Frederick Locke, M.D., a medical oncologist and director of the Immune Cell Therapy Program at Moffitt Cancer Center in Tampa, Florida, talks about a new form of immunotherapy that is being called a milestone in cancer treatment.
Interview conducted by Ivanhoe Broadcast News in February 2017.
Can you tell us about CAR-T therapy?
Dr. Locke: Absolutely. CAR -T cell therapy, also known as chimeric antigen receptor, therapy, is a cellular immunotherapy for patients with B cell leukemia’s and lymphomas. This therapy consists of using the patient’s own immune system cells. We take the cells out of the patients— the patient’s own T cells out of their blood, and they are engineered to be redirected against a target which exists on the surface of their cancer cells, That target is CD19. These are CD19 targeted CAR- T cells.
Is this for a specific kind of patient?
Dr. Locke: Right now we’re running clinical trials for patients with B cell malignancies, B cell cancers. This includes aggressive lymphomas like diffuse large B cell lymphoma, mantle cell lymphoma as well as acute lymphoblastic leukemia. All of these are cancers of B cells. All B cells have CD19, the target of these CARs on the surface of their cells. We take the cells out of the patient and they are shipped to a centralized manufacturing facility where they’re engineered to retarget against CD19 on the surface of the cancer cells.
Then it goes back in to the patient and the hope would be it would—
Dr. Locke: This is using the immune system against cancer. Imagine if we get the flu we have immune system cells that recognize the flu and they proliferate and grow and go and kill the flu or any cells infected with the flu. In this case we’re taking out all the T lymphocytes or T cells, redirecting them all against CD19 which is on the surface of the cancer cells and re-infusing them in to the patient. We get the cells back from the manufacturing facility frozen. We then give the patient some chemotherapy to kind of depress their normal immune system and make some space for those CAR T cells. We thaw out and infuse the CAR T cells in to the vein and they proliferate and grow some more and go ahead and kill the cancer. Those cells then act as if that CD19 is foreign or abnormal. The cells go in the body, they activate for a fight, and they kill the target cells: the cancer cells in this case that express CD19.
How many times does it take to do that?
Dr. Locke: It doesn’t work for everyone. Again these are clinical trials that have been quite successful in patients who are completely refractory to standard chemotherapies and other therapies that exist. We’re seeing pretty remarkable response rates, complete response rates in these patients. It’s really a onetime therapy. We do the therapy one time and we hope that it puts the patient in to remission. In fact the trail that we’re involved with that has the most mature data is in patients with diffuse large B cell lymphoma, a common B cell lymphoma. These are patients who could at best expect about a eight percent chance to get in to a complete remission with standard chemotherapies. In these patients we’re seeing close to a forty percent durable complete remission rate. In fact in the Phase I results which we recently published those complete remissions can be durable as long as a year. Going back to studies done earlier at the National Cancer Institute, patients are in complete remission up to four years. It’s really quite a remarkable therapy.
What’s the procedure like? Is it an injection or?
Dr. Locke: To collect the cells we utilize a machine called an apheresis machine one time: it’s sort of like a dialysis machine. The patient gets hooked up with a normal catheter one in each arm or a large bore central catheter that goes in to a central vein. The blood comes out it goes through a machine that removes the T-Cells that we’re interested in and the blood is returned to the patient. Again those cells are then shipped to the manufacturing facility. Then when the cells come back, the patient gets chemotherapy and then the cells are just infused in to the vein. It’s quite a simple procedure to give the cells. The therapy is not without some potential side effects. You can imagine if the immune system gets revved up people get fevers and low blood pressure. If you have the flu you- you can get quite ill and that’s the immune system reacting. In this case the redirected CAR-T cells can get very angry and excited as they kill the cancer cells. Patients can get low blood pressure sometimes, high fevers and so they have to be monitored in the hospital for at least a week and in some cases longer to make sure that it’s safe and they are recover completely. We’ve been able to safely administer this therapy at Moffitt Cancer Center for our patients and we are seeing response rates that are quite remarkable.
Do you see the responses in a week or does it take longer?
Dr. Locke: You can see the responses happen quite quickly, yes. In some cases within a week patients who have lymphomas where they have enlarged lymph nodes maybe under their arm or on their neck you can see it almost melt away within a week. We do the first disease response assessment with imaging studies one month after the treatment and we certainly see responses at that time.
I guess Forbes rated this as one of the top milestones in 2016, why do you think that is?
Dr. Locke: We’re really excited to be a part of it. On our roles at Moffitt Cancer Center is to bring these industry sponsored CAR-T cell studies to our patients. These are multicenter studies and where we’ve been successful is to very quickly and safely open these studies up to all of our patients and, again, it’s a new therapy. It was created at single centers like the National Cancer Institute and now there are these multicenter studies. Pharmaceutical companies like Kite Pharma, who we’re partnering with, believe that this can get FDA approval for indications like diffuse large B-cell lymphoma and acute lymphoblastic leukemia. It is exciting because with lymphoma patients who don’t respond to their last chemotherapy or relapse very early after standard therapies like a transplant, a stem cell transplant, those patients at best can expect an eight percent chance of having a complete remission. We’re seeing up to forty percent of patients going in to durable complete remission with this therapy. It really offers an option for patients who were otherwise without hope. Even for patients that aren’t achieving durable complete remission we’re seeing over seventy percent of patients having some response to the therapy.
Dr. Locke: It’s a new type of cancer therapy; it’s re-engineering the immune system cells against the cells in our body. Immunotherapy has really come on as quite an advance in cancer care in the last five years. This is another step. We’re actually taking the cells out and reprogramming them to get the strongest response possible from these chimeric antigen receptor T cells or CAR T cells.
In other immunotherapy isn’t that what they do also or is that different?
Dr. Locke: Most FDA approved immunotherapy’s are drugs or monoclonal antibodies that are infused in to the vein that go and turn the immune system on, or specifically turn the brakes off, kind of interrupt the natural ability of the immune system to stop an immune response before it causes damage. This therapy is different it’s actually a cellular immunotherapy, it’s engineering a patient’s own cells against the cancer. Right now the greatest cellular therapy success is with these CD19 targeted CAR-T cells against B cell leukemia’s and lymphomas. We hope that eventually this sort of therapy, against alternate targets, can be widely utilized against solid tumor malignancies such as lung cancer and breast cancer. Our scientists are actively working on developing new CAR-T cell therapies or other engineered T cell therapies against those malignancies as well.
What stage are you in, in the trial? How close is this becoming available?
Dr. Locke: The trial that we’re involved with is with Kite Pharma and the study is primarily aimed at patients with refractory aggressive diffuse large B-cell lymphoma. The Phase I results were published very recently in the scientific journal Molecular Therapy. Out of the seven patients treated in the Phase I portion of this study three remain in complete remission over a year out. The Phase II study has completely enrolled over a hundred patients and we’re awaiting the planned primary analysis of that study which includes at least a six month follow-up of all patient that were treated. Those results will be presented likely in early May.
Anything else about CAR-T that you think the public should know about?
Dr. Locke: Only that this is a really exciting time. We’re really happy to be able to bring this therapy to our patients. It’s pretty amazing to see patients go in to remission when we really had low hope of standard therapies working. This treatment has really been quite remarkable. It doesn’t work for everyone so we’re working to find the next thing that can help those patients that don’t respond to this therapy. We believe that it’s very promising that this CAR-T cell therapy could get an FDA approved indication for diffuse large B-cell lymphoma and possibly acute lymphoblastic leukemia as well in the near future.
Do you think like in a year, two years?
Dr. Locke: I’m hopeful that in 2017 we’ll see indications for both aggressive B-cell lymphomas, like diffuse large B-cell, and acute lymphoblastic leukemia. As I mentioned Kite Pharma is one pharmaceutical company working on these multicenter studies which we’ve helped to lead. There are several other pharmaceutical companies that are also working on indications for acute lymphoblastic leukemia and lymphoma.
The candidates for this, what’s the percentage of patients that have this kind of—
Dr. Locke: Diffuse large B-cell lymphoma is one of the most common blood malignancies out there and it is curable up front with chemotherapy in approximately sixty percent of patients. In patients who relapse, a small percentage of those patients can respond to chemotherapy and be cured with autologous standard stem cell transplant. The remainder of patients end up being refractory to chemotherapy and other standard treatments or relapse early after standard autologous stem cell transplant. If this gains FDA approval we think that thousands of patients in the United States per year could be eligible for these therapies. In fact the manufacturers are preparing for that. There will be the capacity to manufacture many thousands of these engineered CAR-T cell products. We here at Moffitt Cancer Center plan to be ready to administer these treatments to our patients. We really think that this is a therapy that can work very well for some people and we want to bring it safely and quickly to our patients.
When you say they’re engineered is it customized for that patient or what happens?
Dr. Locke: The customization is that we’re using their own cells. In fact the engineering of T cells involves putting in the chimeric antigen receptor. That is basically a molecule that gets put in to the patient’s own cells which redirects them. Sort of like putting GPS navigation in that T-cell, it makes it a CAR-T cell. After it’s infused back in to the patient, it knows where to go and it tells the T-cells to activate for a fight when they recognize CD19 on the surface of these cells.
Can you tell me a little bit about Jeff’s case?
Dr. Locke: Dr. Jeff Backer is a patient that was actually referred to see us because of refractory lymphoma. With standard therapies he was growing in between treatments. The lymphoma was actually growing in between each treatment cycle and we really needed to interrupt that progressive lymphoma and do something different. Fortunately he was eligible for our clinical trial that we had open and we were able to quickly collect the cells and ship them out for manufacture and then administer the CAR-T cells and so far are very pleased with the results. It’s been over six months that he’s in complete remission. No evidence of the lymphoma and we’re very pleased. Certainly a success.
Where are the cells engineered, is that here at Moffitt?
Dr. Locke: No, the cells are collected here at Moffitt on apheresis machine, which is sort of like a dialysis machine, and they are shipped out fresh, in this case, to Kite Pharma’s manufacturing facility. It’s a centralized manufacturing facility where they’ll be ready to manufacture thousands of these products should it be granted FDA approval. Then that’s where they engineer them and reprogram the patient’s own T-cells and then they freeze them and ship them back to us. We have scientists here at Moffitt Cancer Center, including myself, who are working on new cellular therapies similar to this for both solid tumors and other blood cancers as well. We’re pretty excited to be involved in this particular therapy and be ready to administer other similar therapies when the time is right for our patients.
How long does it take from the time the cells are extracted from the patient to be engineered and then to be replaced?
Dr. Locke: When we collect the cells and ship them out fresh the turnaround time is less than three weeks. We get the cells back frozen in less than three weeks. The actual manufacturing process really only takes about six to eight days. There’s obviously shipping and the freezing process and making sure that everything is safe to administer. In what’s a relatively short period, in about three weeks, we are ready to infuse the cells again after some conditioning chemotherapy to make space for the CAR-T cells.
END OF INTERVIEW
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