Dr. Manish Shah (Host): Welcome to Weill Cornell Medicine CancerCast, conversations about new developments in medicine, cancer care, and research. I'm your host, Dr. Manish Shah. And today, we will be talking about a novel immunotherapy approach called bispecific T-cell engager, or BiTE, therapy.

Our guest today is Dr. Mateo Mejia. Dr. Mejia is an Assistant Professor of Medicine in the Division of Hematology and Medical Oncology at Weill Cornell Medicine, caring for patients with multiple myeloma. His research focuses on the genomic drivers of aggressive forms of myeloma, how genetic information can be used to develop novel treatment approaches, and the connection between race, ethnicity, and myeloma. He's an expert in BiTE therapy, and myeloma is where a lot of this action is happening. So, Dr. Mejia, welcome.

Dr. Mateo Mejia Saldarriaga: Thank you so much. This is a great invite. I'm really happy to be here.

Dr. Manish Shah: So, we've had several different discussions in the past about immunotherapy and how that's been transformative in cancer care. We've talked mostly about drugs like PD-1 or PD-L1 inhibitors, or an inhibitor of CTLA-4 that turn off the brakes and allow the immune system to activate against a tumor.

We've also talked about TIL therapy, where we take a tumor biopsy and we take the immune cells that are in that biopsy, expand them and activate them, and then reinfuse them into the patient. And that's been really quite transformative.

But today, we're going to talk about something completely novel, and almost next generation type stuff here, which is called the bispecific T-cell engager or BiTE therapy. Dr. Mejia, tell us about BiTEs and what they are and how they work.

Dr. Mateo Mejia Saldarriaga: I think that's a great introduction, because it is a type of immunotherapy, but it's quite different to the other ones you mentioned before. So, bispecifics, they are a little bit different in the sense that we're not taking off any breaks. We're not taking the immune cell that is already in the tumor. What we're actually doing is re-engaging our immune system that, for whatever reason, is not doing what it's supposed to, which is go kill cancer, keep cancer under control. We're literally putting next to each other, that immune cell that is not doing what it's supposed to, with the cancer cell.

For example, I do myeloma. So, these molecules, what they do is imagine it's like a person with two hands. And the left hand is going to grab the T cell that is not doing what it's supposed to. And the right side is going to take the myeloma cell. And they're going to put them together. By doing that, the T cell gets activated and actually attack the myeloma. We're using the same analogy. Here, we're not taking the breaks. Here, we're actually almost like pushing the car, so it starts doing what it's supposed to again.

Dr. Manish Shah: That's terrific. I love that analogy. So, an antibody is a molecule that binds to a specific target. And typically, there are two arms to an antibody. And each arm is made up of two different proteins. And what's unique about these BiTEs is that instead of both arms attacking or binding to the same protein, they're binding to different proteins, and the different proteins are on different cells.

So if you imagine, one arm is binding to a T cell. T cells are the cells that are supposed to be activated against a cancer, but for some reason when cancer develops, the T cells are not effective. And the other arm is binding to the target, which might be a cancer cell-- in this case, a myeloma cell. And when you have a single protein molecule that binds to both of these proteins that are on different cells, it brings them together. And by bringing them together, you could have increased activity. That's what you mean, right?

Dr. Mateo Mejia Saldarriaga: A hundred percent. I think that's a great explanation.

Dr. Manish Shah: And the other point that you made is that it's not hitting a target that is a brake for the T cell. It's actually using the T cell and bringing them close to another cell of interest to try to activate the T cell.

So, tell us a little bit about T cells. There are different types of T cells. One of the most common arms binds to CD3. But are there other T cells that we need to be focused on?

Dr. Mateo Mejia Saldarriaga: So far, in the T-cell engager space, which by the way is not confined to myeloma, that's one of the first uses, but it has actually expanded to many other cancers. The most common way of taking or grabbing that T cell is using CD3. So, CD3 is expressed in all T cells, but not all T cells are made the same or have the same function.

So, you have some T cells that are more what we call cytotoxic, other T cells that are more regulatory. And they do fulfill different roles. We are not sure which one is better than the other. But the approach we take right now is using that CD3, and the net effect of that is usually seeing T-cell activation.

I think the question of can we use one specific subset of T cells is very interesting and that's actually part of our research here at Cornell, is trying to understand if, instead of taking all the T cells, if we focus on one subgroup, will that lead to better results?

But what you will see with T-cell engagers as of now, all of them, the common denominator is that they target CD3 that is expressed in all T cells as a way of growing the T-cell. In the other arm, on the other hand, were changes, right? So, whatever you add to the other arm of the antibody, it's what's going to look for the cancer cell.

So if you're talking about myeloma, we're going to use a protein that is expressed in myeloma such as BCMA or GPRC5D. If we're talking about lymphoma, we're going to look for a protein that is expressed in lymphomas such as CD19 or CD20. And this could actually be applied to many other settings, for example, solid neoplasms. This is what highlights that T-cell engagers is not a treatment. It is almost a platform that, depending on how you design your antibody, it might have different effects or it can be used in other settings.

Dr. Manish Shah: So, a little bit of background. The cells that are in the body are often characterized by the proteins that are on the surface of the cell. And all T cells have a protein called CD3, but they may also have a protein called CD8. And if you have CD3 and CD8, that's a class of T cell called effector T cells. And these are the cells that we think are doing the action against a tumor, for example.

Alternatively, if you have CD3 and a protein called FoxP3, then you might be a different type of T cell called a regulatory T cell. And this is a cell that regulates or turns off or modulates the immune response. So, you can imagine that there are different subsets of T cells that can be defined based on these markers.

The BiTEs, so far, the T-cell engagers, one arm is binding to CD3. So, the point that Dr. Mejia made is that we're not exactly sure is it that we're engaging the Tregs, are we engaging the CD8 T cells, the effector cells, or some other subclass? And that's where a lot of research is.

But we know that effectively by engaging CD3 and the other molecule, let's say it's CD19 for a B-cell lymphoma, when you combine them into this molecule and you give it as a drug, it does cause an activated immune response against the B-cell lymphoma. Is that right?

Dr. Mateo Mejia Saldarriaga: Yep. Absolutely.

Dr. Manish Shah: So, let me ask you then about CAR T therapy where you take a protein, an antigen, and you modulate the T-cell receptor, and then give it back to T cells to activate these specialized cells called CAR T cells. BiTEs are different than that. They share some of the side effects, but they also have differences in terms of advantages. You don't need to create a new molecule for each antigen, for example, right?

Dr. Mateo Mejia Saldarriaga: Yeah, that's a great summary. I will say from all the immunotherapies that we have discussed, CAR Ts and bispecifics are almost like cousins, they're closely related, but there’s key differences.

So, what we want with these two type of therapies is T-cell activation against your cancer cell, right? And as you mentioned before, we achieve that in the case of CAR T by creating this chimeric protein that activates the T cell and, at the same time, looks for the cancer cell. And those cells have been engineered, modified. Basically, we take them outside of the body, we manufacture them, and then we reinfuse.

Bispecifics is trying to achieve a similar effect of activating T cells. But one of the big advantages and big differences is remember that I mentioned that this antibody is sitting in a shelf. It’s already premade. So, we don’t need to extract the cells, modify them, and then reinfuse.

These medications are much more readily available. We’re not really modifying T-cells. There’s no need for manufacturers. So, the big advantage is that even though the net effect is the same, which is T-cell activation. These are treatments that are very different in how we give them to patients.

If you go back to what you were mentioning, they share a lot of the side effects. It's precisely because the net effect, that T-cell activation is the same, but when they happen, how they happen, how we manage them, the dosing, it's different from CAR Ts and bispecifics just because they are not exactly the same type of treatment.

Dr. Manish Shah: So, let's talk about the side effects. There are two main classes of side effects that can happen with overactivation or activation of these T cells, whether you do it by CAR T or by T-cell engagers. One is called cytokine release syndrome or CRS. And the other is called immune effector cell-associated neurotoxicity syndrome or ICANS. Do you want to tell us about these?

Dr. Mateo Mejia Saldarriaga: Both of them are related to the T-cell activation and how they work. So, what I tell patients often is we want the cells to activate. And when we say activation in T-cell biology, it means they go from almost like a resting state to a state that they recognize that there's a threat-- in this case, cancer-- that should be eliminated. And the way they do it is not only they start attacking that cell, but they release a lot of substances or proteins, many of them we call interleukins, that will cause inflammation.

So, imagine it's the exact same process when you have an infection. There's something foreign to your body that needs to be attacked. You produce a lot of these inflammatory substances. And what happens when there's inflammation? Well, we want some of that inflammation. It might help containing that infection or the cancer. But if we take that to an extreme, they can start having symptoms of too much inflammation.

In the case of CRS, of cytokine release syndrome, is nothing else than the clinical syndrome of having too many of these inflammatory molecules. So, the most frequent symptoms that patient develops is actually fever.

So, the way I tell my patients is imagine your immune system is reacting to an infection, but there's no virus, there's no bacteria, there's just a lot of inflammation from this T-cell activation. Fever by itself is quite common. And the reason why we monitor this in the hospital or close to the hospital initially is because, if we see that there's too much inflammation, if we see that there's fever and other organs being affected by this inflammation, like low blood pressure or the kidneys, we can give medications to try to suppress this inflammation.

It is also important to note that CRS is usually more frequent when we start treatment. So, what I tell patients is imagine, at the beginning, the first-time we give those medication, there's more T cells that are dormant. And then, as time goes by, the T cells that we're going to be activating, they already did. So later on, the risk of CRS is much lower. So, it varies from molecule to molecule, from cancer to cancer, but the risk of CRS is usually greater during the first doses of this medication. And that's why we start those medications initially at lower doses and we increase, and we do it in a more monitored setting. Later on, when we know that T cells are already activated, we can be a little bit more relaxed in the setting, that we can do it as an outpatient. There's less frequent follow-up.

If we understand CRS, then we can understand ICANS, because what I tell patients is the ICANS is like the brother of the CRS in the sense that is also related to this excess inflammation, but it's mainly how it affects the brain.

So, our brain is quite sensitive to all these processes. And instead of having fever or other symptoms, ICANS can present with confusion, headaches, changes in your mental status or your mental cognitive capacities that are related to all that inflammation. And again, as we were talking about CRS, if we identify that the patient is having ICANS, we can actually treat it with medications to decrease that inflammation. And with all this management, both CRS and ICANS can be very safely and effectively treated, and they're not resulting in long-term complications or long-term toxicity.

Dr. Manish Shah: So, any of these side effects, particularly the neurologic side effects, can they be long lasting or are they generally short-lived and manageable?

Dr. Mateo Mejia Saldarriaga: So, this varies from bispecific to bispecific and from cancer to cancer. But I think the most frequent type of side effects we see is CRS ranging from 40-80%. Most of the time, it’s just fever, meaning that even if there's CRS, we sometimes don't need to treat it with anything else other than Tylenol.

ICANS is often less frequent, ranging from 5-20%. And most of the time, when it occurs, there's different ways of grading it. It's usually low grade, meaning that it could be just a headache or it could be something quite transient. It's important to highlight because when we speak with patients about all these different toxicities and neurological toxicities, it can be quite scary.

But it's important to highlight that ICANS is usually self-limited and it differs from product to product, but it usually resolves within one to five days. I think it's very important to discuss with your physician about what to expect with the specific bispecific. Because as I said, there's many of them and they all have slightly different safety profiles and expected CRS or ICANS risk.

Dr. Manish Shah: Is there an association between the development of these toxicities and the efficacy of the drug? Meaning, if you get CRS or ICANS, are you more likely to respond?

Dr. Mateo Mejia Saldarriaga: I remember this because I had a patient that we were starting the bispecifics and she developed really high fever. And I went to see how she was doing and I walked in. And I've never seen anybody so happy because of the fever, because she said, "If something is happening, it's working." And in a way, remember that these T cells are causing this inflammation. And if there's this inflammation, we know they're probably activated.

What is interesting is that you don't need fever to see efficacy. In other words, you can have some activation, but not to the point that you end up having CRS and ICANS and it can still be effective.

One of the things I will say is most of the patients who respond, they can respond even if there was absolutely no side effects of this type. So, this is something that when we see it, we know it's happening. But I also tell patients, if you don't develop CRS if you don't develop ICANS, it doesn't mean that it's not going to work. We just need to wait and see what happens.

Dr. Manish Shah: So, you don't need to get sick to get benefit.

Dr. Mateo Mejia Saldarriaga: Exactly. And that's what I tell patients, we can treat this inflammation. So, many people will say, "Well, if we treat the inflammation, are we going to hinder the efficacy of the treatment?" And the answer is no. We don't need to push through. If you're not feeling well, we can treat this inflammation. It's going to make you feel better. And we're not compromising in any way the efficacy of the treatment.

Dr. Manish Shah: So, some of this is actually really critical and foundational in terms of how the immune system works. So, essentially, the immune system is a balance between cells that can become activated against a certain protein. We call them antigens.

And the immune system is set up in a way that once there's an activation, there's like a positive feedback loop and more, more cells come to the area where there's some activation to try to ensure that they kill off whatever is there, whether it's a bacteria or a virus or some foreign body.

And if you don't keep that in check, you could have overwhelming inflammation and then you could develop an ulcer or some significant toxicity from over inflammation. So, the immune system is also set up to turn off that immune activation.

So, there's a balance between activating and turning it off. It's almost like a seesaw. And that's in the context of amplification, where once you get a trigger, things can get really amplified too quickly. And then, you need something to turn it off very quickly.

And when you have a cancer, the cancer's evolved in a way to hide from the immune system, and also turn off the immune system in a certain way. So, it activates the brakes. So, there are different ways to overcome that.

One is to turn off the brakes. That's with the immunotherapy we talked about already, PD-1 or PD-L1 inhibition or CTLA-4. And there are other molecules that are being developed that turn off the brakes.

The other is to increase the activation. One way is by CAR T cells. The other way is by TIL therapy. And now, today, we’re learning about BiTE therapy, which is a way to activate the T cells against the cancer.

But in any of those ways, whether you turn it off too much or you activate it too much, you can get overstimulation of the immune system, and then you have to manage that with immune modulators.

So, I think we're doing it in a very blunt way. The body's immune system does it in a very elegant way with very specific cytokines in very specific locations.

Dr. Mateo Mejia Saldarriaga: Yeah. Exactly. The example that I tell my patients is we're going to create a little bit of fire. And that fire is good because it's going to kill the myeloma, but we don't want to burn the whole house. So, sometimes we need to put down a little bit of the fire.

Dr. Manish Shah: I love that analogy. I'm going to use that. So, these bispecific T-cell engagers, there's several that are approved. Why don't you tell us about the ones that are approved in myeloma?

Dr. Mateo Mejia Saldarriaga: Bispecifics is not a new therapy anymore. It's been approved for the last two years. We are lucky, we have now four different molecules that are approved in the myeloma space. Three of them look at the same protein, the same antigen in the myeloma cell. It's called BCMA. You will see the pattern with all these different medications, is they look at something that is highly expressed by the cancer cell. So, BCMA is something that is highly expressed in myeloma cells more than in any other cell of the body. And it's actually also the target for one of our CAR Ts in myeloma.

So, you can imagine like BCMA, we understand that it's so critical. And it is so highly expressed in myeloma, that was the first antigen that was targeted with these bispecifics. So, there's three medications that are approved. As with everything in myeloma, they were approved when the myeloma has returned many times, at least four times. So, that's what we call relapsed/refractory.

And more recently, we have an approval of another bispecific, also for relapsed myeloma, but this one is looking at a different protein. So, this one is called GPRC5D. And again, it's highly expressed in the myeloma. And it is very interesting to use this as a case example. They both work in the same way. They both take your T cells and activate it against the myeloma cell using either BCMA or GPRC5D. What we have learned is that if a patient stopped responding to one of the BCMA, we can actually go to the GPRC5D.

So, what we can learn from that observation is that, when the treatment stops working for the patient it’s not because the T cells are tired, or not doing what they should, it's many times because that myeloma cell hides or changes the protein in a way that the T-cell is not able to identify it anymore.

So, many of the therapies we use, we can go from one bispecific to another bispecific. Or, for example, what happens often in myeloma, we can go to a BCMA CAR T to another type of immunotherapy that also uses T cells, but it's looking at a different antigen or it's looking at a different way of activating these T cells.

Dr. Manish Shah: That's very interesting. And then, just to round it out, so there are several that are approved for B-cell lymphomas that target CD20, there are three. And then, there's also one that is approved for ALL, acute lymphoblastic leukemia. And that's targeting CD19. And then, in solid tumors, we have two that are approved, one for small cell lung cancer, that's tarlatamab and that is binding a protein called DLL3. And then, we also had a recent approval in uveal melanoma, and that's targeting GP100. So there are already nearly 10 bispecifics that are approved across different cancers.

And I just want to mention another concept which is related to this T-cell engager or a bispecific antibody. Now, recall from the beginning of the conversation, we were talking about the left arm binding to one protein on one cell. And the right arm binding to another protein on another cell. You can also create an antibody where the two arms are binding to the same protein, but different epitopes, different parts of that protein. And that's actually demonstrated by a drug that's targeting HER2. And the drug is called zanidatamab. It's called a biparatopic antibody because it is binding to two distinct non-overlapping epitopes of the same protein and the same antigen.

And recently, at our national GI ASCO meeting, we heard of the data from the HERIZON-GEA study examining zanidatamab plus chemotherapy, plus immunotherapy. And the results were very, very encouraging.

It's really an incredible story of medicinal chemistry modifying proteins-- in this case, antibodies-- in a way that make them even more effective, more immunogenic, activates the immune system in a better way.

Dr. Mateo Mejia Saldarriaga: I agree with you. I think we're still seeing the early days and our bispecific antibodies, they still look pretty much like what we expect to see for an antibody, as you were mentioning. But for example, in myeloma now, we also have trispecific antibodies where imagining the antibody grew a third arm. And that arm is looking at even another protein in the myeloma.

So, this is going to keep getting more and more complicated. But it's fascinating, because as you said, the more we learn about how they work, the more we can leverage that knowledge into creating better medications.

Dr. Manish Shah: That's wonderful. So, let me begin to close this session out. Thank you very much for this really incredible and engaging discussion. In terms of this class of drugs or research in this area or even in general myeloma, what excites you the most?

Dr. Mateo Mejia Saldarriaga: I just spoke about trispecific antibodies. There's already some data in heavily pretreated patients that looks really good. You might think that because we're targeting more agents, the toxicity is going to be worse. But at the same time, I think we learned how to modulate that activation a little bit better. And now, we don't create such a big fire. So even though we're targeting more proteins, some of these molecules, they actually look safer. So, imagine if these medications are already active, what if we could create an even more effective, but yet even safer alternative? That's quite exciting.

The other side of this is, usually in cancer, you develop medication that is approved when the myeloma has come many times. And once that is approved, we start moving it earlier and earlier and earlier. And that's exactly what happened with myeloma. Now, we have clinical trials that are looking at this immunotherapy approaches such as bispecifics as early as first-line. So when the patient is newly diagnosed and not only in patients who are newly diagnosed, but also we're trying to understand how can we best combine this with some of our other available treatments.

Myeloma has been a type of cancer that historically has used a lot of medication that modulate your immune system. And now, this is almost like a completely new frontier because we need to use those medications not only to kill myeloma, but what we have realized is by combining these medications, we can actually enhance the T-cell activation from these bispecifics and achieve even better results.

So, just to summarize, earlier use of this immunotherapies, combinations to make it better, and new bispecifics that are probably safer and even better than what we have already.

Dr. Manish Shah: That's terrific. You've highlighted another theme that we've discussed on the podcast over several episodes. And that is that if you have a target and you're able to hit the target well, the earlier in the disease course you utilize that target, the more effective your treatment's going to be.

And that's essentially what you're saying here as well. If you think of these bispecific antibodies as a way to activate against the target, the myeloma cell, the earlier you use it, the better and the more effective it is.

Dr. Mateo Mejia Saldarriaga: And there was some data presented at ASH 2025 on the combination of teclistamab, one of this BCMA bispecifics, with daratumumab, which is a medication that is already approved for the last 10 years in myeloma in relapsed/refractory. Just one line. And the response is quite impressive. So how's it going to look when we do it with first-line, when the patient is newly diagnosed?

Dr. Manish Shah: Well, Dr. Mejia, thank you so much for this great conversation. You can download, subscribe, rate, and review CancerCast on Apple Podcasts, Spotify, YouTube, or online at weillcornell.org. We also encourage you to write to us at cancercast@med.cornell.edu with questions, comments, and topics you'd like to hear us cover in the future. That's it for CancerCast, conversations about new developments in medicine, cancer care, and research. I'm Dr. Manish Shah. Thanks for listening.

disclaimer: All information contained in this podcast is intended for informational and educational purposes. The information is not intended nor suited to be a replacement or substitute for professional medical treatment or for professional medical advice relative to a specific medical question or condition. We urge you to always seek the advice of your physician or medical professional with respect to your medical condition or questions. Weill Cornell Medicine makes no warranty, guarantee, or representation as to the accuracy or sufficiency of the information featured in this podcast, and any reliance on such information is done at your own risk.

Participants may have consulting, equity, board membership, or other relationships with pharmaceutical, biotech, or device companies unrelated to their role in this podcast. No payments have been made by any company to endorse any treatments, devices, or procedures. And Weill Cornell Medicine does not endorse, approve, or recommend any product, service, or entity mentioned in this podcast.

Opinions expressed in this podcast are those of the speaker and do not represent the perspectives of Weill Cornell Medicine as an institution.