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At the end of her clinical training as a hemo-oncologist specializing in bone marrow and stem cell transplantation, Katy Rezvani, MD, PhD, realized that she had this love of immunology and looking after patients who undergo stem cell transplantation, especially allogeneic stem cell transplantation—taking a graft from one healthy donor and giving it to another person. She knew that much of that curative effect is driven by the immune system, so she began to ask the question: can you isolate that robust anti-leukemia immune response from all the side effects that come with doing a stem cell transplantation?
That question launched Rezvani into a successful career in understanding and developing allogeneic immune cell therapies. In this episode, Rezvani tells me why she’s so captivated by one particular immune cell—NK cells—for cell therapies. We discuss how NK cells compare to T cells and the different ways they are being engineered to treat cancer and other diseases with accessible and affordable cell therapies.
Rezvani is a professor at MD Anderson Cancer Center and, most recently, was dubbed the vice president and head of the Institute for Cell Therapy Discovery & Innovation. Rezvani also holds the inaugural Melvyn N. Klein Family Endowed Directorship for the Institute for Cell Therapy Discovery & Innovation.
This interview has been edited for length and clarity.
IPM: What are the challenges of using NK cells as cell therapies? How do they compare to T cell therapies? Can they be allogeneic?
Rezvani: It’s an allogeneic product, which means that the immune system of the host is going to reject it, and at the moment, there is no way around it. It’s an HLA mismatch, and we have no choice but to give something for depleting chemotherapy to at least temporarily ablate the residual host T cells and NK cells so that our CAR NK cells have the ability to proliferate and persist for some time. T cells are very long-lived and can persist for the lifespan of a person, but conventional natural killer cells have a limited lifespan. Their half-life is somewhere in between a week and 10 days, and that’s how long you do an adoptive infusion; after a week or 10 days, your NK cells are gone unless you support them with cytokines. If you support them with cytokines, they can persist longer. People have tried giving NK cells to patients and then giving them injections of cytokines, but the problem with that is a lot of these cytokines also carry their own toxicities.
To overcome that, we use the CAR vector that also incorporates the cytokine gene interleukin 15 (IL-15), which drives NK cell proliferation and persistence. We found that using these CAR NK cells that also have the “R15 transgene,” we can detect the persistence of our cells at low levels even for a year or more after infusion. We see a nice expansion of the cells early on when the patients’ counts are very low because of the lymphodepletion we’ve given, and after that, the CAR NK cells persist for months at least and at very low levels.
There’s a degree of intolerance that’s been established, but that’s certainly a challenge, and at this stage, I don’t see a way of us getting away with not giving lymphodepletion—even with autologous CAR T. People have shown that in the absence of lymphotipation, you do not get the proliferation and persistence of CAR T cells, and you don’t get a clinical response. So, it’s not just because we want to prevent rejection. You also need to make this “space” for the cells to proliferate in and get rid of some of those immunosuppressive cells, like regulatory T cells.
T-cells carry a lot of toxicities. CAR T cells cause cytokine release syndrome and neurotoxicities—very unique toxicities. As a transplant physician, I had never observed the toxicities that we see with CAR T cells, which means you need to give these products in highly specialized centers, such as the MD Anderson Cancer Center, and you need to have access to an ICU. In our institution, somewhere around a third to a half of our patients require ICU care. That’s why I joined MD Anderson 20 years ago.
Our group and also many others across the world asked this question: “What if we can use an allogeneic donor where you could potentially, from one healthy donor, make multiple products—dozens, hundreds, thousands—and have these stored and available as a truly off-the-shelf product?” Then the question was, “What are the characteristics of an ideal off-the-shelf product?” The jury’s out because we all have our favorite cell types. I’m interested in NK cells, but there’s amazing work being done with gamma delta T cells, cytokine-induced killer cells, macrophages, and alpha beta T cells that have had the T cell receptor deleted, so there’s a lot of effort being put into that.
What I think we all agree with about an allogeneic cell product is that you want to be able to infuse it into a patient without worrying about HLA matching and you want to have an excellent safety profile because, ideally, we’d want to be able to ship these cells to other centers that may not be having that infrastructure that we do. We want to be able to manufacture the cells at scale and to be able to cryopreserve them so that they can be shipped frozen and then thawed and infused at a patient’s bedside. That’s how you can really reduce the costs of treatment. That’s very important and why we put all of this effort into generating this allogeneic.
IPM: What immune cell therapy are you working on that excites you?
Rezvani: We ended up making this love child of T cells and NK cells, which is the TCR NK cells. NK cells don’t normally have T cell receptors or the full CD3 signaling machinery. Now we have these TCR NK cells that are like NK cells that can work like T cell receptors. I’ve also become very interested in the myeloid cells and how monocytes and NK cells talk to each other.
Our immune system is the army and the immune cells are different types of soldiers that have been trained in different ways to tackle the enemy using different strategies. So, now we’re bringing in monocytes, which could be like the navy, and then we are bringing in the T cells, which are like your Air Force, and I’m hoping that we can really empower this incredible immune system that we have to try and now tackle those different to treat diseases such as solid tumors, glioblastoma, pancreatic cancer, and ovarian cancer. We have to make headway in these types of diseases.
I don’t think that a single cell type can succeed alone, and that’s why I think it’s really important to try and either look at ways of developing cell therapies that encompass multiple and different cell types or come up with a way that your NK or T cell therapy can also recruit the patient’s own endogenous immune cells to take part in this fight against the cancer that’s going on.
IPM: Congratulations on being named the director of MD Anderson’s Cell Therapy Institute (CTI). What have you set out to achieve at the CTI?
Rezvani: I’m very honored to be given the huge task of leading the CTI together with many of my colleagues. This is a joint effort with many investigators both on the research side and on the clinical side at MD Anderson. The goal of the CTI is to develop novel cell therapies that could be transformative for our patients with cancer. We are not wedded just to one cell type. It’s very much looking at the immune system and looking to see how we can harness the power of the immune system to develop engineered therapies for our patients.
Most of the clinical studies that we’re doing were phase one and early phase two. With the support of the CTI, we’re very interested now in moving into phase two studies, phase two, and even multi-center studies to validate our discoveries and also to make them available to other centers. We’ve put a lot of time and effort into scaling up our manufacturing and into developing ways of preserving ourselves so that [the cells] still maintain their functionality and will be just as potent.
We’re a cancer center, but we also see the value of cell therapy in reducing the suffering from other diseases, such as infectious diseases. We have trials with viral-specific T cells against life-threatening viral infections for patients who are immunocompromised, such as cytomegalovirus and JC virus (human polyomavirus 2). During COVID, we had COVID-specific T cell trials. We’re interested in using our therapies for the treatment of autoimmunity. There’s been a lot of excitement about the potential of cell therapy for patients with lupus and patients with scleroderma, and this is a collaboration that we will be doing with our colleagues at UT Health.
The CTI is very much also bedside to bench because we want to do extensive correlative science using blood and tissue samples from patients who have taken part in our trials to really try and understand determinants of response and resistance.
IPM: Do immune cell therapies have companion diagnostics?
Rezvani: Some of our trials are very biomarker-driven. We have a trial that is first-in-class and first-in-human, where we engineered our NK cells to have the full CD3 signaling complex and also to recognize NYESO, which is a tumor-associated antigen that’s normally intracellular, so a CAR cannot target it where the T cell receptor could. So, for that particular trial, we know that the patients that are candidates for that have to have a certain HLA type—they have to be HLA2-positive—and then they also have to have the target antigen, which is NYESO. As a result, we are screening patients for inclusion of both of those biomarkers.
But then there is a big challenge around using an allogeneic donor because not all donors are created equal. We are all very different. If you’re like me, every five minutes, you catch a cold, and then if you’re like my husband, you never catch a cold. We have different immune systems and the same goes with healthy donors and umbilical cord blood. The postdocs in the lab would come and say to me, “This is a good NK cell donor for my experiment, and this is a bad NK cell donor for my experiment.” I said to them, “Well, we need to understand what defines a good and bad [donor NK cell].”
So, we put a lot of effort into understanding what makes an optimal donor for cell manufacturing. We are using genomic, epigenomic, and proteomic analysis to try and understand what defines optimal donor for cell therapy, which I think is going to be very important to understand better and avoid really batch variability. And we’re going to be scaling up these approaches for many more patients than we are now.