Scott Kopetz, M.D., Ph.D. Hi, I'm Dr. Scott Kopetz, associate vice president of

Translational Integration, and I'm here with Dr. Katy Rezvani, vice president and head of the Institute for Cell Therapy Discovery and Innovation. And this is the Cancerwise Podcast. Katy, welcome. Thank you so much for joining us.  

Katy Rezvani, M.D., Ph.D. Great, thank you very much, Scott. It's great to be here and to have this chat with you today.  

Scott Kopetz, M.D., Ph.D. We're really committed to bringing insights into innovation and a lot of the exciting research going on. And I can't think of a more exciting space than cellular therapy. And so, I guess maybe the first place to start is: Can you explain what is cellular therapy, and how does that differ from other types of immunotherapy?  

Katy Rezvani, M.D., Ph.D. Thank you, Scott. And again, it's so wonderful to be here and to be able to share our experience and our vision of what we are trying to achieve with the Cell Therapy Institute Discovery and Innovation at MD Anderson. So, let me take a step back and really talk about immunotherapy. So, immunotherapy, as the name suggests, is using the immune system as a therapeutic strategy. So of course, our immune system is extremely powerful, and has evolved to protect us against external enemies, such as viruses, bacteria, infections, but also internal enemies, and by that I mean cells that go rogue, such as cancer cells, etc. And really, it was the seminal work of Dr. Allison and Dr. Honjo that, as you know, received the Nobel Prize for Medicine back in 2018, showing that the immune system can be harnessed to fight cancer. And this really led to this huge field of immunotherapy, which is now accepted to be as one of the main pillars of cancer treatment together with chemotherapy, surgery, radiation, precision medicine, etc. So, cellular therapy is actually a form of immunotherapy, where instead of giving a drug to a patient to take the brake off of the immune system, to allow the immune system to fight the cancer cells, in cellular therapy, what we do is we take immune cells out of a patient's body, and in a specialized lab, we engineer those immune cells to endow them with, for lack of a better word, like cancer-seeking missile capabilities. And we do that by engineering the cells to express these, kind of like a GPS system, which we call a "chimeric antigen receptor" or a CAR. When these immune cells are engineered with this CAR molecule, they are then capable of seeking out the cancer cells, selectively killing those cancer cells and then ignoring healthy cells. And actually, we currently have seven FDA-approved CAR T-cell products for a number of hematologic malignancies, lymphoid malignancies and multiple myeloma. And actually, more recently, there's been approval by FDA for cell therapies for solid tumors. So, the field is really moving to try and harness the power of cell therapy for the treatment of solid tumors, so we have tumor-infiltrating lymphocytes, or TILs, that have been FDA-approved for the treatment of melanoma, and also a different form of engineered T cell, which is called T cell receptor, T cell-engineered cells, for the treatment of patients with certain forms of sarcoma.  

Scott Kopetz, M.D., Ph.D. That's great, really a nice overview of the landscape here. And I think I want to dive in, because I'd say for many oncologists and certainly patients who are interested in this, the terminology can be really hard to understand. And so, I wanted to kind of break that down and dive into those distinctions. So, you mentioned the CAR T cells, the, kind of TCRs and then the TIL products. And you can see we love acronyms in the field, right? So, maybe if you were describing this to a patient, how would you really make a distinction between those three types?  

Katy Rezvani, M.D., Ph.D. Yeah, great question, Scott. So, actually, let me take a step back and also talk about the different types of immune cells because we are going to get into that. As you know, as scientists, we all have our favorite cell type. So, let me go back and talk about our immune system. So, as I mentioned, our immune system can fight against these viruses, these cancer cells, etc. And just like any army, we have cells, components that are specialized in different aspects of that fight. So, the same way in the Army, you may have your Marines, your Special Forces, your snipers, etc., we have different immune cell types. And so, for the purposes of, kind of our discussion, let's talk about two specific immune cells because those are the ones that are most studied and most advanced. One is T cells, as I mentioned to you, and the other one is natural killer cells, which as you know are my favorite cell type. And so, each of them have specific properties that make them particularly suited for engineering and for fighting cancer cells. So, that's why, you know, you will hear some people talk about CAR T cells or CAR NK cells, really, it refers to these different immune components. And as you very clearly also mentioned, there are different cell therapy products that have received FDA approval. So, what are TILs? As again, the TIL stands for tumor-infiltrating lymphocyte. The name says it, says it all. These are T cells that naturally have managed to home into a tumor. So, they have this ability to home into the tumor cell and to try and fight that cancer. And so, what scientists have done is try and seek out and basically isolate these tumor-infiltrating lymphocytes and in the lab, grown them, grow them. Again, let's go back to that analogy of the Army, right? You need your soldiers, you need a large number of these soldiers. So, what you do with these tumor-infiltrating lymphocytes that have already got into the enemy, like across the enemy line, you take them out and in the lab, you can grow them numerically. And you produce massive numbers of these T cells, and you can then give these back to patients after a few days of chemotherapy to make space for them. And this was really work that was pioneered by Dr. Steven Rosenberg at NIH, and now has received FDA approval, is available for our patients.  

Scott Kopetz, M.D., Ph.D. So, that really is surgery to remove and then growing up, and really thinking about billions of cancer cells. Exactly. And that's such an impressive engineering feat to be able to do that. 

 Katy Rezvani, M.D., Ph.D. Exactly, exactly. And these cells are just they have the natural ability to really make their way into the tumor. And they've been very successful in resulting in responses in patients with melanoma. Somewhere in the region of 50 percent of patients with very advanced melanoma do respond to TILs. And as you know, this is now being applied to other types of solid tumors. I mean, for instance, in colorectal cancer, are there trials ongoing with these TILs?  

Scott Kopetz, M.D., Ph.D. There are, yeah, there are. But I think, you know, one of the key features as you highlight is you actually have to have those soldiers present, right, and so it really requires that the immune system to have recognized already and to have those present in order to expand. And that, you know, contrasts certainly with the CAR T, and you highlighted that, that that's really seen a lot of FDA approvals and hematologic malignancy. So, what's the analogy there for the CAR T? How does that differ from the TILs?  

Katy Rezvani, M.D., Ph.D. So again, TILs, as you just stated, they have to be there, and they have to have at least this ability to make their way to the tumor. So, CAR T cells take the approach one step further. Instead of having cells that already have the ability to find their way into the tumor, with CAR T cells, you just give them the GPS system. So, basically you take the T cells out of a patient's blood. Doesn't involve surgery, unlike TILs, as you mentioned. So, you take the T cells out of the patient's blood through a blood draw, and in a specialized lab, you take these T cells, you grow them. So, again, numerically increase your number of soldiers cells. You endow them with this GPS or this cancerseeking missile through engineering, which we often do by using a viral approach, but you can also do it non-viral approaches, and then we grow the cells further. The process usually takes 10 to 14 days, and the cells are then sent back to the patient from the specialized lab, where they are then given, just like a blood transfusion, to a patient, again after a few days of chemotherapy conditioning, to really make space for the incoming soldiers, your incoming CAR T cells and to make the environment more acceptable to them.  

Scott Kopetz, M.D., Ph.D. So, this is, you're giving them that GPS signal there. And so, you have to have some target that's present on the cancer cell and then know that's kind of expressed by that tumor. As opposed to the TILs, which you may not always know what the T cell is attacking, but you have a sense that it's attacking something on the cancer cells.  

Katy Rezvani, M.D., Ph.D. Exactly.  

Scott Kopetz, M.D., Ph.D. So, that's really kind of an important distinction in how we're thinking about it. And while we said that TILs have been more advanced in solid tumors, CAR T, more in hematologic malignancies, we're seeing a lot of the cross, CAR Ts in solid tumors, and really exciting areas to explore.  

Katy Rezvani, M.D., Ph.D. Yes, and there's been a lot of focus now in trying to get cell therapies to be successful in, for the treatment of solid tumors. But as you know, solid tumors are more, much more challenging than hematologic malignancies. And much of it is related to the environment of the solid tumors, you know, you have so many challenges to overcome. One is actually a physical barrier, right? You have a mass of tumor cells, whereas often with hematologic malignancies, the cancer cells are circulating in the bloodstream, they're in the bone marrow, they're the lymph nodes. Your T cells like to go to bone marrow, to lymph nodes, they kind of circulate in the blood stream. So, now you're trying to get them going to this, kind of solid mass that could be in your rectum, in your pancreas, in your brain, etc. And then even when they enter that solid mass, that physical barrier, you have the complexity of that environment that is very hostile to your incoming soldiers. So, there's not enough nutrients there, there is not enough oxygen there. And as you know, cancer cells don't just sit there and allow themselves to be killed by the immune cells. Cancer cells literally fight back. They release toxins that doesn't affect them, but yet can completely disempower the immune cells. And so, these are all the strategies that we need to keep in mind when we do our engineering and design our engineered cell therapies for solid tumors.  

Scott Kopetz, M.D., Ph.D. So, that's really where that engineering comes in, right? Where you're going back to your soldiers, right, where you're really equipping them and training them in different ways that they may not normally have done.  

Katy Rezvani, M.D., Ph.D. Exactly. You need to armor them, and you need to protect them.  

Scott Kopetz, M.D., Ph.D. It's a great overview of, kind of the T cell space, but I really wanted to have you compare and contrast the natural killer cells. And I always tell patients I love the term "natural killer cells." It's like, made by a PR firm, natural and they're killers, like who wouldn't want that? Right? It's amazing. But tell me a little bit about NK cells. How do they differ from the T cells?  

Katy Rezvani, M.D., Ph.D. Right, so I like to call NK cells the step cousin of T cells. They were discovered later, which is why in terms of research, kind of engineered NK cell, I would say they're behind, they were behind by about a decade or so. But let's take a step back again. So, natural killer cells are, again, part of our immune system, naturally. On a per cell basis, they're one of the most effective killers of tumor cells. But what makes them particularly attractive for cell therapy is that you can take natural killer cells from one person, give it to another person, and they don't cause toxicity. If you were to do that with T cells, if you were too give my T cells to you, for instance, they would cause severe toxicity in the form of this syndrome called graft vs. host disease that many of us transplanters have to deal with when we transplant our patients. And this is because of the biology of natural killer cells in that they don't have the necessary receptors on their surface to cause graft vs. host disease. So, around a decade ago at MD Anderson, we asked this question. You know, CAR T cells are fantastic, CAR T cells have resulted in really significant responses in patients with heme malignancies, you get complete remissions that range anywhere from 40 to 90 percent, depending on the tumor type. But as I mentioned earlier, CAR T cells, at least the ones that are FDA-approved, are made from the patient for the patient, right? And this is what we call an autologous product. It's just, it's a patient-specific, single-use product. And because of that, it's very expensive to make. You have to do this sophisticated manufacturing, growing your soldiers, engineering them, etc., for each patient at a time. And so, this results to costs in the region of $500,000. That's how much these CAR T cells cost, which means that many patients that could potentially benefit from these life-saving therapies are not getting access to these treatments, not in the United States, and certainly not in many countries, and especially in the developing world. And also, CAR T cells carry certain toxicities that are very unique to them. Because these soldiers are trained and they're very active, they release a lot of, they cause a lot inflammation when you give it to the patient so the patients can develop high fevers, they can drop their blood pressure, they can develop neurotoxicities. So, somewhere, again, in the region of a third to half of our patients require care on the intensive care unit, which means that these CAR T cells have to be given in centers such as MD Anderson or other like, big hospitals where there is the infrastructure to care for the patients. So, around a decade ago, we asked this question, what if we can find a cell type that carries a more favorable safety profile, so less toxicity, and that potentially from one healthy donor, you can manufacture multiple products, let's say dozens or hundreds or even thousands, and then you could freeze them, store them and have them available as an off-the-shelf product. So, now you would overcome the problems related to safety, the problems related to the fact that the patients have to wait for the manufacturing of CAR T cells, which can take a few weeks, so access will be higher and then cost. Because for one manufacturing run, which is two weeks, instead of getting one product, now you could get a hundred products. So, if you do the math, the cost of manufacturing now will be about one percent. And so, then, of course, then the question is: What should be the source of your NK cells? And this is what we call an allogeneic product, which means from one donor, treat multiple people. And who should be, you know, the donor? It could be someone, you know, off the streets, a relative of a patient, some people are looking at stem cells. Well, as it happens at MD Anderson, and we have an umbilical cord blood bank that our good friend, Dr. Shpall, established around two decades ago and cord blood is a by-product of birth. It's usually a little bit of blood that's left in the umbilic vein when a woman gives birth and is usually discarded. And as it happens, umbilically cord blood, is a very rich source of natural killer cells. So, then we developed the strategies for isolating natural killer cell from umbilical cord blood and our bank has more than 40,000 cord blood units that have been collected, frozen, available. You can just go and basically pick them up. And then you thaw them, isolate the natural killer cells in the lab, you grow them, you engineer them, you put a chimeric antigen receptor in them, you armor them, you freeze them and then when a patient comes, you can just thaw and infuse the cells again after a few days of lymphodepletion. And so, this is how we started the CAR NK program here at MD Anderson. And our first in-human study, again in blood cancers, started back in 2017. And then really that was the start of this big cell therapy program that now we have at MD Anderson. And as you know, we now have like more than, we now have 12 clinical trials that have been FDA-approved, including solid tumors, including colorectal cancer.  

Scott Kopetz, M.D., Ph.D. That's wonderful, and such an amazing, amazing story and amazing resource, and I think really speaks to the strengths of the institution to be able to have such a comprehensive strategy there. What are some of the areas within the NK studies that you have going? What are some of highlights? What do you excited to see move forward into the clinic?  

Katy Rezvani, M.D., Ph.D. Going back to what you said, really, this is the strength of our institution. We have, I think, some of the world's best scientists and clinicians. And the science that we do here, in immunology, in cancer genomics, in engineering, and the collaborative, really infrastructure allows us to take these sorts of therapies to the clinic. So, I start from concept to a clinical trial, we can achieve that within 12 to 18 months. So, we now have a number of CAR NK cell programs in solid tumors. I'm very excited around really trying to make the cell therapies work for these hard-to-treat cancers, such as pancreatic cancer, ovarian cancer, glioblastoma, etc. We've started a program where we've engineered our natural killer cells to express a T cell receptor. So, this is kind of a love child of T cells and natural killer cells. I always say my first love was T cells. My Ph.D. was actually all in T cells, but T cells have certain advantages, and they express T cell receptors that allows them also to recognize certain markers that are hidden inside of the cancer cell. CARs allow you to look at markers that are expressed on the surface of cancer cells. So, we've engineered our natural killer cells now to express T cell receptors, and we have a number of clinical trials, both in hematologic malignancies and solid tumors in that setting. I'm very excited about that. We also have very sophisticated tools now, such as CRISPR engineering, that allows us to very precisely target certain checkpoints, and again, to try and protect our natural killer cells from the immunosuppressive tumor microenvironment. As you know, in 2020, two women, Jennifer Doudna and Emmanuelle Charpentier, received the Nobel Prize for Chemistry for their discoveries in CRISPR. And we've already taken that approach to the clinic. We have clinical trials with CRISPRengineered NK cells in glioblastoma. And our next generation that will be going to the clinic very shortly is a combination of CAR NK cell engineering and CRISPR gene editing. So, really, again, very much empowering and armoring the NK cells, whilst also protecting them from the tumor microenvironment. But what I'm very excited about now is also to combine our NK-cell therapies with drugs, with drugs that can have, and then this way you can have this orthogonal approach of bringing synergistic activities of different approaches because I really do believe for some of these difficult-to-treat solid tumors, perhaps our therapies alone, targeting one antigen alone, is not going to be enough. And so, now we are very, as you know, collaborating with your team, and I'd love to get your thoughts on that, on looking how we can bring our CAR NK cells together with some of these targeted therapies that can modulate the tumor microenvironment and make it more receptive to our cell therapies.  

Scott Kopetz, M.D., Ph.D. Yeah, no, and I think it's a fascinating area to really think about: How do we take these advances now and put them in the right context in the right patients? And I think as you highlight, one of the areas that we're very excited about, working with Pia Morelli, a colleague of both of ours, to think about: How do we even bring some of these technologies to patients who may not have any disease evident on their CT scan with colorectal cancer in this point, with the idea to say, can we intervene very early? And the fact that safety profile of the NKs have been encouraging really allows us to try some really innovative and hopefully curative approaches. So, I love that we're kind of, thinking big and really trying to cure patients.  

Katy Rezvani, M.D., Ph.D. I totally agree. I mean, currently, all of our CAR NK cell trials, as you know, have been in the setting of very advanced disease. If you look at some of our trials in hematologic cancers where we now get response rates in the range of 70 to 80 percent, so really impressive, these are patients that have had anywhere from eight to 14 prior lines of treatment. So, we are talking about multiple different lines of chemotherapy, checkpoint inhibitors, radiation, bone marrow transplant, etc. And if we can bring these therapies, considering the very encouraging safety profile of natural killer cells earlier in the disease course, it will save our patients the burden of going through multiple lines of very toxic treatment, as you know, many of these, especially bone marrow transplant, can carry a lot of side effects. But also, it will probably improve our response rate in the setting of solid tumors. So, I'm very excited about our collaboration with Pia Morelli to give these cell therapies in the setting of minimal residual disease, of very low-volume disease. And I think that with time we will be able to bring these therapies earlier in the treatment course of patients.  

Scott Kopetz, M.D., Ph.D. Absolutely, so much innovation coming in your institute and really look forward to seeing the future of this and the real excitement around the whole spectrum of therapeutic options that this will enable. Katy, thank you so much for being here and for such a wonderful, stimulating discussion. Thank you. For more information or to request an appointment at MD Anderson, call 1-877-632-6789 or visit MDAnderson.org. And thanks for listening to the Cancerwise Podcast from MD Anderson Cancer Center.