Dr. Jonathan Serody discusses immunotherapy as a way to treat cancer, specifically adoptive cell therapy, checkpoint inhibitor therapy and stem cell transplants. He explains how they work, what kinds of cancers they help treat and what the process is like for someone who has these treatments. Dr. Serody is the Elizabeth Thomas Professor of Medicine, Microbiology and Immunology in the Division of Hematology and Oncology, and has a joint appointment in the Department of Microbiology and Immunology.
“This is using your immune system to treat your tumor in a way that bypasses the need for chemotherapy or radiation therapy.”
-Dr. Jonathan Serody on treating cancer with immunotherapy
- Three forms of immunotherapy for cancer
- Adoptive cell therapy process & side effects
- Checkpoint inhibitor therapy
- Stem cell transplants
- Support from the University Cancer Research Fund
Ron Falk, MD: Hello, and welcome to the Chair’s Corner from the Department of Medicine at the University of North Carolina.
We have been discussing different kinds of therapy in the Chair’s Corner, and today, we will talk about immunotherapy—different types of immunotherapy, how it works, and how well it works.
We welcome Dr. Jonathan Serody. He is the Elizabeth Thomas Professor of Medicine, Microbiology and Immunology in our Division of Hematology and Oncology. He also has a joint appointment in Microbiology and Immunology. Welcome, Dr. Serody.
Jonathan Serody, MD: Thank you, Dr. Falk.
Three forms of immunotherapy for cancer
Falk: What is immunotherapy, and what does it mean?
Serody: When I am going to discuss immunotherapy today, it will be in relationship to patients with cancer. There are different immunotherapies I think a lot of individuals would know allergy shots as a form, we’re not going to discuss that. This is using your immune system to treat your tumor in a way that either bypasses the need for chemotherapy or radiation therapy or augments the effects of those therapies.
Falk: Different than, in which for example, an infusion happens for a drug that would be a commercial antibody, for example, that would get rid of a group of cells for patients with autoimmune disease, which would be immunotherapy of one kind as well.
Serody: Yes, that is correct.
Falk: This is a very specific kind of immunotherapy that works remarkably well in some kinds of cancer.
Serody: There are three forms of immunotherapy that have become quite interesting for treating patients with cancer. The one I’m going to mostly focus on is called adoptive cell therapy, which is a treatment where we take your immune cells, engineer them to recognize your tumor, grow them substantially in a lab, and then give them back to you. The adoptively transferred cells then, go target your tumor and in some instances, are quite able to kill your tumor.
Falk: Most forms of chemotherapy don’t have the ability to distinguish just the tumor cells.
Serody: Yes that is a significant limitation to that form of treatment. Chemotherapy drugs kill normal and tumor cells, and the difference often is only in how fast they grow. So normal cells that grow fast like blood cells, the GI tract or your hair are affected by chemotherapy often as much as the tumor cells. These cells that we put back in are engineered with an antibody target that recognizes a specific protein that typically is only on tumor cells. In some instances we will target a protein that is tumor cells and non-essential normal cells like B lymphocytes. But increasingly we are trying to target just the tumor cells.
Falk: Are the tumor cells that you’re targeting specific to an individual patient, or is it to a group of patients with the same kind of cancer?
Serody: It’s specific to a group of patients, so the one we’ve pushed forward right now is a cell therapy for Hodgkin’s lymphoma, and certain types of T-cell lymphoma. Anybody with those diseases would be eligible for treatment as long as the tumor expresses a protein called CD30. Then, we re-engineer their white cells, their T cells, to recognize the CD30 on the tumor cells and kill the tumor cell.
Falk: Other than for Hodgkin’s and other T cell lymphomas, what other kinds of patients would immunotherapy work for?
Serody: We’ve engineered, through work in the immunology program on the scientific side, T cells that will recognize other proteins that are present on other tumors. We’ve opened up a clinical trial for the treatment of patients with multiple myeloma, recognizing a protein called CD138 that is on the myeloma cells. We have a clinical trial for patients with acute leukemia, recognizing a protein called CD19.
Falk: So, this is way more specific kinds of therapy than would otherwise be available.
Serody: That is absolutely correct. Patients come into the infusion clinic, they get chemotherapy medicine to improve the ability of the cells we infuse to take. However, it’s not really designed to kill the tumor and has modest side-effects. They get the infusion in the clinic, and go home a couple hours later, and we just follow them. They are able to go back to work within a few days. It’s much different than getting multiple courses of chemotherapy.
Adoptive cell therapy process & side effects
Falk: Let’s walk through exactly what happens with a patient who is about to get this form of therapy. The patient comes in initially and you take their blood. Walk me through what happens once you have their blood.
Serody: Once we take their blood, it is shipped in a courier van over to a facility that’s a couple miles away from the hospital, where the blood cells are isolated. Those blood cells are then infected with a retrovirus that can’t replicate itself. The retrovirus expresses part of an antibody that can stick to the specific tumor target needed to kill the tumor cell. We infect the person’s white cells, or T cells, with this retrovirus.
Falk: In the lab.
Serody: In the lab. Then we grow, in dishes and flasks, those T cells from a few million to hundreds of millions of cells. That takes about typically 10-14 days. We then test the cells to make sure there are no problems with infectious virus within them, that they actually kill the tumor cells that we target and that they’re viable. Once they complete quality control testing the cells are released to then be infused to a patient either in the clinic or in the hospital. In most instances, the person is brought to the clinic, they’re given the chemotherapy drugs over a couple of days, and on the third or fourth day after the chemotherapy drug, the cells are put right back into an IV line over about 5 minutes. That is all there is to the therapy.
Falk: That form of therapy in that specific construct that you have developed is really unique to UNC.
Serody: Correct. The targeted therapy for CD30 disease—there are a very limited number of places in the USA to get this treatment. You can be treated at our program, the one at The National Cancer Institute and Baylor University which uses our construct. There are additional programs that use constructs made in China. If you want to get T cell therapy for CD30 lymphoma, at UNC, you have to come to UNC as we don’t ship the product. The CD138 target for myeloma will be one of two centers in the country targeting that protein, and one of only a handful of centers targeting any protein on multiple myeloma cells.
Falk: That’s a service that is unique and wonderful.
Falk: Once the patient gets the cells back, do they get ill?
Serody: You can get ill. Typically it’s a different illness than you’d get for chemotherapy or radiation therapy. These cells can basically find tumor cells. When they find tumor cells, they grow and expand substantially. This process is somewhat similar to the immune response to the influenza virus. Similar to those effects, you can have fever and tiredness. However in some instances it can progress from that.
Falk: Sort of a ramped-up flu-like illness, but it’s not a virus.
Serody: It’s not a virus, it’s basically the proteins called cytokines that the infused cells make causing symptoms such as fevers, muscle aches, headaches, which are similar to the flu. However in the worst situations this can lead to problems with blood pressure and breathing if not treated adequately.
Falk: How long do those symptoms typically last for?
Serody: They can last typically 7-10 days. There are therapies available now that target some of the cytokine proteins that mediate the symptoms. We can, in most instances, treat patients so they don’t get immensely ill. Most of the patients who develop this are in the hospital for about a week if they develop this. For the CD30 lymphoma therapy we have not commonly seen.
Falk: Those are people primarily with Hodgkin’s lymphoma.
Serody: Correct. It’s also important that we’ve developed, with a number of faculty members in neurology, the intensive care unit, and emergency department, a lot of expertise in how to manage these patients successfully. I think we have a rather robust approach to managing patients after treatment that is critically important to allow them to get through this. I don’t think you’d want to get this therapy in a small community hospital where you didn’t have the expertise available at UNC.
Falk: When somebody start immunotherapy, how often do they get it? Is it once, is it twice? Every week?
Serody: The adoptive cell therapy that we give is typically given once. Occasionally, we’ve given a second treatment if the first treatment was successful but not completely successful. Typically, it’s no more than twice. That differs from the other types of oncological immunological therapy where you get commercial antibody treatments typically every 2 to 3 weeks for sometimes up to a year. For adoptive cell therapy, it’s usually given once or twice.
Falk: Of the patients that you’ve treated with Hodgkin’s lymphoma, who have really failed almost everything else, how well have those patients done?
Serody: It was a typical clinical trial mandated by the FDA, so we started at a low dose to make sure that the therapy was safe. Once we got to the effective dose, with the effective chemotherapy drugs to make sure the cells took, we’ve treated 16 individuals, 12 of whom went into complete remission**. This was a group of patients that really had exhausted all other forms of treatment. About half of the patients that went into remission have remained in remission. We presented this information at a recent meeting of the American Society of Hematology in San Diego CA if your readers wish to have additional information.
Falk: That’s fantastic, because otherwise if everything else has failed, this is a last resort. That success rate is remarkable in so many ways. Some patients are not candidates for this kind of adoptive immunotherapy. Who are they?
Serody: If you don’t have a tumor that is an easily recognizable target for the T cells, you wouldn’t be a candidate for this. Unfortunately, we have not had as much success in the laboratory treating the predominant kind of cancer that patients get, like lung cancer, breast cancer, colon cancer, prostate cancer. Those diseases have been a little bit harder to treat than blood or bone marrow-based diseases. Right now, there is not an effective adoptive cell therapy using the approach we have for those solid tumors.
Falk: It works in some patients with myeloma. Who are those individuals?
Serody: Right now, we think that anybody with persistent or refractory multiple myeloma would be a candidate for this. Once you get to the effective dose, the data from the National Cancer Institute would suggest that about half of those patients who had failed other prior therapies, almost always including stem cell transplant, would respond to this treatment.
Falk: The hope then, that they would have a long term remission. By remission you mean no evidence of disease that can be detected clinically or radiographically or any other blood tests.
Serody: Correct. We’ve not done this for that long, the shortest had been a few months, the median or average is about nine months or three quarters of the year. For the leukemia therapy, there is clearly data from individual centers that started treating patients before us that about 40-50% of patients with acute lymphoblastic leukemia non responsive to anything, are disease-free and alive 3 years after treatment.
Falk: Because this therapy is relatively new, the approach right now is to treat patients who have been refractory to other forms of therapy. One could imagine, because of the specificity of the drug, that in the future, one would want to use this earlier in the course of disease. How early can you imagine that one could use this form of therapy or other conventional chemotherapeutic therapies less toxic?
Serody: I think you could envision a future not that far away where you might use this therapy initially, especially in a younger individual with Hodgkin’s lymphoma. The majority of patients between the ages of 15 and 30 with Hodgkin’s lymphoma often have more complications from the treatment than they do from the disease.
Falk: Especially long term. Long-term complications of the therapy.
Serody: Correct. You could envision that if you could treat those individuals upfront without ever exposing them to a lot of chemotherapy, you might be able to avert all of those complications of lung, heart damage as well as second cancers. Right now, I think most places are looking at this form of therapy as a way to circumvent the need for autologous stem cell therapy transplantation, which is effective but has a number of complications and side effects and can cause death in some patients. This is probably safer than that form of therapy, and if it’s shown to be as effective—and there are studies doing that now, might be a process that would replace transplant, at least for patients with leukemia and B-cell lymphoma.
Falk: What does the future look like 10 years from now, in your mind? Realistically, what kinds of patients would you be treating? Would you be able to go into the cancers you listed that the approach doesn’t work for, like breast and lung cancer?
Serody: We’re going to start trials in 2020 in patients with ovarian cancer to try to see if we can utilize new targets and potentially other approaches to make the cells work better. I think immunotherapy is here to stay. I think our type of adoptive cell therapy hopefully can be utilized much more widely if we can figure out how to treat solid tumors. Potentially, because our therapy has the ability to work forever, if it does, you can envision that as the only treatment that you may need.
Falk: Wouldn’t that be wonderful?
Serody: It would.
Checkpoint inhibitor therapy
Falk: There’s another form of what could be called immunotherapy, which are a group of drugs called checkpoint inhibitors. What are those?
Serody: Checkpoint inhibitors are antibody treatments that were initially evaluated in academic centers. The two individuals this past year who won the Nobel Prize in medicine, won them for the identification of CTLA-4, which Jim Allison discovered and Tasuku Honjo won it for the identification of PD1. These are proteins that block the immune cells from working. Companies developed antibodies that target those proteins. They can rejuvenate the immune response to cancer.
What’s been pretty clear to us over the last decade, is that a considerable number of individuals generate their own immune response to their own tumor, that over time, loses steam. Eventually the tumor wins out. These checkpoint inhibitor antibodies—by blocking these checkpoint proteins that are important in the ability of the immune cells to lose steam, rejuvenate that immune response and allow you to use your natural immunity to reject the tumor.
Falk: When one thinks about prevention of tumors in general, our immune system is constantly surveying our bodies to avoid or get rid of possible tumor cells.
Serody: So yes, I think that most of us now believe that you’ve probably had a tumor for a very long period of time as a microscopic element that was being successfully controlled by the immune response. Eventually for still not well understood reasons the immune system no longer controls the tumor and that’s the patient can identify either symptoms or a tumor mass. These are probably present for years, under some successful immune control, before they’re not. They’re not, because the immune system exhausts itself over time. These checkpoint inhibitors take the brake off the immune cells to allow those cells to work again.
Falk: An intriguing concept is to have your own immune system really keep all sorts of diseases in check. When that process dissipates, when the immune system dissipates—you used the word exhausted—when it otherwise stops working, tumors and other kinds of diseases become apparent.
Serody: Correct. Checkpoint inhibitor therapy, which is targeting PD1, PD-L1, CTLA-4 with multiple commercial antibodies available as therapies for patients.
Falk: So a lot of different drugs available now, all that come under the guise of checkpoint inhibitor drugs.
Serody: Correct. They work about 15-30% of the time. Perhaps in metastatic melanoma, they might work a little bit more successfully—maybe 50-60% of the time if you combine two drugs. That’s what Jimmy Carter got to treat his metastatic melanoma in the brain, and he’s now in remission. Because they only work 15-30% of the time, there’s been a lot of active work, including at UNC, where we have 7 or 8 open trials, and a successfully large genomics effort to try to figure out why some patients respond, the majority of patients don’t, how to increase the responders, and how to figure out how to make this therapy effective in the non-responders.
Falk: There are side effects of checkpoint inhibitors. There are many of them. Can you list a few of them for us, please?
Serody: They’re the typical side effects you would see for other autoimmune diseases. We’re reinvigorating your immune cells to recognize your tumor, but they’re also reinvigorated and potentially able to recognize some part of you. The most common is thyroid dysfunction, which leads to low or high thyroid function. That happens in about maybe 1 in 5 patients. You also can see lung inflammation that are immune-mediated, kidney problems that are immune-mediated, colitis or diarrhea that is immune-mediated, liver dysfunction that’s immune-mediated. All of these are seen in perhaps 5 to 20% of individuals getting this treatment.
Falk: There’s a consequence of depressing one’s immune system, and there’s a consequence of revving up one’s immune system.
Stem cell transplants
Falk: Talk to us for a minute about stem cell transplant. You alluded to it earlier on.
Serody: We always think it’s interesting, because immunotherapy is not a very novel concept. The notion of immunotherapy goes back about 100 years, to a fellow named William Coley who was at the surgical hospital in New York that became Sloan-Kettering, and was giving bacterial products to patients who had sarcomas and had spectacular success.
An older form of immunotherapy that is used worldwide is stem cell transplant. In most instances, when we talk about this as immune therapy we are taking somebody else’s bone marrow or stem cells from the blood stream and giving them to you after you’ve been treated to make sure that you accept those cells. Those immune cells from the donor have the ability to go into your body and recognize your tumor as foreign and kill them. We utilize that pretty regularly as a way to make sure that that malignancy, mostly leukemia and lymphoma, doesn’t come back.
Falk: The huge difference between a stem cell transplant is that the stem cells are coming from another person—a donor. In the adoptive immunotherapy protocol, it’s the patient’s own cells that are being reinfused.
Serody: That’s right. The problem with stem cell transplant is not only can the donor cells recognize your tumor cells as foreign, but they can recognize you as foreign. That’s a process called “graft-versus-host disease” which can be quite debilitating to patients. It’s been very difficult over the past 40 years to find a way to optimize the ability to kill the tumor without causing those cells to hurt the patient.
Falk: If you think about it, you can rejuvenate an immune response by using stem cells, you can rejuvenate an immune response by adoptive immunotherapy—putting back the patient’s own cells that have been enhanced to kill a specific target, and then a checkpoint inhibitor that also revs up an immune response.
Serody: Correct, and as you said, in most instances, we’re much more enthusiastic about using your own immune system, which is the adoptive cell therapy or checkpoint inhibitor therapy approach. This gets around the problem of another person’s cells reacting against you that can happen with stem cell transplantation.
Support from the University Cancer Research Fund
Falk: One of the important messages for our listeners, is that the really, really innovative work that you’re doing and saving lives, emanates from money that is provided by the state of North Carolina to the cancer center, the UCRF. Can you tell us a little but more about that program?
Serody: Sure, and that’s a great question, Ron. UCRF stands for the University Cancer Research Fund, which was started about a decade ago as a substantial investment by the state of North Carolina in cancer care for North Carolinians. Without those funds, some 45-48 million dollars that come to our cancer center, we couldn’t have recruited the individuals who lead these efforts to develop these therapies, we couldn’t have developed the infrastructure nor the manufacturing facility where we make these products. We couldn’t have recruited the staff to follow the patients, or the staff to help bring the patients here from different parts of the state.
That’s actually been probably the most critical part for us. This support has enabled us to provide a life-saving therapy to fellow North Carolinians that would not be available without the unbelievable generosity of the people of the state of North Carolina.
Falk: It’s a treasured resource.
Falk: Thank you, Dr. Serody for joining us today.
Serody: Thank you.
Falk: Thanks so much to our listeners for tuning in. Our next episode in this series will be about biosimilars featuring Dr. Hans Herfarth.
**Numbers in transcript reflect updated data as of this episode’s publishing date.