Engineering NK Cells for Enhanced Potency and Persistence

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Emily:                    Hi Everyone, I'm Emily Le from Discovery on Target. I am very happy to have Dr James Trager, Senior Vice President from Nkarta therapeutics with us today. He will be giving a presentation at the NK Cell-based Cancer Immunotherapy meeting as part of the 16th annual Discovery on Target conference in Boston on Wednesday, September 26th. James, thank you for joining us.

Dr. Trager:           Yeah, thank you so much for inviting me, Emily.

Emily:                    You will be speaking about engineering NK cells for enhanced potency and persistence. Can you give us a quick preview of this talk and share it's significance?

Dr. Trager:           Well, first, NK cells have characteristics that should lend themselves to development of effective cancer therapies. They recognize tumor cells very broadly, across many indications. They have very high cytolytic activity. They have an ability to discriminate between healthy and diseased cells. They have an ability to recruit the adaptive immune system.  But I have one friend who compares NK cells to a recent college graduate who's got all the ability in the world but just hasn’t quite figured out how to apply it yet.

So at Nkarta, we think we have some tools that will help NKs to unlock their potential. Specifically, we're using technology that was originally developed by our founder, Dario Campana, who's now at National University of Singapore. He's been working on NK cells for many years and has pioneered a suite of technologies to expand natural killer cells to clinically meaningful doses, and to engineer them to enhance their in vivo persistence, heighten their sensitivity towards tumor cells, and to evade some of the major inhibitory factors present in the tumor micro environment that block NK antitumor activity. I'll be presenting some preclinical results showing how we’re combining these elements into one package that we think will be a very attractive clinical candidate.

Emily:                    What are the next steps in your research and the vision of Nkarta in NK cell therapy development?

Dr. Trager:           Well, like everybody in this field, there's a couple of major challenges. First is reducing the NK technology to practice in the context of a GMP manufacturing environment.  Much of our technology has already been used in the clinic, and that's an enormous leg up in terms of demonstrating feasibility of the process. But, of course, we're going to be adding some new elements that haven't been assessed previously- in general, there's a very thin history of engineering of natural killer cells for clinical use. And along with that, there are elements of the manufacturing process that we're busy streamlining and optimizing. Again, that’s a challenge for everybody in the field of cell therapy - to take ideas that work on the bench and translate them into manufacturing paradigms that are fit for both clinical development and eventually for commercial use.

The second major challenge that we're all grappling with is how to bring cellular immunotherapies for cancer to bear in solid tumor settings. In that context, NK cells potentially have some advantages over T cells, one being their ability to recognize multiple signals that may be expressed on tumor cells. In contrast, T cells typically recognize just a single epitope that may not have complete penetrance in the tumor and may be easily edited out. Even better, many existing standards of care in cancer upregulate the ligands that are recognized by natural killers. Figuring out how to put these pieces together, how to make the best therapeutic combinations, the best therapeutic sequencing, select the appropriate clinical populations for application of natural killer cell therapies is an exciting challenge we all face.

Emily:                    So, you've been working on this field for quite some time now, what are some of the common myths about the NK cell therapy that you’ve seen so far?

Dr. Trager:           Well, I'm not sure if it's quite a myth exactly, but there's a lot of discussion in this field over the development of what are called off the shelf therapies.  That derives from the ability to use natural killer cells in an allogeneic context. And the ability to produce and utilize natural killer cells allogeneically is certainly an attractive feature of NKs; allogeneic cells have advantages, both for manufacturing, and in terms of product potency.
But there are disadvantages, too. To use allogeneic NKs without extensive engineering typically requires either lymphodepletion of patients, or very tight HLA matching with the patient – or both. Lymphodepletion can interfere with the ability of NKs to enlist an adaptive response, so it can abrogate some of the potential advantages of an NK cell therapy -  and obviously, the lymphodepletion itself is a pretty exacting therapeutic regimen that may prevent application in some patient populations.

Haplotype restriction may prevent these cells from truly being an off the shelf solution. Nkarta is certainly isn’t dismissing the use of allogeneic NK cells: the biology will determine which direction we choose to go, but it's important for everybody to bear in mind that there are trade-offs and potential shortcomings in allogeneic approaches. And in most cases they’re hard to describe as a truly off the shelf products.

Emily:                    Is there any message you want say to the scientists who work in this field?

Dr. Trager:           I would just say it's great to see the variety of approaches that are being taken in this field. It's really, a highly variegated and imaginative field. People already using really very, very different approaches, from the use of immortalized cell lines, to autologous or allogeneic cells, stem cell derived NKs, different platforms for the expansion of cells, and focus on different elements of the biology.

It's fun to work in such a rapidly developing field and one that I believe is on the cusp of meaningful application. The biological challenges of understanding NKs and their best use is still daunting - just arriving at a mutual understanding of basic terms that are frequently used in the field can be tough. Understanding what memory NKs are, for instance, and what different researchers mean when they use the phrase, is still a challenge.  Harmonizing our understanding is going to be crucial going forward if the field is going to progress. Meetings like this one are really an important venue to bring researchers together, to exchange notes and views, and get on the same page in our understanding of the biology and the terms that we use.  Speak the same language and make progress together.

Emily:                    As the conference is approaching, what presentations and sessions are you looking forward to the most at the NK cell-based immunotherapy?

Dr. Trager:           Well, I hate to single people out because there's so many great talks, so I'm going to just mentioned a couple of folks that I haven't had the opportunity to hear speak before because that's always exciting. One is Kai Wucherpfennig -  he's done incredible work in immunology for a long time, so to hear him speak and hear him discuss his lab's work on the inhibition of MIC protein shedding should be a treat - that's in the opening session on modulation of NK cells. Another talk I'm looking forward to is David Finlay's discussion during the clinical development session, on NK cell metabolism.  That should be a fascinating talk and it's a very timely one, really, as we start to think about the use of NK cells in solid tumor settings. Those are just a couple that I would pick out, but again, it's a really great lineup, so I'm looking forward to the whole meeting.

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

Dr. Trager:           Oh, you're welcome, and thanks again for inviting me to the conversation.

Emily:                    That was Dr. James Trager, Senior Vice President from Nkarta Therapeutics. 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.