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According the National Cancer Institute, the foundations of cancer treatment have typically been surgery, chemotherapy, and radiation therapy. Noe however, immunotherapy has become what many in the cancer community now call the fifth pillar or cancer treatment. One that is emerging onto the scene is an approach called adoptive cell transfer; collecting and using patient’s own immune cells to treat their cancer. My guests in this panel discussion today, are Dr. Amitkumar N. Mehta. He’s a hematologist oncologist specializing in lymphoma at UAB Medicine and Dr. Luciano J. Costa. He’s a hematologist oncologist specializing in lymphoid malignancies and blood and marrow transplantation at UAB. Welcome to the show gentlemen. So, Dr. Mehta, I’m going to start with you. Tell us a little bit about the evolution of immunotherapy and how that’s breaking on to the cancer scene.

Dr. Amitkumar N. Mehta, MD (Guest): So, for the immunotherapy lymphoma doctors – for lymphoma doctors, it is not a new therapy. Rituximab was the first immunotherapy which was approved for lymphoma treatment in late 1990's and it was added to the backbone of CHOP chemotherapy. Over a period of years, we have actually evolved and now we have antibody drug conjugates and more immunotherapies like checkpoint inhibitors. The latest addition to the immunotherapy is the adoptive T cell transfer treatments or what we call CAR chimeric antigen treatment for the lymphomas. It’s a unique treatment which has actually changed quite a bit of treatment paradigm of various kinds of lymphomas.

Melanie: So, Dr. Costa, as we are explaining to other physicians how this type of immunotherapy and therapy is emerging onto the scene, explain a little bit about the chimeric antigen receptors and this CAR T cell therapy. How did it come about?

Dr. Luciano J. Costa, MD (Guest): Absolutely, so the concept here is – has been pursued actually for decades, but really didn’t come to reality until very recently. One way – a simple way to understand this is cancer, in order to develop, needs to evade the immune system. Our body is coming up with new cancer cells on a daily basis and part of the reason why we are not developing cancers all the time; is because there is immune surveillance from our own immune system that destroy cancer cells. So, by definition, if a cancer does develop it is because the cancer has evaded the immune system.

So, the cells in our immune system that destroy cancer are also the same type of cells that destroy cells that have been infected by virus for example. And those cells are called defector T cells and they have a very broad repertoire that recognizes different targets; usually different infections that can accord to the cells. The concept here is quite sophisticated and fascinating is if you take those cells that have a specificity against multiple different random antigens that become kind of insignificant; take those cells out of the patient and then you transfect those cells using a virus, you transfect the cells with a molecule that is called chimeric antigen receptor. So this is a molecule that does not exist in nature, is not an antibody; it’s really a built from the bottom up molecule that has portions that resemble an antibody for example so it can recognize a specific target, and has portions that actually signal to the T cell to grow and to proliferate. So, that way, you can engineer those receptors for the specific target that you desire, transfect those receptors on the T cells, expand those T cells, and then reinfuse those cells in the patient. And those cells will bind to whatever contains the target, expand and essentially drive a very robust and rapid immune reaction against whatever cell contains that target.

So, really the challenge beyond that point, is not about the technology any longer, the challenge becomes find the right target on the right cancer in order for that technique to be effective. So, currently, the disease for where this is most developed is with lymphoma and acute lymphoblastic leukemia to have a very suitable target called CD 19 and there are several other malignancies following a little bit behind who have other targets that are amenable to therapy with those CAR T cells.

Dr. Mehta: And the beauty of the technology is that these cells are from patient themselves and, so they persist in the system and they actually can reach out to every tissue including brain and also they have a memory component so they last way longer in their own body.

Melanie: So, they are really little soldiers that are multiplying in there, but they are from the patient’s own body and as the core Dr. Mehta, of this adaptive immunity, what does it mean when people hear that they are the equivalent of giving patients a living drug? Is that what you are talking about, that because they come from the patient themselves, is that how that works?

Dr. Mehta: Exactly. So, as I mentioned these are the soldiers from the patient themselves, they are kind of trained in the lab to identify a specific target on the cancer cells, they are expanded, they are armed, and they are infused in the patient’s body. Now when they go in, before we do that, patients receive not chemotherapy, what we call a lympho depletion that means they get the therapy to deplete their T cells in the body. What the benefit of this approach is their body is now hungry to receive the T cells at the same time, we give them trained and expanded, armed T cells, their own T cells and infuse them so that the body adapts, takes them, nurtures them, they grow, but they are trained, armed and they exactly know where to go especially directing towards the antigen which is present on the cancer. And with that, they attack on the cancer and the idea is to completely eliminate the cancer.

Melanie: Dr. Costa, as many cancer therapies cause several worrisome and sometimes even fatal side effects. What are some of the risk benefits? Speak about that ratio with CAR T cell therapy, what are some of the current issues in management, once you have detected how these are working.

Dr. Costa: Yeah, that’s a very important point. And I would highlight cellular therapy of some sort is not new to cancer treatment particularly treatment of blood cancers. The most well-established type of cellular therapy has been with so called bone marrow transplant that can be performed with the with either their own cells or with the cells from the donor. And that has a very well-defined spectrum of toxicities that are very well known. This is something different. Because in one way, we are not just using their own cells with any manipulation. Those cells are being genetically engineered and on the other hand, we are not using cells from a donor, so many of the problems that come with a standard bone marrow transplant, that has to do with rejection and something called graft versus host disease; is something that does not occur – should not occur with a CAR T cell from the own individual.

However, there is a series of very specific toxicities that are unique to this therapy and that the field is now learning very rapidly to recognize and to manage. One of those toxicities is so called cytokine release syndrome which essentially consists of a downstream effect of a very intense activation of the immune system and the expansion of those – and activation of those T cells and other cells that are cross activated by the T cells that causes the release in the blood stream of a series of different cytokines, the one that has been a better recognized is called interleukin 6 and those cytokines can cause very broad spectrum of side effects ranging from mild fever going through decreasing blood pressure, respiratory problems, liver problems, kidney failure becoming even a situation of hypotension and multi-organ failure. Fortunately, we have learned to recognize and to manage that toxicity and that can be very rapidly overcome in most cases by using an antagonist of the interleukin 6 or an antagonist of interleukin 6 receptor that blocks the reaction, improves the symptoms without apparently any impairment of the effect of the T cells on the cancer. The other reaction that generates great concern; is called – is an encephalopathy, essentially neurological impairment then occurs after this therapy. This neurologic impairment can be quite minor. In some patients, it can become light confusion, some difficulty writing, sometime difficulty forming words, but in more advanced stages can become really – the patient can even become comatose and in early trials, even patients have died due to brain edema. The mechanism of that is still a little bit uncertain. What is most believed to be the case is that the cytokines can cross the blood brain barrier and really trigger sort of a localized reaction in the nervous system and cause the brain swelling while the therapies that we use for example the blockage of the interleukin 6 does not have the capacity to permeate the central nervous system. That reaction can be closely monitored and in most cases, can be reversed promptly with the use of corticosteroids.

So, in order to safely perform the therapy, it is required that the physician and the nurses team that is administering this therapy is very, very familiar with those toxicities. It is fundamental that you have a systematic approach to monitor for those toxicities, recognize and treat those promptly. And when that is done; fortunately, fatal cases become very uncommon.

Dr. Mehta: So, that’s a great point and as you mentioned, with the specialized treatment; we have very specific immune related toxicities and that’s one of the reasons that the physicians and the support staff should be trained and experienced to not only recognize those toxicities earlier and intervene earlier to prevent the fatalities. So, to speak, there is a learning curve with that. Also, these T cells are directed towards CD 19, the currently approved treatment perspective. They are also universally expressed on the B cells and technically what we are doing is some of the B cells which are normal, they get also destroyed. So, these patients might have long-term what we call B cell aplasia and that can lead to low production of immunoglobins and infections. So, in that case, these patients need to be followed very closely. So, overall, not only the physicians but also the supportive staff, the APPs, and nurses should be trained to recognize these complications earlier so that we can intervene earlier.

Melanie: Dr. Mehta, since the CAR T cell therapy was approved recently for treatment of children with ALL; do you see that adults with advanced lymphomas may be close behind and do you expect any other types of this type of therapy to be approved soon?

Dr. Mehta: So, the first approval was end of August when the CAR T cell directed towards CD 19 was approved for acute lymphoblastic leukemia in a pediatric age group, the upper limit of the age group of 25 years. After that, on October – mid October, the FDA also approved the CAR T treatment directed towards CD 19 for lymphomas which included diffuse large B cell lymphoma, primary mediastinal lymphoma, transformed follicular lymphoma, and any aggressive B cell lymphoma. There is also a third product which might get an expansion of the approval which got approved for leukemia for lymphoma maybe early next year. With this success, there is a great deal of enthusiasm. Because once as Dr. Costa mentioned before, the technology is there, now we are to identify a specific antigen which are uniquely expressed on the cancer cell and also this programed and trained T cells can go in and invade to the cancer. The next in line and Dr. Costa can speak a little more to that, is a CAR T in myeloma which has shown very, very promising activity and the date were presented both in ASHCO as well as ASH this year where the CAR T are directed towards BCMA specific antigen in multiple myeloma. Now, this both approaches has opened up the doors of multiple opportunities to look into different cancers. Technically, any cancer where the cancer cell expresses specific antigen and you can program your T cells to target that antigen; you can have a CAR T. The solid tumors, is a little bit challenging at this point. A solid tumor what I mean to say is breast cancer, or colon cancer, or lung cancer and others because of the fact of that in solid tumors the tumor microenvironment is very, very immune resistant. That means they don’t allow – that environment doesn’t allow the immune cells to invade into the tumor space. But we will have more different kinds of T cells programmed so that they can invade so in the future, we might see more so to speak technology to see whether the cells can invade into that.

Melanie: Dr. Costa, do you have something to add to that?

Dr. Costa: Yes, I would like to add to Dr. Mehta’s comment on multiple myeloma, that it is a very common cancer, blood cancer, the second most common type of blood cancer after actually lymphoma and one that for most patients is fatal as opposed to lymphoma where fortunately we are able to treat and cure the majority of patients with aggressive lymphoma with a first or second line of therapy. So, myeloma unfortunately, eventually near all the patients will end up with highly refractory disease so newer treatments are needed. Just like CD 19 was identified as the ideal target for the pediatric ALL and for B cell lymphomas. Such target has several targets have been identified in multiple myeloma. The most promising one is called B cell maturation antigen or BCMA and there are currently at least four different companies very aggressive with developing BCMA target CAR T cells. Some are in phase one clinical trials and we hope to have at least one of those trials at UAB in about one year. But the interesting part is CAR T cells is a fascinating technology and has really shed a lot of light into immunotherapy. But it is important to keep in mind that CAR T cell is not the only way to approach immunotherapy in those hematological malignancies. Dr. Mehta previously mentioned the monoclonal antibodies the so called naked monoclonal antibodies such as rituximab which has been a tremendous success for now 15 years. And there are several in between approaches for example, using the very same target at times that we use for the CAR T cells to target with antibodies that contain drugs that are attached to it so there is a payload of that antibody that allows to deliver a specific poison to the cancer, directly into the cancer tissue and minimize the exposure of normal organs.

Another very fascinating approach is instead of taking the cells out of the body and engineering the cells to the chimeric receptor to target that specific target on the cancer cell. There is the technology of so called bispecific antibodies which are antibodies that in one hand bind to the target in this example BCMA, but on the other hand, they the very same T cells that are the professional killers of the immune system in a way facilitating that robust immune reaction against the cancer with a product that can be manufactured in large scale without the logistic complexity of the CAR T cell therapy. So, those are other avenues that are being pursued and they have many of the same efficacy that remains to be seen, but have some of the same toxicities and complexity and I think over time we will know which approach is best to pursue but it is just important to keep in mind that CAR T cell therapy is not the only way to take advantage of the advances in immunotherapy.

Melanie: Dr. Mehta, first last word to you here in summary, tell other physicians what you would like them to know and this is a huge and very fascinating topic and we didn’t even really get into the cost basis of this and some of the limitations that you researchers are facing. But let other physicians know what you would like them to know about this type of therapy and when they should refer to a specialist.

Dr. Mehta: So, that’s a great question and per the FDA indication, those who have failed two lines of treatment or those lymphomas who are primarily refractory; they will be eligible for this kind of treatment. It is highly specialized and of course the referral will need to be earlier. We cannot wait until the disease is progressing, rather an earlier approach so that we can have the patients in the process. It has multiple steps in that. We want to make sure that the patient’s performance status is good; their heart, lungs, kidneys are good enough to sustain such kind of treatment. They also undergo apheresis, that means collection of T cells. The T cells go back to the commercial facility. They get ready, armed and then they are sent back. The whole process may take somewhere between two weeks to up to eight weeks. And then the patient gets admitted for the chemotherapy and gets the infusion and then needs close follow up. The most important part and I love to say that, that the collaboration would definitely benefit the patient, so, the community doctors who are serving the communities should approach these specialists and these specialized centers who are doing CAR T earlier, recognize the patients, send them before they progress, so that they are in the system and they start getting evaluated.

You also mentioned about the cost which is a big factor because of the fact that both of them they are around half a million dollars of infusion without the admissions and the other chemotherapy that is an additional step that we need to go through the insurance company to make sure that it is approved. We also want to make sure that the patients get proper financial assistance and directions if they had any copay so that they can seek the financial support to get this kind of treatments. So I think the most important part that my message to the physicians who are serving the community is make sure that you identify those patients earlier and make the referral earlier and pick up the phone and call us and we UA

Melanie: Dr. Costa last word to you and then tell us about your team. Why is UAB so great to work with and give us your version of the wrap up.

Dr. Costa: Thank you so much. So, I couldn’t agree more with the words from Dr. Mehta. Dr. Mehta and
I have the privilege of being subspecialized in a – really it is a small sector of oncology and even that is at
various times challenged to keep up with the progress and all the options available. We are both very
deeply involved into clinical research and that’s a very dynamic world where protocols, open and close
and get modified all the time. So, I think the key message to the listener, to the oncologists,
hematologists managing patients with aggressive blood malignancies is if you are facing a situation that is not trivial upfront standard patient, if you have a relapsed patient, a challenging patient; feel free to call us. We welcome the advent of CAR T cell therapy that again, brings some more visibility to what we have to offer but it is certainly not the only thing we offer, and it might be times where we have a different experimental therapy that might be just as exciting or just as promising. Both Dr. Mehta and I, we are involved in very – we have a very broad diverse portfolio of clinical trials including several immunotherapy trials for lymphoma and multiple myeloma and we will be delighted to work with the physicians for the best outcome of their patients.

I think why UAB is special; I think is the people that we have and the privilege that we have to serve the population of Alabama. That’s our mission to be here as a resource to our people at to the resource our colleagues who are in the community carrying the heavy burden of treating cancer patients throughout the states. We have put a lot of time and effort and planning on being positioned to provide novel therapies to patients with advanced blood malignancies in a way that is timely, is ethical and is efficient. And we have both Dr. Mehta and I; we are co-directing this new program at UAB that is being developed as an extension of the bone marrow transplant and cell therapy programs and I think we have made big strides on streamlining the path of referral to make sure the patients who come to UAB with a lymphoma, with a multiple myeloma they have a quick and broad access throughout the available in experimental therapies and the way the cases are discussed, and proper treatment is assigned promptly. We are very proud of the work that we have done and we then we have a lot more ahead of us and we are very proud to be able to serve the people of Alabama and our colleagues in the community.

Melanie: Thank you so much gentlemen, for being with us today and for al the amazing work that you are doing. A community physician can refer a patient to UAB Medicine by calling the Mist line at 1-800-UAB-MIST. That’s 1-800-822-6478. You’re listening to UAB MedCast. For more information on resources available at UAB Medicine, you can go to www.uabmedicine.org/physician . That’s www.uabmedicine.org/physician . This is Melanie Cole. Thanks so much for listening.