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Melanie Cole (Host):  Welcome to Emory Healthcare Rounds. I’m Melanie Cole. Today’s topic is the next steps for lymphoma and chimeric antigen receptor CAR T-cell therapy. My guest is Dr. Jonathan Cohen. He is the Medical Director of Infusion Services at Winship Cancer Institute of Emory University and in the Department of Hematology and Medical Oncology. Welcome to the show Dr. Cohen. So, tell us what’s the evolution of immunotherapy? How is it breaking on to the cancer scene and then explain a little bit about the evolution of CAR T-cell therapy.

Dr. Jonathan B. Cohen, MD, MS (Guest):  Sure, absolutely. Well thanks Melanie for having me. I’m happy to be here today. So, CAR T is just one of a number of recent advances in immunotherapy for hematologic malignancies and really for cancer in general. But it certainly is not the first. There has been a lot of interest in immunotherapy and its use in cancer for many years with a number of different cancer subtypes and this is just I think the next step along that pathway. So, what is so exciting about CAR T therapy is that it allows us to modify a patient’s own T-cells to attack their specific cancer and so in the case of non-Hodgkin lymphoma for example; we can attack one of the markers on the B-cells that makes up their lymphoma that allows their own immune system to take out any of their residual cancer.

Melanie:  So, how has CAR T changed the scene as there are many different types of immunotherapy now and who do you envision this is most beneficial for?

Dr. Cohen:  So, CAR T-cells are currently approved only for patients with diffuse large B-cell lymphoma, at least within our lymphoma patients. There is also approval currently for pediatric acute lymphoblastic leukemia. And so, right now, it’s still a fairly small number of patients that are actually eligible to receive this, but over the next year to two years I expect additional approvals to come through and more patients to be eligible. What’s particularly exciting is that in the past, for patients with relapsed aggressive non-Hodgkin lymphoma; we were looking at something like a stem cell transplant which could be effective maybe half of the time and for patients who either were not candidates for transplants or who progressed after a transplant, there were very limited options and almost none of them were ultimately cured. What this new technology allows us to do is offer patients a potentially curative intervention even if they either are not able to go to transplant or progressed after transplant and this is something that we hope will be applicable to a large number of our patients.

Melanie:  So, what does it mean when they say CAR T-cells are the equivalent of giving patients a living drug? What does the therapy entail and how are they manufactured and managed?

Dr. Cohen:  So, what makes CAR T-cells special is that these are the patient’s own T-cells, it’s their own immune system that’s at work. And what we do is we take out their T-cells through a process called apheresis, this is an outpatient process and patients typically tolerate this quite well. And subsequently, we administer low dose chemotherapy which allows their immune system to accept the cells once they are reinfused. While the patient is however waiting in between apheresis and reinfusion; the cells are sent off to a manufacturing facility where they actually are engineered to identify the specific target and in most cases, it is CD-19 which targets B-cells and then they are shipped back to Emory or to the institution where they are going to be infused. And at that point, it is really a cell therapy just like stem cell transplantation. The cells are prepared and then infused at the bedside into the patient. Currently, this is all done as an inpatient, but I can certainly envision a scenario where this could even all be done as an outpatient in the future.

Melanie:  Isn’t that amazing that it is basically teaching these little soldiers to go in and recognize and that’s a way that people can sort of imagine this in their head, yes?

Dr. Cohen:  Absolutely. So, one of the things that’s nice compared to other forms of cell therapy is that we are using the patient’s own cells and, so we don’t have to worry about things like graft versus host disease or rejection or anything like that that can sometimes complicate stem cell transplantation when we are looking at a donor. In addition, the patient doesn’t have to worry about finding a donor which is often a complication or a challenge at least for patients that are looking at stem cell transplantation. And so, it’s great that we are able to collect the patient’s own cells and then they are returned right to that same patient. And as you point out, these really are living cells. These are active immune cells that are just altered in a way that allows them to function in the way that we want them to.

Melanie:  Like all cancer therapies; CAR T-cell therapy can cause several worrisome side effects. What are some of the side effects and what are some of the current issues in medical management once you detect what’s going on?

Dr. Cohen:  So, this is I think a very important point. Right now, even though these are FDA approved therapies, they are very tightly regulated by the FDA and our center and all centers that are offering this therapy go through a series of certifications and training for all of the staff that are going to be involved. And the reason is that anytime T-cells are infused into a patient or really any immunotherapy is administered; the hope is that the immune cells will take out the cancer, but the risk is that it can also activate the body’s immune system and cause a number of complications.

Two of the most common complications that we have seen with CAR T therapy includes cytokine release syndrome which we often refer to as CRS. There have also been several serious neurologic complications including encephalitis and even coma. These are things that typically happen within the first few weeks after infusion and for that reason; all of our patients that are receiving CAR T-cells are required to first of all, stay in the hospital for several days and subsequently stay local to our – or close to our center for several weeks afterwards. There are fortunately therapies that are available to help counteract these complications, but they can be very serious, and many patients will ultimately require intensive care and very aggressive therapy to resuscitate them when this occurs.

Melanie:  Dr. what follow-up is required and can you share any outcome data that you have?

Dr. Cohen:  So, this therapy fortunately is once you have gotten through the infusion, you are generally done with the active therapy, but that is only the beginning of the follow-up and so, again, many patients will be required to stay in the hospital for up to a week after their infusion to ensure that they haven’t had any acute complications like CRS or neurologic complications and then we also follow them closely for several weeks afterwards as an outpatient. Again, to make sure that these major complications are not occurring, and patients are counseled extensively and given cards and given instructions for what to do in the event that they were to have one of these toxicities. They can initially be quite subtle, and it may start out with just a fever or just not feeling well but can rapidly progress and so the acute follow-up takes place at our center with patients being seen regularly and being again extensively counseled on reasons to come to the emergency department. And I would point out that this effort is obviously a big effort for our own cancer center but also requires cooperation and discussions with the emergency department and the intensive care unit at our center so that everyone is prepared for managing some of these complications.

In the long run, most patients will actually do just fine once they have recovered from the acute infusion and any of the potential reactions. One of the largest challenges that we have seen so far is that there can be a hypogammaglobulinemia related to targeting of B-cells and many of our patients do receive intravenous immune globulin supplementation for a long period of time afterwards. It remains to be seen whether this will truly be required for all patients or if it will be something that just needs to be monitored; but it is a consideration of all oncologists because many of these patients will ultimately leave our center and go back to their communities.

Melanie:  Are you able to use this in both children and adults?

Dr. Cohen:  So, this therapy can be utilized in both children and adults. As it stands right now; the indications for lymphoma is from a clinical trial that was performed in adults, but it can be up for adults pretty much of any age as long as they are healthy, whereas for leukemia right now, it is primarily used in children and adolescents. It is not being used as frequently in older patients with leukemia. There are however, a number of clinical trials that are still ongoing that are investigating this therapy in a number of other settings including other lymphoma and leukemia subtypes. My expectation is that in the coming years this will be available for patients of any age as long as they are otherwise healthy and fit.

Melanie:  What does current research indicate for future developments and treatments? Give us a little blueprint for future research.

Dr. Cohen:  Sure, so right now, I think there are two main areas in my mind at least that are important. The first is trying to improve outcomes for the current indications. So, as it stands right now, I would estimate that roughly 30-40% of patients with non-Hodgkin lymphoma will achieve long-term benefit from this therapy. Meaning that they will sty in remission for several months or even years. And that’s really the goal here. Obtaining remission or a partial response for several weeks to a few months is probably not going to move the needle significantly for many patients but what we are really trying to do is maximize the number of patients that can obtain long-term remission. And so, there is already research going on to try to augment the impact of CAR T-cells whether that is with combination therapies or post-infusion or pre-infusion therapies and, so I think that is one area that I think is still in need of continued investigation. We will have a study at Emory for example, looking at some additional therapies to be administered post-CAR T to try to maintain that remission.

And then the other are I think that’s important is really identifying additional targets and additional diseases that may benefit from use of CAR T so for example, Hodgkin lymphoma is another type of lymphoma that although most patients are cured; we have patients that ultimately pass away from it and I think that that’s an area where I would love to see more development of CAR T-cells and other immunotherapies.

Melanie:  So, in summary Dr. Cohen, tell other physicians what you would like them to know about CAR T-cell therapy for patients and when to refer to a specialist.

Dr. Cohen:  So, I think what I would recommend that people consider is that CAR T is probably still at least in early 2018 a therapy that is available for a limited number of patients. These are going to be patients with diffuse large B-cell lymphoma that are either not eligible for a stem cell transplant or who have progressed after a stem cell transplant and are fit and able to travel to a center to receive this therapy. So, we still are very selective in the patients that ultimately move forward with this therapy, however, I think any patient that has relapsed aggressive non-Hodgkin lymphoma that is a candidate for aggressive therapy should be referred to one of our centers for evaluation and discussion about the potential role of CAR T therapy.

Melanie:  What can a physician expect from your team after referral in so far as communication with the referring physician and tell us about your team approach?

Dr. Cohen:  Sure, so we are very lucky at Winship. We have a very comprehensive approach to management of all of our patients that are referred for evaluation. One of our particular benefits is that we are disease specialists and not simply specialists in a particular procedure. So, a patient that may be referred for evaluation of their lymphoma will see one of our lymphoma doctors such as myself who can discuss with them stem cell transplantation as an option, immunotherapy or CAR T as an option as well as additional therapy options and, so they really will benefit from the breadth of knowledge that our specialists have on all of the different interventions for patients with lymphoma.

We work very hard from the time that the patient is referred to communicate both with the patient and with their referring physician and their office. And so, after the initial consultation; we typically will correspond by phone with referring doctor as well as sending a comprehensive note. For those patients that do ultimately proceed with CAR T therapy; there is an evaluation process that takes place and we often will have our cell therapy coordinators work closely with patients to make sure that all of this evaluation occurs. This often does involve discussion and coordination with the referring center especially in the setting of a patient that may live far away from Emory.

In addition to our cell therapy coordinators and our physicians; we also have an expert nursing staff both inpatient and outpatient and in the infusion center that are well-skilled in the management of complications related to cell therapy and can also provide counseling to patients with what to expect based on their own experience. We are also very lucky to have pharmacists, social workers, and dieticians that we work with very closely on a daily basis that can provide recommendations to patients, especially those that may have some challenges with regards to resources or other comorbidities and may need assistance for example with managing a diabetic diet while they are going through treatment and so forth. So, we are very fortunate here and patients can expect to meet a large number of professionals that are really all committed to insuring their success throughout their entire process.

Melanie:  Thank you so much Dr. Cohen, for being with us today. What an absolutely fascinating topic. You’re listening to Emory Health Care 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 listening.