multiple studies now have shown that tumor mutations burden determined by tissue analysis is an imperfect biomarker of response to immunotherapy, as there are tumors in patients with high tumor mutation burden that do not respond. And there are some tumors in patients with low tumor mutation burden that actually derive benefit from immunotherapy.

So it's certainly as a tissue biomarker, it's not perfect. It can be derived from blood-based analysis, but this comes with its own challenges as well. One of the causes of extremely high tumor mutational burden is a genetic condition that predisposes to high mutation rate, because of defects in DNA repair mechanisms. And this is called microsatellite instability.

Patients with high microsatellite instability benefit from immunotherapy, as these cancers harbor a large number of mutations that encode for altered foreign, in a way, proteins that are easy to be recognized and cleared by cells of the immune system. And as I said, tumor mutation burden and microsatellite instability can be determined from liquid biopsies depending on the panel that is used.

And blood-based tumor mutation burden is actually emerging as a biomarker of response to immunotherapy. But there is issues related to reproducibility, standardization of the NGS assay that is used, as well as thresholds to kind of indicate what is high TMB versus low TMB. And certainly, further prospective studies are needed before the clinical implementation of blood derived tumor mutation burden.

Again, I'm going to stress the point that I made at the beginning is that, these are potentially very informative blood-based biomarkers, but they're still kind of snapshot-type biomarkers. And there is a lot of value into tracking how cancer evolves during therapy. And there's therefore, great advantage to studying dynamic measurements of ctDNA features by longitudinal local biopsies.

Arthur Brodsky, Ph.D.: Having a film on this, as opposed to the snapshot that you mentioned earlier. And we actually have an audience question that fits in nicely here. So if someone's not on a clinical trial where they're offering these blood based tests, can patients ask their care teams about receiving these?

Elsa Anagnostou, M.D., Ph.D.: This is a great question. And it also has to do with whether these tests are reimbursed for disease monitoring. And as of now, this is not the case. The FDA approved indication is for blood-based tests is to use as an approach to identify targetable mutations, to then guide targeted therapies.

So can liquid biopsies be obtained during the treatment course? Absolutely. And some institutions, it's style-dependent, as well. Some institutions do it. But there's caveats related to reimbursement of these assays. And then going back to what we were discussing before, as a field, we don't 100% know what constitutes a ctDNA response.

So say we get these serial measurements, there is no consensus as of yet. Although we have great ideas and we think we know what is a molecular response, there is no consensus yet in terms of how to utilize serial liquid biopsies to make therapeutic decisions. It is coming. And certainly with more clinical trials, one of them being the ones that we are doing, this data is getting generated as we speak.

Arthur Brodsky, Ph.D.: That's good to know. So looking even further ahead, could blood tests potentially enable us to detect cancers in their earliest stages when they're at their most treatable? And what is the state of the science of that right now?

Elsa Anagnostou, M.D., Ph.D.: Absolutely. So liquid biopsies most certainly have potential applications in cancer early detection, either as standalone, or in combination with imaging, and other analytes. Detection using liquid biopsy approaches is a very active area of investigation. And there's actually a lot of hype about using liquid biopsies across the spectrum for cancer prevention and early detection.

And you can imagine one approach here being, and I'm going to use the lung cancer screening paradigm, liquid biopsies are combined with imaging, or other analytes to screen individuals at high risk for lung cancer. There's challenges. And I think we should take a few minutes to talk about those. Because one has to be cognizant of the challenges which are related to the smaller tumor volume at earlier stages that requires ultrasensitive assays. And as we discussed previously, cell-free DNA is a mixture of DNA fragments from different sources, of which the cancer-related fragments take up only a very small fraction.

So the levels of these truly needle-in-the-haystack molecules are at times, below the level of detection of current liquid biopsy assays. There are several very promising approaches and significant steps forward, which actually support the potential utility of liquid biopsies in early detection and interception strategies.

And these studies have employed machine learning, which are algorithms that learn to identify patterns in big data. And by these mechanisms, or by these algorithms, genetic and epigenetic features are analyzed, ultimately predicting cancer versus non-cancer status. And approaches that combine blood based multi-cancer tests and imaging, as I mentioned before, have also been reported and hold promise. What would I have to say here is, as a field, we need to conduct more prospective clinical trials to prove that such strategies improve outcomes.

Arthur Brodsky, Ph.D.: That's great to hear. And so on that note, I think you're kind of getting right up to the cusp of it, but I was hoping that now you could kind of just I guess, leave us with your vision and your hopes for where the science and technology of blood-based tests in immunotherapy might head in the near future.

Elsa Anagnostou, M.D., Ph.D.: Absolutely. And the point I want to make is that, we are probably reaching a plateau with sensitivity of mutation-based liquid biopsy approaches. So our kind of traditional approach of tracking mutations and levels of mutations over time. So as we discussed at the beginning, there are blood tests that involve elements other than ctDNA that hold promise, such as circulating tumor cells, immune cell types, and pro-inflammatory cytokines, like interleukin-6, for example. These may be informative as single analytes, or in combination with ctDNA.

Circulating tumor cells certainly hold promise, and certainly, the presence of circulating tumor cells identifies individuals at higher risk of developing metastatic disease. but these particular biomarkers, if you will, are not validated in a prospective manner. So we cannot draw definitive conclusions. There are studies that focus on PD-L1 expression, on circulating tumor cells, or soluble PD-L1, as an alternative to tissue PD-L1 that you mentioned at the beginning.

However, again, findings here are conflicting. And these approaches do not allow us to draw a definitive conclusion. So what I wanted to end with is, discuss the brave new world of next generation cell-free DNA analysis. This is something that we're all very passionate about. And it's very, very promising.  And we're now seeing an increasing number of efforts that analyze additional features of cell free DNA passed mutations and mutation levels. And these have to do with DNA fragment sizes, different motifs in the mutant DNA fragments, epigenetic signatures. And these are all integrated by machine learning methods, as I mentioned before, to actually boost the sensitivity of the traditional driver gene mutation-based liquid biopsies.

We're also seeing the emergence of techniques that focus on plasma methylation patterns, given the differences in methylation profiles between tumor and normal tissue. And one of these efforts are not ready for broad clinical use. There's been remarkable progress. And I'm confident that any technical or practical barriers can be addressed, again, through ongoing collaborative research initiatives and prospective interventional clinical trials.

And I'm going to end with this, as a cancer researcher dedicated to bench-to-bedside translation, I'm truly mesmerized by the wealth and the depth of blood-based tests that truly give us hope for precision immune-oncology, and more broadly, for precision medicine.

Arthur Brodsky, Ph.D.: I think that's great note to end on. And thank you so much for sharing your time and expertise with us today, Dr. Anagnostou. For our audience, 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 treatments across a wide variety of cancer types. You can browse our entire library of past webinars and immunotherapy patients summit series content between the world's leading immunotherapy experts. You can access information on other resources including, treatment, emotional support, and financial assistance. And finally, you can receive help to find an immunotherapy trial that might be right for you.

I'd also like to thank one last time our sponsors Bristol-Myers Squibb and Alkermes for making this webinar series possible. And thank you all for your attention today. I hope you found our webinar very interesting, and informative, and educational. 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 and a number of cancer types.

Finally, Dr. Anagnosto, thank you so much again for helping to highlight how these blood tests might improve cancer immunotherapy, as well as the amazing work that you are doing to help patients. We wish you the best of luck!

Elsa Anagnostou, M.D., Ph.D.: Thank you. And thanks again to the Cancer Research Institute that supports all these important efforts.

Arthur Brodsky, Ph.D.: Thank you. Take care, everyone.

Elsa Anagnostou, M.D., Ph.D.: Good bye.

*Immunotherapy results may vary from patient to patient.

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