Targeting Tumor Marker B7-H3 with Engineered Natural Killer Cells - Nicholas Zorko
January 11, 2023
Nicholas Zorko, MD, PhD, Assistant Professor of Medicine, Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN
Alicia Morgans, MD, MPH, Genitourinary Medical Oncologist, Medical Director of Survivorship Program at Dana-Farber Cancer Institute, Boston, Massachusetts
Alicia Morgans: Hi, I'm so excited to be here with Dr. Nick Zorko, who is a young investigator for the PCF from 2022 joining me here at the PCF annual meeting. Thank you so much for being here with me today.
Nick Zorko: Thank you for inviting me to come talk with you too.
Alicia Morgans: Wonderful. Well, I'm so excited about your science and about your project. Can you share a little bit about what you and the team at the University of Minnesota are planning and pursuing for this Young Investigator Award?
Nick Zorko: Yes, I absolutely can. So the University of Minnesota is very focused on natural killer cell therapies. Most of the other cellular products that are currently being investigated are T-cell based. We're one of the few places looking at natural killer cells for solid tumors as well. So our project focuses on redirecting engineered natural killer cells to target the tumor marker B7-H3. And what's really interesting about B7-H3 is that it's very highly expressed on prostate cancers and fortunately many other cancers as well, but in the context of there's very low PD-L1 and checkpoint inhibitor expression on these same cancers. So we think this is a great target. There's very little expression of B7-H3 on normal tissues that many other groups have found and confirmed too. So we think this is going to be a great target for treating prostate cancer with these cellular therapies.
What we've done is we've been able to engineer natural killer cells and then we've added a chimeric antigen receptor specific for B7-H3. So this makes a cell that's normally not antigen specific and takes it to make it antigen specific. We have a couple of other modifications that we've been able to make with our therapeutic partners as well, Fate Therapeutics, and that includes high affinity CD-16 that allows us to add a second monoclonal antibody to redirect the cells as well to give it a second kill signal. And then there's IL-15 receptor, IL-15 receptor alpha fusion, which gives it the go and proliferate signal. And then we've made some metabolic changes as well by knocking out CD-38. So really there's four genetic modifications we've made to these cells.
Alicia Morgans: Wonderful. So tell me a little bit about where things stand. Are you in cell lines right now? Are you in mouse models or other preclinical work or are you launching soon into the clinic?
Nick Zorko: So we are in preclinical work right now. We have a working product now, which we're super excited to get our hands on and we are starting validation this week actually my technicians back at home in Minnesota are working on their first experiment while I'm here. We were super excited to get that laid out and ready to go. We're going to try to move as fast as we can with cell lines and then go to more 3D models using some of the live imaging techniques that we've developed in the lab. And then we're hoping to get this to into an animal model within the next six to eight months, I would hope.
Alicia Morgans: Wow, that is lightning speed. And you and the team, as you said, at Minnesota have been working on these cell based therapies, these NK targeting therapies for some time. Do you anticipate that in the next few years you'll have a first in human for this particular product?
Nick Zorko: That is our goal, yes, to have a first in human maybe in the next two or three years. The goal was to have a clinical trial open for first in human for this B7-H3 targeting Car-NK by the end of my Young Investigator Award.
Alicia Morgans: That is an amazing accomplishment. We know that you'll get there and we are really, really excited to hear how things go. Anything else you want to add? Are there considerations that we should have as clinicians as we think about these NK targeted therapies coming down the line? What does the side effect profile look like? Are we still talking about cytokine release type syndrome or are there other symptoms or side effects that we should be aware of as these are being developed?
Nick Zorko: So our thought is that with NK cells, there's actually less cytokine release syndrome compared to T-cell based products. That's one of the reasons we're so interested in it, that we believe that it's safer. NK cell products can also be designed as off the shelf as well. So there's not a concern for graft versus host disease like there is with T-cell products that have an intact T-cell receptor. So that's one of the great things we can expand and make a master line of these cells and then infuse it in any patient. There's no collection of autologous cells and then modification of those cells required. We can use the same cell product in all of our patients. So the vial gets sent, it gets thawed and it gets infused. So there's not a lag as there is with conventional T-cell chimeric antigen receptors. These can be available right away for patients that really need treatment now and not in six weeks if we're worried about progression.
And then, like I mentioned cytokine release syndrome is thought to be much less. There's a pretty minimal signal so far from what we've seen in some of our other NK cell engager molecules compared to T-cell engagers. So we think these will be safer, potentially eventually be able to be used in the outpatient setting that's further down the road. But it's an ultimate goal to truly try to reduce the hospital stays and increase the safety of these products for patients.
Alicia Morgans: And of course give a broader opportunity for patients to be able to get them because prostate cancer patients are often older and have multiple comorbidities. So that is so important and wonderful that you and the team are really focused in that direction. I am so excited that you are focusing your efforts on prostate cancer and I think the community is really lucky to have you. Congratulations again on your Young Investigator Award and please keep up the good work.
Nick Zorko: Thank you very much and thank you again Dr. Morgans, for having me here and letting me talk about my work. I really appreciate and I'm excited to continue our work.