Separating the self from non-self cells is an important part how your immune system is supposed to recognise disease, and the same mechanisms are how cancer evades that immune surveillance.
So, what if that escape route can be closed off?
Dr Alberto Pavan describes his research into how lung cancer can be brought to the attention of immune cells, the molecular signs of treatment success, and how these microscopic changes can hopefully translate to longer, healthier lives for patients
Read the original article: https://doi.org/10.1093/oncolo/oyab047
Image Source: Chinnapong/ Shutterstock
Transcript:
The following transcript is automatically generated.
Will Mountford:
Hello, i’m Will welcome to ResearchPod. It is the nature of cancer that the cells comprising it are so very almost your own, but gone enough arrived that they are no longer serving the health of your body but have become the origin of a whole family of diseases. Separating the self from non-self cells is an important part of how your immune system is supposed to recognise disease, and the same mechanisms are how cancer evades that immune surveillance. So what of that escape route could be closed off? Today I’m speaking with Dr Alberto Pavan about his research into how lung cancer can be brought to the attention of immune cells, the molecular signs of treatment success and how these microscopic changes can hopefully translate to longer, healthier lives for patients. And joining me from Venice, Alberto Pavan, Alberto hello.
Dr Alberto Pavan:
Hello, hi, thank you for having me. I’m a medical oncologist and I’m currently working at the oncology unit of Venice and Venice Mainland. I’m specialised in thoracic oncology. Well about me my interest in oncology started back in the days when I was a medical student and, interestingly enough, when I was studying tocaryngology, because I found fascinating that in that field, it was always necessary, in order to deal with every disease, and especially with head and neck cancer, to have a multidisciplinary approach, and that was also always fascinating to me. Soon after, i started my residency in oncology in Padua at Istituto Oncologico Veneto, where I had the chance to join the team led by Giulia Pasello and Laura Bonanno, who both are involved with clinical research in the field of thoracic cancers and, in particular, in lung cancer. There, i had the chance to participate in academic trials aimed at the understanding of the features the molecular and genetic features of cancer cells and the tumor microenvironment, but I had also the chance to share the non-academic trials involving new drugs and new treatment approaches for lung cancer patients. I have concluded my residency with the work about liquid biopsy and its clinical usage, while monitoring the outcome of patients undergoing immune therapy. So, since 2020, i’m here in Venice working as a medical oncologist.
Will Mountford:
Immune therapy is one of the major trends in cancer research generally, and lung cancer has been one of the diseases that has seen some of the most significant progress in coming up with treatments matched to disease types. So I suppose, as a kind of a crash course in the background of lung cancer and non-small cell lung cancer specifically, what does the last 10 years look like leading up to today’s research that we’re talking about?
Dr Alberto Pavan:
Well, i strongly agree with you, because immune therapy has changed the treatment scenario of non-small cell lung cancer in the last 10 years. It was discovered that cancer cells have a particular crosstalk with the immune system. Cancer cells are able to hide themselves from the immune cells using a particular kind of protein that is located on their surface, therefore avoiding the killing caused by the immune cells themselves. That led to the development of a new class of drugs, which are called the immune checkpoint inhibitors, commonly referred as immune therapy that are able to disrupt this kind of hiding mechanism, so that the immune cells are able once again to detect and kill neoplastic cells. When this immune therapy works very well as a standalone treatment when the expression on the surface of the cancer cells of this immune checkpoint the main one is called the PDL1, has a value of over 50%, whereas when this value is lower than 50%, immune therapy needs to be combined with the chemotherapy in order to boost its clinical activity. This introduction of immune therapy was very important and changed the prognosis of metastatic patients. But there is also another group of non-smosal lung cancer patients that are affected by a disease that is not metastatic because it has not spread out to other sides of the body but on the other side, is not eligible for a surgical, a radical intent surgical treatment, and this situation is what we call the locally advanced non-smosal lung cancer. This kind of disease, up until 2017-2018, was treated with a chemotherapy in combination with radiotherapy, and that was the standard of care. In 2017, the results from the Pacific Trial Study showed that the one-year maintenance with immune therapy after chemo radiation was able to improve the outcome and the survival outcome of the treated patient, with about half of the patients still alive five years after the completion of this kind of treatment, compared with about one-third of the patients still alive with the standard of care. This was a considerable success, but we know that, luckily, we still lose about a half of our patients, and so the nowadays, the unmet need is to understand what is the tumor like, what is the tumor environment, so the tumor cells, both the tumor cells and the other cells that represent the surroundings of the tumor cells and that may interact in tumor growth and tumor aggressivity or in tumor response to our standard of care, especially in a time where it was where tumor cell has already received a chemo and radiation treatment. This is a very strange setting because it involves not a lot of patients, but these patients may undergo a radical intent treatment with chemo, radiation and immunotherapy. So we want to understand which patient might benefit from standard of care, which patient may be at a higher risk of early recurrence or may benefit from a more intense treatment course or a follow-up time that is maybe a little bit shorter than the other ones. So this is our background mainly for our exploratory analysis that we’re going to talk about today.
Will Mountford:
Yes, the multiple different kinds of lines of therapy and the combinations and the survival rates. I think it’s important that we kind of ground things in the lived experience of patients who are going through that and to accurately talk about what that experience is like and how that relates to the trial settings. I think we should maybe first go through some of the language that we’re going to be using, because there’s a couple of acronyms that anyone who’s listening to this from a patient or patient advocacy background might not be the most up to date with. Probably clinicians will know what’s going on, but for the rest of us human beings out there, if we could maybe just do a quick run through of some of the acronyms like TIICs, RITCs, you’ve used some of these phrases in full, but if we’re going to kind of discuss them, i think it’s worth just making sure that everyone knows where we’re starting from.
Dr Alberto Pavan:
Yeah, well, in our, in our study, the aim was to explore the environment of the tumor. This is where it gets a little bit tricky, because often it’s very hard or quite impossible to obtain fresh tissue, new tissue from a new biopsy in patients who received chemo and radiotherapy. This because often it’s not practically feasible and whenever it is feasible, the histological material that we can get is quite scarce. so the analysis that we want to perform is not going to happen. So in our study we decided to look to another category of patient, a group of patients with affected by non-small cell lung cancer that are affected by a subset of this disease that is called sulcus superior, non-small cell lung cancer. This is a very little group of patients that are amenable of radical intent surgery, but only after chemo radiation. This way we have a group of an homogeneous group of patients that received at 100% chemo and radiation and, on the other hand, we have a surgical sample that we can analyze with no problem of lacking material. So when we, all the patients that we’ve included were treated with chemo and radiation and were reevaluated with radiologically reevaluated, with a CT scan and with a PET scan performed every three months. So this is one information that we have about the response, the radiological response, of the patient to our treatment. On the other end, we performed an analysis on the tissue sample, on the surgical tissue, and there we characterize TEC, which means tumor infiltrating immune cells, which are the immune cells that are present inside the tumor bed, inside the tumor environment. We also characterize the RVTC, which is a residual viable tumor cells, which are the tumor cells that are still present and still alive after our treatment. We also characterize the PDL1, the presence of the PDL1, so the immune checkpoint that we talk about soon, in order to understand the relationship between, among these features of the tissue, so the immune cells, the tumor cells and PDL1, but also their relationship with the clinical and radiological response. Another simple, very simple analysis that we performed was that we collected a simple blood sample before treatment and we calculated two ratios The ratios between circulating neutrophils and circulating lymphocytes, which are both subgroup of immune cells that are circulating in our bloodstream, and also the ratio between circulating platelet and circulating lymphocyte, also at baseline.
Will Mountford:
so, before everything was performed, I think that explains things very neatly of being able to understand what’s happening in the tumor. If you’ve got the immune activation inside of there, how much of the threat of a viable tumor cell is left, and then the blood assays as well. So thank you for going over those so succinctly, and now I’ll leave it up to you to tell me what that all means in terms of the findings.
Dr Alberto Pavan:
Well, the findings were both surprising and unsurprising, because, on one hand, we discovered that a lower rate of a viable tumor cells is linked with a better response. This is an unexpected result, as seen in other trials. For example, the checkmate H1-6, which involves another group of patients, is a study evaluating chemo and immunotherapy as a pre-surgical treatment, and also in this study a lower rate of viable tumor cells was linked with a longer event-free survival and a lower risk of cancer recurrence. On the other hand, we discovered that a particular subgroup of TEC called CD68, which identifies a group of active macrophages, was linked with a lower rate of a viable tumor cell and also with a better response to treatment. This is new in the field of lung cancer, but it was already discovering for other neoplasms, such like breast cancer, where patients that have this subtype of lymphocyte at a higher rate showed a better response to pre-operative treatment. I think this is important because with time we are understanding the peculiarities of the immune microenvironment, because everything started with the immune checkpoint. So we knew that if we have a PDL1, we can act in that mechanism. But surely our immune system is more complex than that. It’s not based only on one mechanism to control and to perform it’s anti-cancer activity. This way we found a particular group of cells that maybe are more involved in creating an immunohot microenvironment in comparison to other subgroups of immune cells. When I speak about hot and cold microenvironment I mean that every tumor has its surroundings and has its peculiar type of immune cells that helps or not its development. This way we know that some tumors need to be stimulated, needs to be attacked with a lot of different weapons, whereas others just need the immune checkpoint inhibitors. So understanding this kind of crosstalk with this particular subset of immune cell is quite important, quite stimulating. I think one unexpected result was to find that the PLR, so the ratio between platelet and lymphocyte, is linked with the presence of CD68 present inside the tumor. This way, i know it’s an exploratory study, but this showed some kind of signal that with a simple blood test a standard blood test, not liquid wipes, not advanced analysis or that needs maybe specialized laboratories to be performed a simple blood test could tell us which are the patients who might benefit from the start from what we have now, that is, a standard treatment which is chemo, radiation and immunotherapy, and maybe others that with maybe a lower rate of platelet to lymphocyte ratio are at a higher risk of maybe having a recurrent disease or have another site of disease, therefore getting a worse prognosis. So these are the main signals coming from our studies.
Will Mountford:
Just be clear that this is all correlation, not causation, that it isn’t a direct because of the chemo radiation there is more CD68 T cell.
Dr Alberto Pavan:
Yes, it’s more a correlation. Hopefully with expanding our study we’re gonna understand if there is also a causation, because if we find that maybe some subset of tumor cells are able to secrete some cytokines that can cause the presence of CD68 more than other cancer, then we might understand also why this mechanism is correlated also with a better prognosis. For now it’s a correlation, but hopefully expanding our set of patients we’re gonna find a real causation. About the correlation between the platelet-to-lymphocytes ratio and the presence of CD68, this I think, in my opinion is still more of a correlation because the real role played by the platelets in a cancer microenvironment is still quite unknown. Because we’ve understand that platelets are not so passive like we thought they could be, just something that repair wounds. They are more active. They can secrete cytokines, they can interact like cells, even if they are not cells, because they are just membranes that are active in the wound repairing. So I think in the future, when the situation and the understanding of platelets will be more clear, maybe we could find also a causation to the CD68 present. But I think that it’s maybe not the next future, not for the next future.
Will Mountford:
To bring things back to the patient experience, you highlighted that the blood test was quick and easy to do, and how does that fit into the general tolerability of the treatment schedule and all of the rest of the monitoring that’s happened?
Dr Alberto Pavan:
Well, normally the treatment is divided into parts. The first part is surely the hardest one because it involves both chemotherapy, which is administered with a weekly schedule So every week for about a month, a month and a half, the patient needs to come to the day hospital, undergo chemotherapy and a concurrent administration of radiotherapy, which is administered with a daily basis for all the months and a month and a half. This is surely the hardest part, because chemotherapy is not the chemotherapy of 10 years ago, because vomiting, nausea, there are a lot of symptoms that we can tackle with success. So almost every patient that undergoes this kind of treatment is able to perform it to the end of the treatment itself and did not need to discontinue the treatment. But there are symptoms such as fatigue and such as esophagitis. So the pain while eating, drinking, pain in the throat, that could be tackled with a topic or a treatment but might last through all the period that the patient is receiving especially is receiving radiotherapy, because chemotherapy performs its action on the whole body. You receive it through your bloodstream and it goes everywhere and hits every tumor cells it find in the bloodstream and in your body, whereas the radiotherapy is very, very specific to entailer it to the tumor site and all the structures that are involved. So very often if the main tumor or the main location of the disease is in the center of the thorax, often the esophagus is the weak part of all the structures, so it’s the one that hurts But it’s something that after a couple of weeks, after a month of the completion of the hardest part of the treatment, the chemo radiation, is something you could recover. Second part is the one with the immune therapy that is also administered through your bloodstream once every four weeks. It’s surely a treatment that better tolerated than every other oncological treatment because it’s fast and often it has no adverse event. That happened in the short course. But as every drug that as a physician we use, we administer, also immune therapy has some treatment related adverse event that are always linked to an excessive response by the immune system, because the action of the immune therapy is to boost the response of our immune cells against the cancer cells. But it could happen that this response might hit also normal cells and cause autoimmune-like diseases that, if recognized with timely recognition, are all diseases that could be treated and that are not life-threatening. The importance is to identify them quickly and start steroid, start all the medications that are needed to tackle this kind of disease. They are diseases, but it’s a very gray area between a real autoimmune disease and a diverse event. So the stopping of the treatment and the steroid and everything that is needed to tackle this kind of adverse event could really bring the patient back to the normal status. So timely recognition is crucial. This kind of treatment lasts for about one year after the completion of the chemo-radiation course. During both treatment, the clinical revaluation and the radiological revaluation is performed normally every three months. So as physicians we know that this is the moment where when the CT scan is performed is always crucial for the patient, because the psychological impact that could have on the normal of the daily life, but also in the way the patient deals with the cure and the disease, depends on that moment. So psychologically is very challenging. So it’s the moment where we take more time with the patient himself in order to explain everything we see with CT scan or the PET CT scan and the action that we as a team me as an administering physician and the patient as the one I’m joining in this difficult journey are gonna undergo in the next month. That could be hopefully just a follow-up time, so just other CT scan with three or four month time or, if necessary, the start of other treatment. That could be challenging.
Will Mountford:
But he did mention that the idea of undergoing quite heavy treatment and with the immune infiltrate landscape work that you’re doing, ideally people do have that indicative response that does say they will respond to immunotherapy if and when they need it. But for people who are not getting that tumor infiltration correlation, if they are not best suited for receiving immunotherapy, does that mean that it’s just going to be more chemotherapy for them or is it dose escalation to a different treatment modality?
Dr Alberto Pavan:
Well, in my opinion, in the future we could have two different scenarios. First, i think this patient maybe a patient that based on the data we can consider at higher risk maybe deserve a shorter time of follow-up in order to identify even a little progression of the disease, in order to tackle it with the less invasive treatment needed, which often is other courses of, maybe stereotactic radiotherapy that are targeted on just on the site of the disease. That is no, no more responding. The other scenario, i think, might involve the usage of new treatment combination. We know from recent trials, such as the cost trial, that the combination of different immunotherapy agents after chemotherapy therapy might improve the survival compared with the standard immunotherapy. So in oncology nowadays we are often talking about the de-escalating the treatment. I think that having tool to stratify and to identify the patient who might benefit from standard treatment and does not need a combination, as performing the cost trial, that has its results but as its downfalls, as adverse event, might benefit just from the standard immunotherapy for one year. Maybe the one that, with our tools, are identified to have a higher risk and to have a worse prognosis might benefit from a heavier combination of immunotherapy after the completion of chemo radiation. So I think these are the two scenarios. Maybe the first one the shorter follow-up time is the one that is gonna happen in the next future, but I think that having the results of the cost trial and our results might open the other scenario quite soon.
Will Mountford:
With that in mind, and with the expansion that you mentioned earlier, if people want to find out more about participating in either this trial directly or any similar trials that might be happening at their hospital, are there any plans for follow-ups with wider recruitment that they could participate in?
Dr Alberto Pavan:
Yes, currently at Institute of Oncological Veneto and also my center, we are recruiting in the IRON trial, which is similar trial but is of the one we are talking about today, but it’s an expansion. We are including patient that have diagnosis of locally advanced nose mousseline cancer. For this patient we are performing the same analysis and also we are involving our radiology in order to perform also some kind of next-generation radiology with, which is called Radiomics is a new field of radiology that could correlate with the use of new software pattern of the radiological images, with the information that we have by the study of the histology and the study of the clinical status of the patient. So this way we hope, to other non-invasive tools to predict the benefit or to identify a patient with the better or worse outcome that need maybe something more than the standard of care, and so the information are available at the Yov Veneto website website. You just need to type in to Google, where the and the principal investigator of the trial is Julia Pazello, and the trial is currently ongoing.
Will Mountford:
If you send over the links for that, i’ll be sure to put them in the description text for the podcast. Surely Well, i think that covers all of the background process findings and you know future for the results. do you want to maybe think in terms of any summary for maybe how this will influence what patients go through right now or how it might influence standard of care in the future? you know any optimism, any hopes you have for how this changes life for patients and for clinicians helping those patients through a tough time.
Dr Alberto Pavan:
Well, the first message is that in the last five years we understood our enemy. The understanding of our enemy, which is the tumor and non-small salon cancer, has helped us improving the quality of the weapon we can use. Nowadays we have strong, very strong weapons that use maybe the most powerful system that could tackle cancer, which is our immune system. This way we improved not only the overall survival but also the quality of life of patients affected by this disease and with the study like ours, we could have in the next future the tools to identify and to tailor the right treatment to the right patient.
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