This is part 2 of our series on the latest advances in immunotherapy.
In this podcast, Gregory B. Lesinski, PhD, MPH, and Bassel El-Rayes, MD , discuss the exciting world of immunotherapy, the breakthroughs that are being discovered at Winship Cancer Institute of Emory University, and when to refer to a specialist.
Part Two: Understanding Immunotherapy: A Breakthrough in Cancer Treatment
Featuring:
Learn more about Gregory B. Lesinski, PhD, MPH
Bassel El-Rayes, MD is the chief clinical research scientist responsible for coordinating and providing high-level direction to the clinical cancer research programs and clinical cancer trials across the Emory campuses. El-Rayes is Professor and Vice Chair for Clinical Research of the Department of Hematology and Medical Oncology at Emory University School of Medicine and has served as Director of the Winship Gastrointestinal Oncology Program since joining Winship Cancer Institute in 2009. Board certified in hematology and medical oncology, he treats patients with gastrointestinal malignancies.
Learn more about Bassel El-Rayes, MD
Gregory B. Lesinski, PhD, MPH & Bassel El-Rayes, MD
Gregory B. Lesinski, PhD, MPH, is Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine in Atlanta, Georgia. Since 2008, the Lesinski research team has focused on the interactions between the immune system and cancer. This knowledge is being leveraged to develop novel therapeutic approaches for patients with cancer, and improve upon existing therapies.Learn more about Gregory B. Lesinski, PhD, MPH
Bassel El-Rayes, MD is the chief clinical research scientist responsible for coordinating and providing high-level direction to the clinical cancer research programs and clinical cancer trials across the Emory campuses. El-Rayes is Professor and Vice Chair for Clinical Research of the Department of Hematology and Medical Oncology at Emory University School of Medicine and has served as Director of the Winship Gastrointestinal Oncology Program since joining Winship Cancer Institute in 2009. Board certified in hematology and medical oncology, he treats patients with gastrointestinal malignancies.
Learn more about Bassel El-Rayes, MD
Transcription:
Melanie: Hello, this is Melanie Cole and this is part two of our two part series on the latest advances in immunotherapy. My guests are Dr. Bassel El-Rayes and Dr. Gregory Lesinski. Dr. Lesinski, your research team is focused on the interaction between the immune system and cancer. How are you using this knowledge? How is it being leveraged to develop these novel approaches and improve upon some of the existing therapies?
Dr. Lesinski: So, we have a very active research program at Winship and part of what we do is heavily collaborating with our clinical colleagues like Dr. El-Rayes as well as others, across disciplines, and this enables us to directly take our research to the patients. And we do this in a way which focuses primarily on understanding why that immune system in the setting of an advanced cancer is so different than that of a normal healthy adult. So, we have a number of exciting projects occurring right now at Winship and within our GI oncology program. Part of that research effort is really focused in on these types of cancer that normally do not respond effectively to immune therapy.
If we are able to overcome some of the barriers for effective immune recognition of cancer, we could have a very major impact on a large number of patients with diseases that are typically among the most aggressive and take for example pancreatic cancer. This is a major research interest and clinical interest within our group and this disease has a very characteristic phenotype or appearance to it in that it is a cancer that is both intercalated with and surrounded by a protective fibrotic what we call stroma, and this is not – if you take out a pancreatic tumor, it’s not exclusively proliferating cells. There is a lot of fibrosis, collagen, immune cells that are actually suppressive rather than activated in nature and what our group is doing is we are studying this what’s called tumor microenvironment, this collection of multiple cells and trying to understand one how it excludes those T-cells or other innate immune cells from the cancer area where they could in fact recognize and eliminate those tumors and we are trying to identify new targets within this complex cellular milieu that can be leveraged to gain better access of cells that you either transfer adoptively to a patient or cells within the body that may be turned on by these immune check point inhibitors and we are trying to neutralize them, study it in the laboratory and then move that knowledge into clinical trials for patients in the early phase setting by pursuing combination therapy approaches.
For example, one therapy may go after the stroma or particular components within it that are shutting off the immune system response to the cancer while concurrently stepping on the gas pedal if you will, and activating those T cells to then become more cytotoxic and better killers and recognizers of those tumors in the body. So, these approaches are at the very beginning stages, but we certainly have a number of concepts that are emerging that we are quite excited about and we feel could have an impact once we gain additional knowledge.
Melanie: And Dr. El-Rayes, looking forward, to the next ten years in the field, what do you feel will be some of the most important areas of research? What does this current research indicate for future developments in treatments? Give us a little blueprint for future research.
Dr. El-Rayes: So, this is a very exciting time to be involved in research in cancer because we are sort of at, if you want, a turning point where we actually may finally have the upper hand in the fight against cancer. And the immune system, I think, is going to be key in us winning that war against cancer. I think the things that we are looking for in the next years are number one: Why do we see different responses in patients? Why do some patients respond in a phenomenal way to immune therapies while others do not? And then understanding that will I think, open the door for us to know how to do a second manipulation if you want, to the immune system to try and get a better response in the people who do not respond right now.
Dr. Lesinski spoke a little bit earlier about for example approaching the tumor microenvironment. That is going to be a very key area of research I think, in the next ten years because a lot of the reasons why the immune system does not work is because of resistance in the tumor microenvironment. Then the other part that is going to be coming up as a hot area of research is how do we expand our ability to use cellular therapies, cellular immune-based therapies like CAR-T cells and adaptive T cells more broadly in cancer. How do we make those T cells? How do we manufacture them? How do we expand their use and how do we enable those T cells to be more effective when we give them to patients?
So, those are going to be two very hot areas and then the third hot area, I think of research, is an area that Dr. Lesinski spoke about earlier is how do we ensure that as we administer these more potent immune treatments, that we do not run into those side effects that we are seeing, those immune side effects. And there our enhanced advanced understanding and knowledge of why some people get those autoimmune effects and others don’t, is going to be key in us sort of tailoring the immune therapy so that patients get the maximum benefit with the minimum risk and we avoid running into the problems of over stimulating the immune system and getting these unwanted side effects.
So, I think those would be the three key areas. Understanding why some people are resistant to immune therapy and addressing the mechanisms of resistance, enhancing and expanding our ability to use cellular therapies in this area and then a better understanding of why do some people get autoimmune effects from the drugs and how can we be proactive and preventing those or maybe proactive in selecting the patients who should not get immune therapy or get different kinds of immune therapy.
Melanie: So interesting.
Dr. Lesinski: And I would like to add too, this concept of biomarkers, understanding who is going to gain benefit such as Dr. El-Rayes had mentioned from the therapy. We are also undergoing a real revolution in our ability to do genetic analysis of tumors in individual patients such that we may be able to identify genetic signatures and do it in a patient individualized manner for these therapies. And the other thing I’d like to add with regard to the areas of future research, I agree with everything mentioned by Dr. El-Rayes, but there have been a few recent reports linking changes in the microbiome within individuals to response or resistance to immunotherapy. So, there’s this continued understanding of both genetics, both at the host level, as well as the interactions with the microbiome and how it may influence one’s response to immunotherapy across a variety of settings. So, this is certainly an exciting area on all fronts.
Melanie: And Dr. El-Rayes, last word to you, in summary, please tell other physicians what you would like them to know about this exciting world of immunotherapy and when you want them to consider referring to a specialist.
Dr. El-Rayes: So, I think where we are right now, is we have a hint on certain diseases where immune therapy appears to be effective. We spoke about some of the diseases earlier like stomach cancer, liver cancer, MSI high colon cancer. I think for those patient populations we need to strategize and think of where do we incorporate the immune therapy in the course of treatment. So, that’s the challenge in that set of patients.
And then for people who are seeing patients out in the community who do not fit the diagnoses that have shown to be sensitive to immune therapy like pancreas cancer for example; I think those patients at some point in their course warrant to be evaluated for clinical trials that are testing new immune therapy modalities. Because those patients may still benefit from immune therapy, although not the ones that are in the clinic right now, but the ones that are coming down the pipeline. So, I think this is an area where we have all to be open-minded and try to think about how best to apply it in the standard clinical setting and how to think about referring patients who may not be candidates for it in the standard setting to get enrolled in clinical trials and have access to this new therapies through the clinical trials program and get access to the newer immune therapy drugs that are coming down the pipeline.
Melanie: Thank you so much gentlemen, for such an interesting segment. Winship Cancer Institute of Emory University is an NCI comprehensive cancer center. Should you have questions or wish to discuss the care of your patients please use our referral form or call us at 888-WINSHIP, that’s 888-946-7447. You’re listening to Emory Healthcare Rounds. For more information on Winship Cancer Institute of Emory University, please visit www.emoryhealthcare.org/referwinship that’s www.emoryhealthcare.org/referwinship . I’m Melanie Cole. Thanks so much for tuning in.
Melanie: Hello, this is Melanie Cole and this is part two of our two part series on the latest advances in immunotherapy. My guests are Dr. Bassel El-Rayes and Dr. Gregory Lesinski. Dr. Lesinski, your research team is focused on the interaction between the immune system and cancer. How are you using this knowledge? How is it being leveraged to develop these novel approaches and improve upon some of the existing therapies?
Dr. Lesinski: So, we have a very active research program at Winship and part of what we do is heavily collaborating with our clinical colleagues like Dr. El-Rayes as well as others, across disciplines, and this enables us to directly take our research to the patients. And we do this in a way which focuses primarily on understanding why that immune system in the setting of an advanced cancer is so different than that of a normal healthy adult. So, we have a number of exciting projects occurring right now at Winship and within our GI oncology program. Part of that research effort is really focused in on these types of cancer that normally do not respond effectively to immune therapy.
If we are able to overcome some of the barriers for effective immune recognition of cancer, we could have a very major impact on a large number of patients with diseases that are typically among the most aggressive and take for example pancreatic cancer. This is a major research interest and clinical interest within our group and this disease has a very characteristic phenotype or appearance to it in that it is a cancer that is both intercalated with and surrounded by a protective fibrotic what we call stroma, and this is not – if you take out a pancreatic tumor, it’s not exclusively proliferating cells. There is a lot of fibrosis, collagen, immune cells that are actually suppressive rather than activated in nature and what our group is doing is we are studying this what’s called tumor microenvironment, this collection of multiple cells and trying to understand one how it excludes those T-cells or other innate immune cells from the cancer area where they could in fact recognize and eliminate those tumors and we are trying to identify new targets within this complex cellular milieu that can be leveraged to gain better access of cells that you either transfer adoptively to a patient or cells within the body that may be turned on by these immune check point inhibitors and we are trying to neutralize them, study it in the laboratory and then move that knowledge into clinical trials for patients in the early phase setting by pursuing combination therapy approaches.
For example, one therapy may go after the stroma or particular components within it that are shutting off the immune system response to the cancer while concurrently stepping on the gas pedal if you will, and activating those T cells to then become more cytotoxic and better killers and recognizers of those tumors in the body. So, these approaches are at the very beginning stages, but we certainly have a number of concepts that are emerging that we are quite excited about and we feel could have an impact once we gain additional knowledge.
Melanie: And Dr. El-Rayes, looking forward, to the next ten years in the field, what do you feel will be some of the most important areas of research? What does this current research indicate for future developments in treatments? Give us a little blueprint for future research.
Dr. El-Rayes: So, this is a very exciting time to be involved in research in cancer because we are sort of at, if you want, a turning point where we actually may finally have the upper hand in the fight against cancer. And the immune system, I think, is going to be key in us winning that war against cancer. I think the things that we are looking for in the next years are number one: Why do we see different responses in patients? Why do some patients respond in a phenomenal way to immune therapies while others do not? And then understanding that will I think, open the door for us to know how to do a second manipulation if you want, to the immune system to try and get a better response in the people who do not respond right now.
Dr. Lesinski spoke a little bit earlier about for example approaching the tumor microenvironment. That is going to be a very key area of research I think, in the next ten years because a lot of the reasons why the immune system does not work is because of resistance in the tumor microenvironment. Then the other part that is going to be coming up as a hot area of research is how do we expand our ability to use cellular therapies, cellular immune-based therapies like CAR-T cells and adaptive T cells more broadly in cancer. How do we make those T cells? How do we manufacture them? How do we expand their use and how do we enable those T cells to be more effective when we give them to patients?
So, those are going to be two very hot areas and then the third hot area, I think of research, is an area that Dr. Lesinski spoke about earlier is how do we ensure that as we administer these more potent immune treatments, that we do not run into those side effects that we are seeing, those immune side effects. And there our enhanced advanced understanding and knowledge of why some people get those autoimmune effects and others don’t, is going to be key in us sort of tailoring the immune therapy so that patients get the maximum benefit with the minimum risk and we avoid running into the problems of over stimulating the immune system and getting these unwanted side effects.
So, I think those would be the three key areas. Understanding why some people are resistant to immune therapy and addressing the mechanisms of resistance, enhancing and expanding our ability to use cellular therapies in this area and then a better understanding of why do some people get autoimmune effects from the drugs and how can we be proactive and preventing those or maybe proactive in selecting the patients who should not get immune therapy or get different kinds of immune therapy.
Melanie: So interesting.
Dr. Lesinski: And I would like to add too, this concept of biomarkers, understanding who is going to gain benefit such as Dr. El-Rayes had mentioned from the therapy. We are also undergoing a real revolution in our ability to do genetic analysis of tumors in individual patients such that we may be able to identify genetic signatures and do it in a patient individualized manner for these therapies. And the other thing I’d like to add with regard to the areas of future research, I agree with everything mentioned by Dr. El-Rayes, but there have been a few recent reports linking changes in the microbiome within individuals to response or resistance to immunotherapy. So, there’s this continued understanding of both genetics, both at the host level, as well as the interactions with the microbiome and how it may influence one’s response to immunotherapy across a variety of settings. So, this is certainly an exciting area on all fronts.
Melanie: And Dr. El-Rayes, last word to you, in summary, please tell other physicians what you would like them to know about this exciting world of immunotherapy and when you want them to consider referring to a specialist.
Dr. El-Rayes: So, I think where we are right now, is we have a hint on certain diseases where immune therapy appears to be effective. We spoke about some of the diseases earlier like stomach cancer, liver cancer, MSI high colon cancer. I think for those patient populations we need to strategize and think of where do we incorporate the immune therapy in the course of treatment. So, that’s the challenge in that set of patients.
And then for people who are seeing patients out in the community who do not fit the diagnoses that have shown to be sensitive to immune therapy like pancreas cancer for example; I think those patients at some point in their course warrant to be evaluated for clinical trials that are testing new immune therapy modalities. Because those patients may still benefit from immune therapy, although not the ones that are in the clinic right now, but the ones that are coming down the pipeline. So, I think this is an area where we have all to be open-minded and try to think about how best to apply it in the standard clinical setting and how to think about referring patients who may not be candidates for it in the standard setting to get enrolled in clinical trials and have access to this new therapies through the clinical trials program and get access to the newer immune therapy drugs that are coming down the pipeline.
Melanie: Thank you so much gentlemen, for such an interesting segment. Winship Cancer Institute of Emory University is an NCI comprehensive cancer center. Should you have questions or wish to discuss the care of your patients please use our referral form or call us at 888-WINSHIP, that’s 888-946-7447. You’re listening to Emory Healthcare Rounds. For more information on Winship Cancer Institute of Emory University, please visit www.emoryhealthcare.org/referwinship that’s www.emoryhealthcare.org/referwinship . I’m Melanie Cole. Thanks so much for tuning in.