Novel Strategies to Produce Better NK Cells for Cancer Treatment

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Emily Le:                              Hi, everyone. I'm Emily Le from Discovery On Target. I am really pleased to have the opportunity to speak with Professor Jeffrey Miller from Division of Hematology, Oncology and Transplantation at University of Minnesota. He will be giving a keynote presentation at the NK Cell-Based Cancer Immunotherapy meeting as part of the 16th annual Discovery On Target conference in Boston on Wednesday, September 26.

                                                Jeff, thank you for joining us.

Jeff Miller:                           Thank you.

Emily Le:                              You will be speaking about novel strategies to produce better NK cells to treat cancer. Can you give us a preview of this talk and share its significance?

Jeff Miller:                           We did working on NK cells clinically for the past 20 years, and I think what we've learned over that time is that understanding the basic biology of NK cells, we have made many advances to perhaps get better efficacy using NK cells with cancer. We started off using autologous NK cells in stimulating one's own NK cells in the body. Really in about the year 2000, we started using haploidentical allogeneic donor NK cells. What I was going to do in the talk is really go through the history of NK cell therapy, go through moving from autologous to allogeneic cells, and I think what's most exciting in the field now is going to off-the-shelf NK cell products. These are products made in large batches. This will permit us to give multiple cell doses for patient. It really allow us to start considering NK cells as living drug products. Citing it's scalable is probably really the wave of the future and there's many, many technologies that I think we're going to hear about during the day about how others are also trying to achieve the same goal.

Emily Le:                              What are some of the common myths about NK cell therapy and how is it compared to the T cells?

Jeff Miller:                           NK cells and T cells share very common mechanistic machinery. In other words, they produce cytokines and gransines to directly kill cell targets. The real difference between NK cells and T cells is their recognition memory mechanisms. NK cells have a whole host of activating and inhibitory receptors. It's really the net sum of these receptor interactions that determine whether a target is going to be killed. I think most of the audience probably knows that T cells have very specific T cell receptors that recognize antigens from tumors that are specific peptides.

                                                In some ways we think that NK cells from the innate immune system are really an earlier component of the immune system, and I think the big thing that is starting to be recognized is how powerful they can be for cancer therapy.

Emily Le:                              CAR T cell therapy has been very successful with the recent FDA approvals. However, these effective immunotherapy comes with a high price tag. Would this be the same dilemma for NK cell therapy?

Jeff Miller:                           Yeah, so we're hoping not. The one major, major difference, and this really gets to some of the future aspects that I'll be talking about as well as others during the day, is really about the concept of using off-the-shelf NK cells. I think what makes the current FDA CD19-targeted CAR T cell products is that the products are really designed to be patient specific. In other words, you take a patient with cancer, either acute leukemia or lymphoma, you harvest their lymphocytes. Those lymphocytes are then sent to a central manufacturing center in the United States. They're genetically modified. They're stored down and they're sent back to the treatment center where the patient will be seen. This is part of the reason that the cost is so high. I think what we're hoping and the most exciting thing for us now is whether we can really get clinical efficacy with an off-the-shelf NK cell product. Here, although it will be expensive to make a large batch of these cells, we're hoping that we can make enough cells in a clinical batch to possibly produce anywhere from 200 to 400 doses and this could be enough cells to treat a whole group of patients on a clinical trial.

                                                I think that this will dramatically bring down the cost. It will certainly increase exportability. The goal is to have these cells in the freezer. You need a dose of cells, you take it out of the freezer, you thaw it, and you give it to the patient. This will dramatically bring down costs compared to the individual genetic modification.

Emily Le:                              Where do you see NK cell therapy field going in the next five years?

Jeff Miller:                           The biggest thing is whether we can achieve this goal of off-the-shelf NK cell therapy. As you and the talk, when we started giving allogenic NK cells in the year 2000, we use individual haploidentical donor NK cells. That means we typically use family relatives that were [inaudible 00:05:13] half matched, and we had to perform individual collections over five hours to get enough NK cells to make a dose of these cells, and it really limits us quite a bit. We've only tested NK cell therapy as giving typically one dose. In a few trials, we've tried to give a second dose of NK cells, but we're really limited by the individual collections of these lymphocytes from the related donors and it's really not feasible to collect these from donors more than one or two times. This gets to the cost issue that you and I just talked about. I think the future is really, can we get an off-the-shelf platform?

                                                Well, I'm going to be talking about induced pluripotent stem cell-derived NK cells. Others have talked about getting stem cells from umbilical cord blood progenitors or expanding them from peripheral blood or even the possibility of using cell lines, and I think we're going to hear about it during the schedule that is planned for the day.

Emily Le:                              I see. Is there any advice you want to give to the young scientists in this field?

Jeff Miller:                           Yeah. It's a great question. It's really a great time, I think, to get into NK cell therapeutics. As we've already discussed, this is really being spurred on by the FDA approval of two genetically modified T cell products, and I think it's really led to an explosion of excitement in immuno-oncology. For the young scientists, it's a great time to get into the field. I think the thing that I would remind everybody is that the workings of living cell products, NK cells specifically is really, I think, dependent on the basic biology of these cells, how they recognize targets and how to really have the biology drive affect the cell therapies.

                                                I think that young scientists need to be persistent. They need to have good science. They need to really enmesh themselves in this new field of translational research, which is taking basic biology of cell recognition and building in some of the practical aspects to bring it into the clinic. I mean, that's certainly been what we've been trying to do in our lab. We've been working on these recognition mechanisms. We've been trying to understand how to make NK cells better, how to make them more potent, how to make them survive after you infuse them into patients. This has led to very, very basic biologic questions and how to make NK cells antigen specific, whether they be with CARs or whether they be with immune engagers really that selectively bind to activating receptors of NK cells and tailor them to be antigen-specific.

Emily Le:                              What presentations and sessions are you looking forward to the most at this NK Cell-Based Cancer Immunotherapy meeting?

Jeff Miller:                           Yeah, because of what's going on in the immuno-oncology space, I think we really have a wonderful opportunity to compare technologies to compare possibilities. I think the goal is very, very clear. Everybody wants to develop effective cell therapies against both hematologic malignancies where we perhaps have more experience but really try to understand how to go beyond hematologic malignancies and get to solid tumors. What I think what has really been put together at this Boston meeting is a group of scientists. In addition, a group of companies that have really defined themselves as being vested in NK cell therapies and I think we're going to hear about an update of a number of new possibilities driven by basic science about how to make NK cells really the wave of the future for cancer therapy.

Emily Le:                              Wonderful, Jeff. Thank you for your time and insights today.

Jeff Miller:                           All right. Thank you, Emily. You have a good day.

Emily Le:                              That was Professor Jeffrey Miller from University of Minnesota. He will be speaking at the NK Cell-Based Cancer Immunotherapy meeting in Boston as part of the 16th annual Discovery On Target conference. If you'd like to hear him in person, go to www.discoveryontarget.com for registration information and enter the key code podcast. I'm Emily Le. Thank you for listening.