New Horizons in Cellular Therapy: Harnessing Our Body’s Natural Killer Cells to Fight Cancer

Natural killer (NK) cells are specialized immune cells that can recognize and destroy threats, including cancer. Due to their unique capabilities, they have great potential in cancer immunotherapy, with multiple NK cell-based approaches already being evaluated in clinical trials.

In this webinar, we explore how NK cells work and how we might apply them against cancer, with renowned NK cell expert Lewis L. Lanier, PhD, and Oscar A. Aguilar, PhD, a Cancer Research Institute (CRI) fellow in Dr. Lanier’s lab at the University of California, San Francisco (UCSF).

A member of the CRI Scientific Advisory Council and National Academy of Sciences, Dr. Lewis Lanier has made a number of important discoveries into NK cell biology, especially the receptors that activate and inhibit them. Currently, he serves as the Chair of the Department of Microbiology and Immunology, the American Cancer Society Professor of Microbiology, and the leader of the Cancer Immunology Program at the UCSF Helen Diller Family Comprehensive Cancer Center. Since 1992, Lanier has sponsored seven CRI fellows studying NK cells.

Dr. Oscar Aguilar’s work focuses on understanding how NK cells bind antibodies and how this influences their activity and ability to respond to threats.

The “Cancer Immunotherapy and You” webinar series is produced by the Cancer Research Institute and is hosted by our senior science writer, Arthur N. Brodsky, PhD The 2021 series is made possible with generous support from Bristol Myers Squibb and Alkermes.

Browse our Cancer Immunotherapy and You Webinar Series playlist on YouTube or visit the Webinars page on our website to see other webinars in this series.

WEBINAR TRANSCRIPT

Arthur Brodsky, PhD: Hello, and welcome to the Cancer Research Institute "Cancer Immunotherapy and You" patient education webinar series. I'm Dr. Arthur Brodsky, assistant director of scientific content at the Cancer Research Institute. And during today's webinar, we'll be focusing on "New Horizons in Cellular Therapy: Harnessing Natural Killer Cells to Fight Cancer." Over the next half hour, we'll be speaking with two CRI scientists who are performing cutting-edge research and natural killer cells or NK cells, and hear from them about these important immune cells and their applications in cancer immunotherapy, both currently and moving forward. In particular, they'll be highlighting what NK cells are and how we know they're important in cancer, the potential benefits that NK cell immunotherapies could offer for patients, and discuss some promising natural killer cell approaches that are currently being evaluated in clinical trials. Toward the end, we'll also hopefully have some time to answer some audience questions, which you can enter via the Q&A box below.

Arthur Brodsky, PhD: So, before we begin, I'd like to quickly thank our generous sponsors of this webinar series, Bristol Myers Squibb and Alkermes. And now it is my pleasure to introduce today's expert guests. First, we have Dr. Lewis Lanier, a world renowned natural killer cell pioneer and CRI Scientific Advisory Council member at the University of California, San Francisco. And we also have Dr. Oscar Aguilar, a CRI-funded postdoctoral fellow in Dr. Lanier's lab whose research is an exploring an important aspect of NK cell biology.

Arthur Brodsky, PhD: So thank you for joining us today. I guess we can hop right in. So first, I was hoping you all could explain what are natural killer cells, and how do we know they're important in cancer?

Lewis Lanier, PhD: Well, I guess I'll take that question, since I've been working on natural killer cells since 1981. They were discovered as an activity in 1975. And about '81, we actually could detect them and identify them. It's about 10 to 20% of the lymphocytes in your bloodstream and in your other lymphoid organs.

And we know they're important based on a really seminal observation by one of my classmates at Chapel Hill, who was a grad student at the same time as me. She discovered the first human that was found to have no natural killer cells. This was a young woman. And what she suffered from was certain viral infections, which ultimately killed her. And these were largely herpes viruses. She had normal B and T cells and other immune cells. But without NK cells, she ultimately died of viral infections.

We've also studied- this is a rare disease – but we've also studied a couple of other patients who had no natural killer cells. The woman got cervical cancer, and the guy has warts he can't control and both of them have trouble with viral infections. So based on Christine Byron's seminal observation in 1989, we really know why us humans have NK cells.

Arthur Brodsky, PhD: I was hoping you could maybe explain a little bit more about the role that natural killer cells play within our immune system as the sentinels that can go around and not only kill cancer cells directly, but also act as an orchestrator of the immune system and trigger other cells, namely T and B cells, to help aid in the immune response. I was hoping you could elaborate on that a little bit.

Lewis Lanier, PhD: Oscar, maybe you could help fill in that question.

Oscar Aguilar, PhD: So, NK cells are really, really- they're equipped with the specialized proteins that can detect anything that's harmful in our bodies. And once they get activated, they release the soluble factors, which then influence the other parts of the immune system. What's also unique about these cells is that they're equipped with these receptors, or these proteins on their cell surface that can detect antibodies that are being generated by our immune systems.

And of course, now with the age of COVID and everything that we've been going through, I think everyone's pretty much aware of what what antibodies are. But these are specialized proteins that are able to target specific proteins. In the case of COVID. It's targeting proteins that are generated by the virus, but we're also employing antibodies for targeting specific proteins that are expressed on cancers.

So using antibodies, NK cells can directly kill antibody coated cells using this machinery that they express. And what's unique and really supporting what Lewis was saying is that there are some individuals that have different variants of this machinery of this receptor called CD16. And they, those people that have variants that have better detection capacity of recognizing the antibody actually have better prognosis.

Arthur Brodsky, PhD: That's really interesting. So I want to dig down into that a little more. Obviously the antibodies are naturally produced by our immune system to help us with threats. But also in the case of cancer, we sometimes use antibodies – in the case of blood cancers, one that targets, one called rituximab, that targets the CD20 receptor. And then another one, Herceptin, HER2, that targets the HER2 receptor in a variety of cancers.

And to your point Oscar, where this CD16 receptor that binds the antibodies influences how patients respond to treatment sometimes, could you, whoever would like to take it, talk a little bit about more about the studies, where it found out that how patients responded to immunotherapy depended on what type of NK cells they had.

Lewis Lanier, PhD: Oscar, please.

Oscar Aguilar, PhD: So there's some studies that have been reported. And by the way, I should mention that CD16 is not only expressed on NK cells, but it's also expressed on other parts of the innate immune system. But they definitely researchers went in, and they've identified specific variants, also known as alleles, of this receptor. And they showed that when they track patients that had this allele, or this variant that was better at recognizing antibodies, they were more effective at controlling and responding to the antibodies that were being injected, and ultimately result in better outcomes for the patients.

Arthur Brodsky, PhD: That's pretty fascinating to hear. And I should mention that these these therapies have been around for a decade or more. And I know, they were initially designed to that, but designed for that. But we've learned a little bit more about how to tap in NK cells' power. So how are newer antibody based therapies using this antibody dependent natural killer cell killing to tap into NK cells power against cancer?

Lewis Lanier, PhD: Well, I've been involved in helping some biotech companies involved in those processes. So what they've been doing is making what's called bispecific antibodies. So antibodies are kind of Y shaped molecules, you have one arm, and you have a second arm. So with the one arm, if you grab the cancer, the second arm can grab the NK cell by one of its receptors that can turn the NK cell on. These are called bispecific antibodies.

So one of the new strategies, and there is already one, I believe, approved drug which works in that manner. So one of the arms grabs this CD16 molecule Oscar mentioned, which will activate the NK cell, the other arm, will grab a molecule that's expressed on the surface of Hodgkin lymphoma cells. Now, you bring the NK cells with the cancer cell together, the NK cell knows who to kill and kills it. So there's a lot of new variations of that theme of using antibodies with one arm that would grab the NK cell and turn it on. And with the other arm grab various types of cancer cells.

For example, if you use a HER2-reactive form that would combine to a breast cancer cell. So, these are in clinical trials currently, so that's been a very new way to engage the NK cell and use it as a cancer therapeutic.

Arthur Brodsky, PhD: That's great to hear. As we've learned more about the NK cell biology and also our engineering skills or engineering tools have increased, it's nice to see those being brought together to to help patients hopefully. And so, those bispecific antibodies are also made for T cells, which kind of get all the glory in immunotherapy these days.

And so, in addition to targeting NK cells with antibodies, like T cell therapies, doctors can also just infuse the actual NK cells into patients for treatment. So, in this context, what benefits do natural killer cells offer? And what are some of these promising cellular cellular therapy approaches that are being evaluated in clinical trials right now?

Lewis Lanier, PhD: So, as you know, you've probably seen a lot of press, there are a lot of these cells called you know, CAR T cells, where you put a new receptor in the T cell, infuse that into patients these are FDA-approved, are working quite well in leukemia lymphoma. But one of the problems is, is that the T cells are responding too strongly. And in fact, when they respond too strongly, as an off-target, have killed people. So, you have to be very careful.

The good thing about NK cells, NK cells have been infused into patients now for more than 20 years, and have never killed anyone. That's the upside. They're safe. So now we're trying to have them work as efficiently as the T cell in going after these leukemias and lymphomas, but without the side effect of the toxicity.

Arthur Brodsky, PhD: That's obviously great to hear. And could you also talk a little bit about – I want to throw it out little technical term here allogeneic, meaning that you wouldn't need to necessarily- you could treat a patient not necessarily by taking their own NK cells, but by having donor NK cells that could be, as they say, off the shelf, that could be kind of waiting for a patient so that they could be not waiting, but they're ready so that when they are needed, they can be deployed quickly. Could you talk about some of these efforts?

Lewis Lanier, PhD: They're in the fridge, that's what you mean by off the shelf. You pull them out of the fridge and warm them up and put them in. So, allogeneic means for example, if you take your NK cells and give them to me, they're called allogeneic because they're not mine. If you do that, with your T cells, your T cells will attack me and cause what's called graft versus host disease. And you know, really wreak havoc.

NK cells are much better behaved. If you take your NK cells and stick them into me, they won't attack my normal healthy tissues, unlike your allogeneic T cells would do. So, that's why there's a lot of excitement about the NK cell, that it won't cause, you know, your NK cells won't attack me, if I get your NK cells. That's allogeneic, which means in theory, you could take your NK cells, freeze them down, and when if I got cancer, pull them out of the freezer, thaw them, inject them into me and not worry about, you know, them attacking my normal tissues. But hopefully preferentially attacking my cancer cells, particularly if I tell them what my cancer cells look like, if I can point them towards that with for example, an antibody or putting in a chimeric receptor.

Arthur Brodsky, PhD: And this could presumably, going back to earlier Oscar, you were mentioning, that how effective NK cells are at binding an antibody and killing the cell that's attached to it, in this case a cancer cell, depends on that CD16 receptor and it has to have a certain type or it won't be as effective. So, could this this donor approach to NK cell therapy, that could presumably overcome that right?

Research is growing at such a fast pace. And we're just the ability that we are able to do to the cells in terms of cellular engineering is moving at such a fast rate that we can definitely take a patient's NK cells and modify them to have this version of CD16, that has better capacity, or any other receptor be the chimeric one or or an endogenous one, that's going to be more responsive at detecting a given cancer.

Lewis Lanier, PhD: And that's being done clinically. In fact, there are companies, which are taking NK cells, and putting in this nice high affinity or this really good in good NK CD16 that binds antibodies very strongly. So, if your NK cells don't have that good version of CD16, it can be put in genetically, and then you give that person also some antibodies that would tell those NK cells to kill the tumor.

Arthur Brodsky, PhD: Interesting, interesting. And so Oscar, I want to dive a little bit more into your research. But first really quick, I just wanted to kind of talk about one last thing when it comes to these NK cell therapies, the actual cell-based ones. Aside from the natural ones, or adding the right version of the CD16, what other kind of modifications are being explored with NK cells that are being tested in therapy, whether it be attaching a CAR receptor, or helping to make a better type of memory NK cell that goes in?

Oscar Aguilar, PhD: Lewis, I think this is your area.

Lewis Lanier, PhD: Okay, so now with CRISPR, it's possible to do lots of modifications of NK cells. So that is being done. For example, there are certain molecules inside the NK cell to kind of slow them down. You can remove those. There is a molecule called fish, which normally kind of keeps NK cells calm is a way.

Arthur Brodsky, PhD: It's a brake?

Lewis Lanier, PhD: It's a brake. You take that out, they go much better. The other possibility, as Oscar mentioned, is you can put in these chimeric receptors. These are receptors that on the outside of the cell, tells the NK cell which tumor to kill, based on recognizing something on the surface of that tumor and then transmitting the activating signal based on the pieces that you put on the inside of that receptor to make the NK cell go. Also, people are putting in growth factors into the NK cells so that they can be more highly activated and can also then divide, as well as just kill, make more of themselves. Those are in patients right now.

Arthur Brodsky, PhD: Sounds really interesting, kind of increasing the size of the army to give them the best chance of rooting out all the cancer cells.

Oscar Aguilar, PhD: So, before I wanted to add also, there's a lot of work that's been done by a number of researchers, including work that's been done in Lewis' lab here. We've found that these NK cells- for the longest time, we thought that they were part of the innate branch of the immune system. And this is a part of the immune system that's generally short-lived, and half-life of an NK cells is about two weeks.

But now, we've identified a number of instances where these NK cells can actually generate memory that are long, that can live for long term, and have the ability to respond to a certain harmful cell more effective the second time around. And this is also something that we're working with trying to understand how to make these cells more effective and what we can learn from them.

Arthur Brodsky, PhD: Interesting. That's really exciting that they could have an immune memory and get more effective over time. And related to that we have an audience question, that after you're given an NK cell treatment, and assuming that the NK cells are able to eliminate all of the cancer cells in the tumor microenvironment, what kind of immune response or immune activity would happen after that?

You alluded to this earlier, Lewis. But I was hoping maybe could share a little bit about more what do the NK cells do after they've done their job against the cancer?

Lewis Lanier, PhD: They prime the pump. So, when they actually kill some of these cancer cells, they kill those cells, which release relief fragments of these cancer cells, that then your adaptive immune system can take up those fragments of the cancer cell. And now you can get B and T cells recognizing. Also, when they're killing, NK cells also secrete factors that Oscar was talking about, that will call in other members of the army, it'll call in the myeloid cells, call in the T cells, say come I need some help. And that can prime the pump.

So, even though initially, the NK cells job is- I call them the Marine Corps. They're first on the beach. They kill some cells, but then they call in the rest of the army, the artillery, the air support, they bring everybody else in. And that can create, you know, T cells or B cells, which can then give you years long memory against the cancer. When it works well, that's how it works.

Arthur Brodsky, PhD: That's really interesting to hear. And so Oscar, your research is really looking at that, the central activity that we've been talking about, about the NK cells bind to an antibody and then triggering and then activating the NK cells so that they can do their job. Could you share any insights you've uncovered so far in your work, as well as how moving forward, some of your insights might aid the development of better NK cell immunotherapies in the future?

Oscar Aguilar, PhD: Absolutely. So, talking about these memory NK cells. What's interesting about them is that there's a subset of these memory NK cells that some patients have, that actually have more effective responses at recognizing antibodies on a given target. So, because of that, my project was really trying to understand well, can we generate the cells in a mouse? And how do these NK cells respond, by doing some studies in the mouse that we can't do in humans, of course.

So, what I found early on though is that mouse NK cells are really, really lousy at killing antibody-coated cells. However, if we can now engineer these NK cells in the mice to mimic and parallel the really potent NK responses that we see in patients. So, my work is really trying to generate this mouse model. And we're almost there at really predicting how the cells behave. And why that's really, really important and critical is because if we understand the signals that these NK cells get, and what then happens to them afterwards, we can then start asking questions about how we can make them more effective therapeutically, at killing not only cancer cells, but also other pathogenic and harmful cells.

Lewis Lanier, PhD: And Oscar mentioned, your average garden variety NK cell lives probably two to four weeks, and then dies and is replaced. But we know that there's these special, this special class of NK cells in humans and mice that can live for months or maybe years. So, Oscar's work is trying to figure out what makes those cells special, what makes them kill better, what makes them last longer. So, if we could actually figure that out, we can make much better NK cells, either through engineering in a plastic dish, or perhaps doing something to the patient to result in the generation of more of that flavor of NK cell. So having a nice mouse model where you can manipulate things and test drugs and test antibodies, would really advanced the field doing experiments that you can't do with people.

Arthur Brodsky, PhD: Yeah, that's fascinating. And obviously then once you can create that self-sustaining and the one that subsists over time, obviously, it eliminates or it makes it so that you might not have to treat a patient again, if their immune system can take it from there moving forward should anything else pop up.

So, we have a question from our audience that kind of piggybacks on your research, Oscar. They asked if there would be a difference between when NK cells are activated with the bispecific antibodies you two were discussing earlier, versus the regular antibodies, the Fc portion on them. Would there be a difference with how it can influence the NK cell activity afterwards?

Oscar Aguilar, PhD: So, I would say that there may be a difference. And the reason why is because these bispecific antibodies sometimes trigger not just CD16, but also additional receptors on NK cells. So you may get even more enhanced responses on the NK cells using these bispecific antibodies, I would predict. Is that accurate, Lewis?

Lewis Lanier, PhD: Yeah, in fact, in the clinic right now are antibodies, which will bind a tumor, the Fc portion of the bispecific will bind the CD16 that Oscar works on. But then the other arm grabs another activating NK receptor. So now, I call it the turbocharger. You've got CD16 engaged, but if you grab and simultaneously tickle another activating receptor, you've turbocharged that response. That's in clinic.

Arthur Brodsky, PhD: That's exciting. And now we have another question from our audience that actually nicely syncs up with what I was planning to ask anyway as a follow up. But talking about these immunotherapy, our current ones, not the necessarily the NK cell ones, but current immunotherapies, like checkpoints work really well on what we call "hot" tumors, that the immune system has already recognized and infiltrated. And then the checkpoint immunotherapy is just take off that final brake and let them do their job.

So, this question from the audience is asking if NK cells might have the potential to turn cold tumors, which wouldn't normally be responsive to immunotherapy, into hot tumors and make them more responsive to immunotherapy?

And the second part of the question that I would add on is, because there's a synergy, potentially, between the NK cells and the T cells, as well as the therapies that that take advantage of both of them, what do we know at the moment about how NK cell therapies might synergize with current immunotherapies?

Lewis Lanier, PhD: Well, I think some of these checkpoint therapies, most of them currently are targeting T cells. However, many of those molecules that are expressed on T cells as checkpoints, they're also on NK cells. So when you put in the drug, you're not just affecting the T cell, you're also affecting the NK cells. But even if it's only affecting the T cells, when you activate T cells, they secrete a lot of goodies that can help the NK cells get going. For example, when you put in these antibodies, for example, to CTLA-4 or PD-1, those are common checkpoint molecules that are FDA-approved. It sets off the secretion of all these cytokines, which can in fact cause some trouble. But they can also, as bystanders, wake up your NK cells, because obviously if you have cancer, your NK cells aren't working real well. But now, if the T cells start providing them goodies, it can wake them up, make them activated, and they can join in the game to go after the tumor.

Arthur Brodsky, PhD: Interesting. Yeah, it's an important point you brought up for sure that with the power of the immune system, you got to make sure to kind of charge it and activate it in the right way, lest you get too big of a response as we sometimes see with T cell therapies. And so, with the with the CAR T cell therapies that you discussed earlier, as well as some of the NK cell therapies,

I understand that at least initially, they've been much more effective for blood cancers, whether it's leukemia, lymphoma, myeloma, and I guess the current thinking is that this is most- or one of the reasons anyway, in addition to some targeting factors, is that these blood cancers don't really have that fortress of the tumor microenvironment around it, protecting them, so it's easier for the CAR T cells and NK cells to actually get to those.

But with NK cells- with solid tumors, which are most of the ones we know, whether it's brain, breast, lung. Those they have that fortress, that tumor microenvironment around them that kind of protect them. So I was hoping that you might be able to speak about some of the challenges of these NK cell therapies and applying them to solid tumors.

Lewis Lanier, PhD: Well, something has to tell the NK cell to come out of the blood and get into the solid tumor, right? They're not just going to go there randomly. So, in many cases, in the local tumor environment, there are cells secreting these molecules called chemokines that bring in other cells. So, if that doesn't happen, if there's no cells in the solid tumor that spit out these tags, which tell the NK cells get out of the blood and come here and help me, then they're not going to go there. So, you've got to figure out how to overcome that problem. And the second is that the solid tumors often secrete a lot of factors that turn off both NK cells and T cells. So, you need to get rid of those.

There are molecules in the clinic right now, to try and neutralize or get rid of some of those suppressive factors, like one called TGF beta. They're good because if the NK cell comes into a tumor gets soaked in TGF beta made by the tumor or the surrounding stromal cells, it down regulates a lot of their activating receptors, and just turns them off. That happens normally, because like, if you get a wound, you know, you couldn't cut your hand, you've got to repair that. You don't want NK cells or T cells coming in and causing havoc. So, that's why physiologically, when you have a site, it can secrete these immunosuppressive molecules, so that you keep things calm enough to repair the damage. In the case of cancer, that's bad. Because it's calming down the cells. You want to get rid of the cancer, not to deal with cut on your hand.

Arthur Brodsky, PhD: It's almost overwhelming to think about the the dance that the immune system does with our healthy tissues, to keep them in order and, in cancer to eliminate the bad ones that are sometimes a little hard to root out. So, real quick before we wrap up, I wanted to give both of you a chance to just give your closing thoughts and share a little bit about where do you see natural killer cell therapies fitting into the field of oncology and cancer immunotherapy? I guess we'll start with you, Oscar.

Oscar Aguilar, PhD: I think this is a really exciting time not only for NK cells, but also for the immune system. I think the more and more we learn about how our cells behave, because the thing is that we know very well how our immune system behaves to virus infections and bacterial infections. But cancer is still stuff that we're- how they behave in the tumor microenvironment is still things that we're learning. And the more we learn, the more effective we're going to be at harnessing the true power of the entire immune system, including NK cells, which are really, really critical. In my non-biased opinion.

Lewis Lanier, PhD: I'm very happy to say I started working on NK cells in 1981, when people didn't even acknowledge that those cells existed. To actually prove that that's true, they do exist, but now to be able to figure out how they work. And more importantly, how do we make them work better. We are getting the tools now to be able to do that. And for cancer particularly, it's nice to have T cells, but we know that's only curing 20% of patients with certain types of cancer.

I say you got to bring the whole army on the field, which will include NK cells. So if you can get a cooperation going, like you do in physiological situations, like during viral infections, where we know that NK cells and T cells cooperate, and you need both of them, proven by that, those patients who don't have NK cells, we need in cancer to bring on everybody. And NK cells will be playing a critical role in that process, if we can make them work efficiently.

Arthur Brodsky, PhD: Definitely, I agree with you both that it's definitely been a very exciting time for immunotherapy lately. And obviously, a lot of patients have been helped. But as you mentioned, the majority still aren't getting helped. And so, as we expand our immune arsenal, hopefully we'll be able to help a lot more of them.

So, that is all the time that we have for today. I just want to thank you so much for sharing your expertise and your insights with us.

And for our audience, I want to let you know that for more of our webinars and additional resources we have for patients and caregivers as part of CRI's Answer to Cancer educational programs, we encourage you to check out our website at cancerresearch.org/patients. Here you can read and watch stories shared by others who have received immunotherapy treatment across a wide variety of cancer types. You can browse our entire library of past webinars and immunotherapy patient summit series featuring the world's leading immunotherapy experts. You can access information on other resources including treatment, emotional support and financial assistanc, and you can find help locating an immunotherapy clinical trial with one of our clinical trial navigators.

I'd also like to thank one last time our sponsors Bristol Myers Squibb and Alkermes for making this webinar series possible. And thank you all for your attention today. I really hope that you found today's webinar interesting and informative. And again, you can watch this and all of our other webinars on our website at cancerresearch.org/webinars to learn more about the immunotherapy options in a number of cancer types.

And finally, Dr. Lanier, Dr. Aguilar, I'd like to really thank you both so much for sharing your insights with us today. And for the incredible work you're doing to advance our understanding of natural killer cells in immunotherapy. We wish you the best of luck.

Lewis Lanier, PhD: Thanks.

Oscar Aguilar, PhD: Thank you, and thank you to the CRI!