Tag Archive for: BiTEs

Understanding Myeloma Therapy Targets BCMA and GPRC5D

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Understanding Myeloma Therapy Targets BCMA and GPRC5D from Patient Empowerment Network on Vimeo.

What are myeloma targets, and how do they impact the effectiveness of therapy? Dr. Krina Patel explains how treatments like bispecific antibodies and CAR T-cell therapy are using myeloma targets such as BCMA (B-cell maturation antigen) and GPRC5D (G protein-coupled receptor 5D) to kill myeloma cells. 

Dr. Krina Patel is an Associate Professor in the Department of Lymphoma/Myeloma at The University of Texas MD Anderson Cancer Center in Houston, Texas. Dr. Patel is involved in research and cares for patients with multiple myeloma.

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Transcript:

Katherine:

We know that the currently approved bispecific antibody therapies target BCMA and GPRC5D. What are these targets precisely and how do they impact the effectiveness of the treatment? 

Dr. Krina Patel:

No, it’s a great question.  

And, again, so BCMA we’ve had for a little bit longer.  

We’ve known about it for a little bit longer, B cell maturation antigen, which definitely we’ve used as much as we can. So, we’ve had CAR Ts for it. We’ve had bispecifics for it. We’ve had antibody drug conjugates that we’ve attached to it. 

So, it’s a really good target that is mostly just on myeloma cells and on very few other cells in the body, for the most part, which is why it makes such a great target. The side effects really should happen only specifically against the myeloma; so, less side effects in terms of toxicity. That’s not 100 percent the case.  

BCMA is in some other tissues, like maybe the nerves, and that’s why maybe we see this toxicity sometimes, potentially in the GI system. Some patients can have it in other places. If you have myeloma in, let’s say, areas like the kidney. If you have a plasmacytoma, it can go to the kidney, things like that.  

But again, for the most part, mostly on myeloma. And what’s really important about these targets is, once you get a treatment for it, what happens to that target. So, that’s a little bit different between these two targets. So, BCMA is a part of the proliferation of myeloma cells. So, it actually helps the myeloma cell survive. And so, the myeloma cells really want that BCMA on there. Now, for CAR T, for the most part, we don’t see people losing BCMA. We might see it go down in the myeloma cells that are left. For some patients, the expression can go down. But for the most part, we’ll see it come back up a few months later if the myeloma’s coming back.  

The way that resistance happens with BCMA is that, when people are on bispecifics, the other treatment, we can sometimes see the BCMA get mutated. And then, maybe the other therapies we have won’t go after it any more.  

So, again, it’s not common, but that’s sorta something we look at when we talk about sequencing therapy or which therapy should we use first. Then, GPRC5D’s a little different.  

So, again, mostly just on myeloma cells. But here, we do know it’s on something called epithelial cells, which is skin, nails, tongue. And that’s why some of the side effects that we see, especially with the bispecific that’s a standard of care already, talquetamab, is skin and nail changes. So, people can get sloughing of their hands and nails; that can get disrupted. And then, taste. People can actually have some significant taste loss, to the point that they can have weight loss from it.  

So, this is why that part is so important that if we have patients with these side effects, we need to hold the drug or decrease it; so, make sure we can turn those around. And then, the way GPRC5D is we think that it’s a little bit more likely that you can lose it once you get a treatment with GPRC5D that the myeloma can actually learn how to shed the antigen.  

So, again, this really becomes important when we talk about combination and sequencing of all these different therapies we have and what’s the best way to do it so that patients can have the best response and the longest response.

Available Myeloma Treatment Options for Patients | An Overview

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Available Myeloma Treatment Options for Patients | An Overview from Patient Empowerment Network on Vimeo.

What are the current myeloma treatment approaches? Myeloma expert Dr. Sikander Ailawadhi shares an overview of treatment options, the necessity of combination therapy in myeloma, and the role of clinical trials in patient care. 

Dr. Sikander Ailawadhi is a hematologist and oncologist specializing in myeloma at Mayo Clinic in Jacksonville, Florida. Learn more about Dr. Ailawadhi.

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Transcript:

Katherine:

What are the types of treatments available for people with myeloma?   

Dr. Ailawadhi:

So, myeloma has a lot of treatments available.  We can classify these treatments into different classes of drugs, or we can classify the treatment as early lines or late lines of therapy. Or we can classify these treatments into cellular therapy or targeted therapy or chemotherapy. There are ways of classifying it.  What I would suggest is we should think about classes of drugs.  We have something called proteasome inhibitors. That class has three drugs FDA-approved. We have something called immunomodulatory drugs. That class has three drugs also approved, but generally, we use two.   

Then, there are something called monoclonal antibodies. There are three drugs approved there as well.    

There are cellular therapies or CAR T-cell therapy. There are two of them approved.  There is also a stem cell transplant that is used as a part of treatment sometimes but is different from CAR T. Then, there are other immunotherapy, something called T-cell engagers, in which also there are three drugs approved. In fact, as I’m saying to you, I’m trying to think…yeah, wow. Every class has three drugs. That’s so weird. And then, there are some other classes of drugs. There is something called exporting inhibitors. There is a drug there. All said and done, there are these different classes of drugs.  

There are some guiding principles for myeloma treatment. Generally, three to four drug combinations or regimens are better than two drugs. So, a patient should be in the initial therapy or later lines. Also, preferably be getting a three-drug combo. And I forgot to mention steroids, which are an important part of every regimen in myeloma, almost every regimen. So, three drugs or four drugs are better than two. That’s important to keep in mind. Longer durations of treatment are generally considered better.  We should not tinker with the regimen’s recipe too soon. As long as the patient is tolerating for a longer duration before making any major changes like maintenance.  

Generally, maintenance in myeloma is not a response-assessed thing like, “Oh, you’ve responded in two months. We should go to maintenance.” Generally, in myeloma, maintenance transition is a time-dependent thing. Okay, you’ve had six or nine months or 12 months. We can go to maintenance, sort of a thing. So, even if somebody has responded, they may need the same treatment for a longer period of time to keep the disease quiet.  

And so, I think these are the different categories of drugs. We pick and choose from different categories to combine and make a regimen. The CAR T-cell therapy, the two CAR Ts that are approved, or the three T-cell engagers that are approved, they are all currently used as single agents. They are not combined with anything, not even with steroids. 

Katherine:

How do clinical trials fit into a treatment plan?    

Dr. Ailawadhi:

Okay, that’s an extremely important question, and you’re asking it from a person in my clinic about two-thirds of the patients who are on treatment at any given time are on clinical trials. So, I am very heavily, I shouldn’t say biased, but a proponent of clinical trials. In my opinion, clinical trials are a part and parcel of treatment for every single patient. In fact, when you look at the NCCN guidelines, which are National Comprehensive Cancer Network, which is large institutions across the country, and they make guidelines for all cancers, it is mentioned in every single setting that clinical trials should always be considered.  

So, I personally feel that whenever the patient is coming up with a treatment decision, we talked about shared decision-making in the beginning, it’s important for them to ask at every single juncture, “Do you have any clinical trials available for me? 

And if you don’t have any clinical trials available, are there any clinical trials that I should consider, even if it means going to a different place and getting an opinion?” I know logistically it’s challenging, but we should at least know our options. So, in my opinion, clinical trials should be considered at every single juncture, because that is how patients get access to either a new drug, a new treatment, or a different way of using the current drugs, which might actually improve upon their current state. So, everybody all the time should consider clinical trials.    

Evolving Myeloma Treatment Options | CAR T-Cell Therapy

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Evolving Myeloma Treatment Options | CAR T-Cell Therapy from Patient Empowerment Network on Vimeo.

What is CAR T-cell therapy, and who is it right for? Dr. Omar Nadeem of Dana-Farber Cancer Institute discusses the role of this therapy in myeloma care and shares an update in ongoing CAR T-cell therapy clinical trial research.

Dr. Omar Nadeem is the Clinical Director of the Myeloma Immune Effector Cell Therapy Program and Associate Director of the Multiple Myeloma Clinical Research Program at the Dana-Farber Cancer Institute. Learn more about Dr. Nadeem.

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Transcript:

Katherine:

Well, I’d like to talk about some new and emerging therapies in myeloma, starting with CAR T-cell therapy. Can you talk about who this treatment option might be appropriate for?  

Dr. Nadeem:

So, yeah, just to kind of give folks background, CAR T-cell therapy is a form of immunotherapy, where we take out an individual’s T-cells and then re-program them, essentially, to recognize myeloma cells. Right now there’s two approved CAR-T products for multiple myeloma, both in the relapse refractory setting. It’s really for patients that have had four or more lines of therapy.  

So, that’s a lot of different combinations that we currently have available. Those therapies stop working before patients are actually eligible for CAR-T cells at the moment. Both of these CAR T-cell products have been gamechangers in terms of improving prognosis for patients.  

The good thing about CAR-T cells is that it is a one-and-done treatment. So, patients, when they go through that initial phase of therapy, they are then off therapy, although we are now starting to study certain therapies that we may administer after CAR-T cells to get them to last even longer than they currently do, but that’s still in, for example, that’s one of the clinical trials or many of the clinical trials that are currently ongoing now, to try to answer that question.  

So, a lot of patients can be eligible for CAR-T cells. They have to have the prerequisite amount of therapies. Again, there are some sort of baseline fitness characteristics that we look at for patient’s ability to tolerate it. But as a whole, I consider CAR T-cell therapy more broadly applicable to myeloma patients than compared to, let’s say, a stem cell transplant.  

Katherine:

How has this therapy revolutionized myeloma care? 

Dr. Nadeem:

Yeah, before the first approval, now a few years ago, in this space we didn’t really have anything like this to offer patients. So, many of the combinations and other compounds that were in clinical trials would have a response rate somewhere around, let’s say, 30 percent. So, 30 percent of patients may respond to that therapy in that space, and that may only last a few months, and that was considered successful not that long ago. Now, with CAR T-cell therapy and bispecific antibodies, these therapies are highly efficacious.  

You see response rates of 70 to 100 percent in some of these immunotherapies, and what that’s translating into is patient’s disease staying away for a year or two years, even three years in some of these clinical trials. And again, this is completely unprecedented compared to what we had before.  

Katherine:

I understand that there are a number of clinical trials for different types of CAR T, or even using it earlier in the disease. Can you share updates in CAR T-cell therapy research? 

Dr. Nadeem:

Yeah, so, exactly as you pointed out, there have been trials already, actually, that have been completed, Phase III studies looking at CAR T-cell therapies in earlier relapses.  So, patients that have had either one of two lines of therapy. 

Both our CAR-T therapies have been compared to standard of care in that space and have shown superiority, and this is something that we all have been kind of waiting for to see if you deploy it earlier, perhaps you’re going to see even greater benefit, and that seems to be the case in some of these trials, and now we’re awaiting, hopefully, approval of some of these CAR T-cell therapies to be administered earlier because in fifth line, it’s very different than treating patients in second or third line, which I think will really vastly improve our ability to deliver this therapy to many patients, as it can be quite challenging for patients that are in fifth line, to allow them to go through the process of CAR-T cells and then having them be administered.  

I was looking at it head-to-head with stem cell transplant, as I mentioned before, and this is in the context of quadruplet and induction therapy followed by either CAR-T cells or stem cell transplant, and then followed by maintenance therapy. So, really trying to see if I can overcome what we typically have achieved with stem cell transplantation.  

We also are doing some studies even before that. So, patients, again, in high-risk smoldering myeloma, which we know have an increased risk of developing newly diagnosed disease in the next few years, perhaps that could be the time where we can give some of these immunotherapies, and that’s some work that we have going on at our center. 

Advances in Small Cell Lung Cancer Research | Hope for the Future

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Advances in Small Cell Lung Cancer Research | Hope for the Future from Patient Empowerment Network on Vimeo.

What new treatments are being studied for small cell lung cancer (SCLC)? Dr. Triparna Sen, a leading researcher in the field, shares promising updates, including advances being made with LSD1 inhibitors, DDR (DNA Damage Response) inhibitors, and DLL-3 targeted therapies.

Dr. Triparna Sen is an associate professor in the department of oncological sciences and co-director of the Lung Cancer PDX Platform at the Icahn School of Medicine at Mount Sinai in New York. Learn more about Dr. Sen.

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Transcript:

Katherine:

Dr. Sen, you are a leading researcher in the field. What is the latest research news that you can share with us about small cell lung cancer?

Dr. Sen:

There’s a lot of great research going on in my lab and labs all across the world. I think for the first time in a very long time, we are really trying to dissect the biology of small cell.   

It has been a research in making for many years. I think we have now really come to a point where we are really trying to understand the disease. I’ll go into a little more about the questions you are trying to answer. So, one of the main questions or one  of the main things that kind of is a hurdle to getting durable treatment options is that the frontline chemotherapy and immunotherapy doesn’t work as well as they should even for the approved regimens, which is the chemotherapy and the immunotherapy.  

The patients often do not have durable benefits. Even if patients have durable benefits, it’s only in a very minority of patient population which means in only about 10 to 15 percent of the total patient population actually do have any benefit from the frontline treatment. So, the main question that we are trying to answer is that why do these patients not respond to immunotherapy and chemotherapy in the frontline.  

What are the mechanisms of resistance to chemotherapy and immunotherapy? Primary resistance, what I mean by primary resistance is that patients who never respond. The disease comes back even while they’re getting the frontline chemo. So, the primary resistance, the mechanisms. Of course, when they have acquired resistance after the maintenance regimen when they come back, why are these patients having this acquired resistance to chemotherapy and immunotherapy? Because only when we understand resistance mechanisms will we be able to then come to the combination strategies.

That’s the next area of research is that once we understand the mechanism of chemotherapy and immunotherapy resistance is then coming up with effective combination therapy. So, what should we combine with immunotherapy in order to make immunotherapy better? I’ll give you an example from the research that we did. 

So, our lab focus is, as I said, on making immunotherapy better. What we understood is that there are certain epigenetic modifiers like LSD1.  

Repressing these, repressing LSD1, with a small molecule inhibitor actually augments or benefits the response to immunotherapy. So now, we are looking at LSD1 inhibitors in combination with immunotherapy. That’s one area that we are focusing on. The second are that we published extensively on is DNA damage response inhibitors which really works in combination with immunotherapy and makes immunotherapy response better.  

Now, we are investigating that in the lab the combination strategies of combining these DNA damage response inhibitors with immunotherapy. So, combination strategies. I think always coming up with novel targets. I will mention there are many novel targets that are right now in the clinical trials actually showing really, really encouraging data.  

I’m talking about DLL3 targeted BiTEs or ADCs we have seen that are showing preliminary data. We have seen a really good really good response in patients. So, finding these targets that are very specific for small cell and that can work in these unique population of patients.  

So, DLL3 targeted agents. There are agents that target B7-H3. So, we are looking at these novel targets and where they could fit in the current therapeutic regimen. Finally, since small cell lung cancer is not a surgical disease, we have to look for other options to find biomarkers. So, liquid biopsy. Liquid biopsy, what I mean by that is understanding the disease not just from tissue but also from blood.  

There’s a lot of research that’s happening in understanding the biology of small cell from blood draws from these patients.  

So, the field of using liquid biopsy or understanding the disease from blood draws is one of the areas that many labs, including ours, are focusing on, and how we can utilize these blood samples to then monitor the disease and also understand the resistance mechanisms to various drugs. I think these are the areas that we are investigating and seems, to me, very important areas that we need to address in order to really manage small cell lung cancer.   

Katherine:

What do these advances mean for small cell lung cancer patients? Are you hopeful?  

Dr. Sen:

Oh, yes. Of course. We’re always hopeful. That’s the goal, right. The goal is to have effective therapies that work and that works for a long time. That also benefits the patients in terms of quality of life which means without very severe adverse effects.   

So, very hopeful. Because I think what was limiting us for all those years for the last 40 to 50 years is that we really did not understand the complexity of small cell lung cancer. It is a very complex disease. It is very different from non-small cell lung cancer which has these mutations that you can target drugs against. So, there are this EGFR mutations and KRAS mutations in non-small cell.  

But small cell, it’s not that. It is not a disease where we have these GATA function mutations that we can devise therapies against. It’s a very different disease. The disease is aggressive. The disease progresses fast, and it also changes its physiology very fast. So, I think for the first time, we really are trying to understand the biology. What that helps is then to come with very informed decisions about therapy.  

So, yeah, I’m very hopeful. Because I think we have now targets that we are actually seeing benefits in patients. I think the more and more we understand resistance mechanisms, we’ll also be able to manage that better.   

Katherine:

That’s very promising news.