MUC4 Nude Mouse Model Trail in HER2+ Breast Cancer
INmune Bio is focused on the innate immune system in many diseases, and our interests that we’re talking about today relate to cancer and the immunology of the tumor microenvironment. And it turns out it’s important because, It’s breast cancer, and in fact, it’s HER2+ breast cancer. HER2+ breast cancer is now with the modern therapies, half of all cancers. It is an aggressive form of cancer and there’s a lot of great solutions for these women with breast cancer, but they still relapse.
And why am I saying HER2+ breast cancer is half of all cancers? It’s all because of HER2. That’s the drug from Daiichi Sankyo. That is trastuzumab deruxtecan, which has revolutionized the care of women with HER2+ breast cancers. It’s what’s called an antibody ADC (antibody drug conjugate) on a trastuzumab backbone. And where traditionally women with HER2+ breast cancer had to have high levels of HER2 expression, which meant that only about 20% of women with breast cancer metastasis had were eligible for immunotherapy. Now, women with low expression of HER2 are eligible for immunotherapy. So that means almost 50% of women have access to trastuzumab based immunotherapies.
And that’s more than double than were before. Yeah. So what am I talking about? What? What I’m talking about is that still with all this great technology and innovation, half of the women who are treated with HER2 relapse after two years. So even though you’ve got a great new cancer therapy that’s making a difference in women’s lives, something that we didn’t see before, you still have half of the patients have cancer progression (tumor stage) and many of them will die from their disease because of this cancer progression. So our particular interest is what is it about those women? That make them resistant to trastuzumab based therapies. And this includes Trastuzumab alone or Trastuzumab ADCs, including in hair tube. And the data we presented today is really a continuation of some data that Roxana Schillaci from CONICET, in Argentina has been working with us for now probably three years, about resistance factors in women with HER2+ breast cancer (cell). That is to say if you look under the microscope at a biopsy from a patient, with HER2+ breast cancer and they express what’s called MUC4.
They express this protein that is on the cell surface. Those women are resistant to trastuzumab based therapies. In other words, I can treat them with trastuzumab and they won’t get better. And what we have discovered or what she has discovered—we are applying to these more interesting therapies like ENHERTU. Is that this MUC4 expression can actually be made to disappear. If you get rid of what’s called “soluble TNF,” TNFα is tumor necrosis factor. The tumor cell (lines) actually make the TNFα. When they make the TNFα, they express this MUC4, which is like a goopy mucus on the cell surface, and it makes it so the antibody can’t bind to the cell surface.
Think about it, if my hand is the is the HER2 and usually the antibody binds it, but if there’s a bunch of goo, and I use a scientific term that is covering that her to the antibody can’t bind, you treat the patient, you treat the animal, you treat the animal with a drug we call MBO3, which is a dominant negative TNFα inhibitor, which neutralizes soluble TNFα. The MUC4 goes away, the antibody binds and you have a trastuzumab effect. The second thing that happens is you convert the inside of the tumor (tissues, not normal tissues) from a cold tumor. That is, there’s immunosuppressive (cancer) cells that do not attack the tumor (types) into a hot tumor that has immunologically active with macrophages that actually phagocytize the tumor and it promotes recruitment of T cells and NK cells. So clearly, MUC4 expression is a problem. Clearly, it is driven by soluble TNFα and clearly, if you neutralize soluble TNFα with NB3 a dominant negative TNFα inhibitor, you reverse that resistance in animal models.
So that’s great, but then HER2 came on the stage now, and HER2 works a little bit differently than Trastuzumab alone because it has this toxin, this deruxtecan payload, which helps it kill the tumors, the resistant tumors. The problem is it still has to bind her too. So, in other words, think about it. If a capsule is coming to dock at a space station. It can’t dock at the space station if something is blocking that docking pod, that docking site. And that’s exactly what happens. The MUC4 expression prevents the trastuzumab deruxtecan from binding. So you don’t get the clinical effect now.
We didn’t know if, because you have both the antibody and the payload, if this resistant mechanism was still going to be relevant. And that’s what this data shows. It shows that, in fact, we now understand what this resistance factor is. We understand that it’s much for aberrant expression that even is active in these women who trastuzumab deruxtecan and that if you get rid of the MUC4 (cell adhesion) by giving them a dominant negative TNFα inhibitor. You can make them sensitive. Now, this was all done in mice. Now we know we’re in the process. We’re working with Daiichi Sankyo and Roxana is working with Daiichi Sankyo, where we’re actually looking at the biopsies of human patients who are resistant to Trastuzumab Deruxtecan or in HER2 to determine if in fact these patients look like the mouse model. That is the express MUC4 if they do, then it’s very obvious that we need to go with combination therapy. In other words, in these women, we can look under the microscope, see if their biopsy at the time they get treated.
Expresses MUC4 if they do. You give them combination therapy within HER2 and DN-TNF, and you should convert a patient who will not respond into a patient who responds. That’s the first point. Now importantly, adding the DN-TNF inhibitor doesn’t add any toxicity. It really is tolerated extremely well. The second thing adding DN-TNF does, it converts the cold tumor of the breast. Into a hot tumor of the breast and hot tumors of the breast are now candidates for immune checkpoint inhibitors (focussing on immune cells). Most breast cancers are not candidates for immune check checkpoint inhibitors because they are cold tumors. So we’re doing one thing, we’re adding NbO3 to these patients that express MUC4 and we get two benefits. The first is you suddenly are able to make having HER2 work, and the second thing is to do, you can consider adding a checkpoint enabler and maybe you can take these women who are have resistant refractory disease and make a difference in their lives.
Common Questions About MUC4?
I think the most common cause is people are really confused about this concept of TNFα. Everybody thinks of TNFα is in the blood, right?And they think there’s only one type of TNFαs. Turns out that there’s two types of TNFα and in fact, many of these women. Don’t have TNFα in the blood because the TNFα is happening very locally. In other words, the breast cancer cell lines itself is making the TNFα. And it feeds back on itself to cause MUC4 expression. So you don’t see TNFα in the blood, you can’t draw the blood, and say, oh, this patient has an elevated level of TNFα. They’re going to be resistant to the therapy. You have to look at it under the microscope. You have to look for the resistant factor, which is much for what you can see under the microscope.
But that’s the beauty of it. You can actually decide prospectively whether this patient should be treated. With this therapy to improve resistance. So that’s the first question. The concept of adding a checkpoint inhibitor is relatively new and untested at this point in the animal models. But, so people are cautious about making double therapy, triple therapy, so to speak. But it is a valid. Concept that they are curious to see more information. And then the third and most important question, which I agree with, is does it we know it happens in mice or in a human tumor cell that are implanted in mice, but is this what happens in humans? And we’ve got to figure that out.
We know women were getting trastuzumab alone. In other words, they’re not getting ENHERTU. But the ones that express MUC4 do much worse than the ones that don’t. So we know that the effects on Trastuzumab is important, and we were suspicious of the effects on Trastuzumab Deruxtecan or in HER2 were gonna be important and it is in the mouse models. We now need to prove that in the human, and that’s what we’re doing now. We’re reviewing slides of patients who have developed resistance or were resistant to InHER2. And I predict that we will show that they express much for, and then there’s only one thing you can do. You got to do the clinical trial and that if you get rid of MUC4 with DN-TNF you in fact will make a difference in immune response rates.
Watch and Share the Video Here: https://oncologytube.com/v/41476
How Will This Affect Medical Oncologists?
The first step is to review. Human slides to correlate the resistance with the aberrant expression of MUC4, the resistance to inherit to. The second thing to do is to repeat these experiments in an immunocompetent mice. What do I mean by that? All the data is developed in nude mice, which have an intact, innate immune system (immune response), but they don’t have an adaptive immune system, so they don’t have T cells. So it’s a bit of an artificial system.
There are now what we call humanized mice, they like to read the New York Times and watch Monday Night Football. But these humanized mice basically have a fully competent human immune system that includes the adaptive and innate immune systems. And we want to repeat some of these experiments and we suspect we’re gonna show even more benefit in these animals with adaptive immune system.
And then finally, we go to man, so those are the steps that we plan in 2023, and we hope to actually be able to actually start clinical trials in a year or so.
What Are Some Key Takeaways In The Trial For Patients with HER2+ Breast Cancer?
So the key takeaways are simple, number one; HER2, as they know has revolutionized the care of breast cancer, particularly women who now express any form of HER2 on their breast biopsy.
By the way, it’s true also for gastric cancer (gastrointestinal tract), selected lung (adenocarcinoma) cancer, colorectal cancer (colon cancer). ENHERTU is a game changer. No question about great drug hats off to the developers, hats off to everyone involved in the delivery of this life saving drug to patients. But at least in women, still, half the patients fail.
Now, that’s not a disaster because that’s the nature of cancer therapies. There’s no silver bullet. Every time you add another one, a few more survive. So in this case you add something in 50% more survive, or maybe not 50%, but let’s say 30% more survive compared to standard of care.
So you’ve made progress. Now we have to figure out what to do for that 50% to fail. And I think we have a good strategy. It’s not chemotherapy that’s going to make the difference. It’s immunotherapy. It’s all about harvesting the immune system. And the beauty of harvesting the immune system is it’s pretty well tolerated.
We can add NbO3 with absolutely no toxicities to inherit two. I think in the future we’ll be adding NbO3 and checkpoint inhibitors, and we believe that certainly the checkpoint inhibitors might add some toxicity because they do have some toxicities. But one of the benefits of NbO3 is it may tamp down some of those toxicities with immune checkpoint inhibitors.
So I think in the future we have the opportunity to add new the immunotherapies to these women who fail, but still do it in a way that is not. Toxic will not have a negative impact on their quality of life. We have to prove that’s me talking based on what I know of these drugs. But I’m quite confident we can gain an therapeutic benefit without sacrificing quality of life.
Your Closing Thoughts
I actually think MUC4 is going to become one of those (specific) biomarkers you need to look at for women at the time, that they get their first biopsy. In other words, if it’s a resistance factor, why wait for a patient (monitoring) to develop resistance before you go, “Ooh, ooh, why were they resistant?”
Oh, look, they have MUC4 expression. Let’s do this. MUC4 expression is easily measured, just like HER2. You use immunohistochemistry on the primary biopsy, and you know at the first moment, That they’re gonna have some resistant problems because NbO3 or TNFα is so well tolerated. If we intervene at that point, you’re going to have fewer women failing in first line therapy.
You’ll certainly have fewer women going to the second line. And at the end of the day, many more of these women are going to have longer, better lives, and we may end up curing a few patients.
Raymond Tesi, MD – About The Author, Credentials, and Affiliations
Dr. Tesi has been our President, Chief Executive Officer and acting Chief Medical Officer since the formation of the Company in September 2015. Dr. Tesi served as CEO, President, and Acting Chief Medical Officer of FPRT Bio Inc., a development-stage biotech business created to develop XPro1595 for the treatment of neurodegenerative illness and other inflammatory diseases, from November 2011 until May 2015. From November 2010 to October 2011, Dr. Tesi served as the Chief Medical Officer of Adienne SRL, an emerging biotech business in Bergamo, Italy that specializes on hematologic malignancy treatments. From June 2007 through September 2010, Dr. Tesi served as CEO and President of the company he created, Coronado Biosciences. In 1982, Dr. Tesi earned his medical degree from the Washington University School of Medicine. Since 1982, Dr. Tesi has been a licensed physician and a Fellow of the American College of Surgery.
INmune Bio, Inc. – INmune Bio Inc. is a clinical-stage biotechnology business developing innovative immunotherapies that reprogram a patient’s innate immune system so that it can fight cancer and Alzheimer’s.
INmune Bio Inc. is developing revolutionary anti-disease medicines that target specific components of a patient’s innate immune system. INKmuneTM and INB03 are drug candidates that may be used to treat cancer (cells). XPro1595 focuses on neuroinflammation as an Alzheimer’s disease etiology. INmune Bio’s product platforms use a precision therapy strategy to treat unresolved medical problems by increasing the body’s innate immune response.