At the recent Longevity Therapeutics Conference in San Francisco, we had the chance to interview Lewis Gruber of SIWA Therapeutics and discuss his company’s senotherapeutic approach to cancer and senescent cells. He was accompanied by his wife, Misty, who is the CFO of SIWA.

Many of our readers are familiar with CAR-T immunotherapy, which has enjoyed some success, but it’s not without considerable challenges. How does your approach differ?

Lewis: We are using a simpler approach of just manufacturing a monoclonal antibody. Of course, we do that in Chinese Hamster Ovary (CHO) cells and purify and produce a monoclonal antibody product so that we don’t have to modify patient cells or any other cells in order to apply our treatment. It’s just a straight typical monoclonal antibody product, the same sort of immunotherapy that’s used in a variety of cancer therapies.

Misty: Which means that monoclonal antibody goes after a specific marker. In this case, he’s found a marker that’s on cancer cells and senescent cells because of the way the markers are produced, and therefore his monoclonal antibody can zap and remove those cancer cells.

So each antibody is tailored for a specific biomarker, but not for each individual.







Lewis: Yeah, it’s for the one biomarker that’s present in all humans, and actually the marker goes back to yeast.

Misty: We can find antibodies to go after specific markers that we find on certain diseases.

Lewis: Going back to yeast and maybe even back to bacteria.

Can you summarize a bit more how that antibody SIWA 318H works?

Lewis: It binds to proteins on the surface of oxidatively damaged cells that may be senescent or cancerous, or just very dysfunctional. By doing so, it provokes an immune response, initially an innate immune response with the natural killer cells. The bottom line is, the immune response not only destroys and removes the cells to which the antibody binds, but immune cells also secrete factors that promote regeneration. So, while we’re removing cells that are not going to function properly, we’re promoting their replacement with new cells from adult stem cell populations.







Misty: The interesting thing about the markers, it’s a product of glycolysis, and high levels of glycolysis were associated even back before World War Two by Otto Warburg. They were shown on cancer cells. Cancer cells and senescent cells have their peculiarities, and they are high producers of this particular marker; therefore, he can hone in on those two types of cells. There are other markers for other types of diseases, but the key to what he did was find the marker, and then he designed an antibody to go to that specific marker.

Researchers have long been seeking common targetable features on cancer cells, so how’d you discover this particular marker?

Lewis: The process that produces the marker has been reported in the literature. As Misty was mentioning, Otto Warburg back in the 1920s discovered that cancer, virtually all types of cancer cells, have a elevated level of glycolysis, and our marker is a side product of glycolysis. Basically, I didn’t really discover the marker; in that sense, the roots of it go back to the 1920s. It’s only been more recently that the marker has been looked at with respect to aging and aging-related diseases.

So, you rediscovered it, essentially.

Lewis: Rediscovered it, and no one had suggested before using the marker to remove cells that might be dysfunctional. That’s where I came in. I was looking for something to remove dysfunctional cells. I saw the association and literature with cancer and with aging, which also translated to senescent cells, and I said that it would be a good marker.







Misty: So the beauty of it is that both senescent cells and cancer cells have this high level of glycolysis. The Warburg effect is when it’s basically caught on cancer, but for it to also be on senescence cells is really perfect.

Was that a coincidence? Or is there a reason for that?

Lewis: Both types of cells conducted an elevated level of glycolysis and there are various explanations in the scientific literature. Both are highly metabolically active. I didn’t see all the presentations at the conference here, but some people think of senescent cells as almost dead, but, in fact, they are among the most metabolically active of cells, and cancer cells are as well because of high proliferation. Both types of cells have a high need for ATP. One explanation in the literature is that they both resort to glycolysis to get additional ATP.

Misty: The only difference being that cancer cells tend to reproduce rapidly, while senescent cells tend not to reproduce. Senescent cells can be cancer cells too, which is why it’s important to go after both in a cancer drug, for example.

Lewis: The senescent cells put all of their efforts into senescence associated secretory phenotype, so they’re producing a lot of cytokines and other molecules, so they need to use glycolysis, but they’re not using it to divide. A simplified way of looking at it is that senescent cells grow, and they need energy for growth; they basically get to the size that a cell would normally be when it divides, and then they just don’t divide. When you look under the microscope, you see large, flattened cells that are senescent cells, because they’ve grown but they just didn’t divide. Cancer cells, of course, will go ahead and do the division and you’ll have two daughter cells, et cetera. The bottom line is that they both have to grow to that large size.







SIWA 318H is able to likely target both senescent cells and cancer cells, as you mentioned, using a surface marker common at both types of cell. Given their heterogeneity, do all cancer and senescent cells have that marker, and, if so, how’s that been confirmed?

Lewis: It was confirmed for me by looking at the literature for the marker and all of the types of cells. I didn’t dwell on it at the conference, but there might even be a slide in the pack that goes through all of the different types of senescent cells where our marker’s present. Basically, a root cause that they both have is that oxidative damage can lead to three different things. It can lead to senescence, it can lead to cancer, or it can lead to death. The bottom line is that the senescents and cancer share this oxidative damage as part of their history, and all senescent and cancer cells have a history of excess oxidative stress and reactive oxygen species.

Misty: I can give a slightly more pragmatic answer in that we tested it ourselves. We had the animal body, and we did a lot of binding tests. Two of the universities, the big institutions that we’re working with have also done separate studies to show binding. That’s always the first step. You don’t want to go out and do a mouse study unless you know that there’s binding, so we’ve done we did a number of different bindings, including, as Lewis mentioned, a type of glioblastoma that is almost impossible to test. It fits the mold of being a cancer cell that has our marker on it.

Lewis: Basically every type of cancer we’ve tested has bound to our antibody, but I’m relying also on the literature where it’s even reported that our marker is found in association with even more types of cancer. We have yet to find out that there’s a cell that doesn’t have this marker. Again, it goes back to oxidative stress and glycolysis; as I did say in one of my slides, cancer and senescent cells both share having been oxidatively damaged and exhibiting in a high level of glycolysis.

Given that, does that mean a vaccine might be developed for senescent cells or even cancer?







Lewis: Yes, and we are working on what we have. We’ve done preliminary studies in mice, and now we’re looking at expanding it into actually other species, even beyond humans, but with respect to the vaccine, but we do have a candidate vaccine already in the works.

Would that be an inoculation early in life that would manifest later in life, or would it always protect against SCs and cancer cells?

Lewis: It could always protect against SCs and cancer cells. As with any drug, you do want to be careful about certain conditions, pregnancy or other conditions where you don’t want to disrupt any things happening. For example, senescent cells have been found in fetuses.

They have a positive role in organ growth, et cetera.

Misty: In the formation of the hand and the fingers and things like that, they do. They are involved in that.







Lewis: The one common thing, strangely enough, with senescent cells is every situation in which they’re beneficial, they’re removed. After they form the different structures in the fetus, they’re eliminated. The same thing is true in wound healing, which is often given as an example of a beneficial effect. Initially, senescence promotes proliferation of repairing cells, but if that’s allowed to go on too long, the wound tends to produce scar tissue, fibrosis, and the bottom line is that in the natural healing process, senescent cells appear for a time and then are removed. That’s basically what we are: we remove senescent cells. Although you do have to be somewhat careful, you don’t want to interfere with the initial stage of wound healing or with fetal development, otherwise, it’s a good rule of thumb that removing a senescent cell or a cancer cell is not a bad thing.

Cancer is quick to adapt and evolve, so, is it plausible that it could do so against 318H?

Lewis: It would be much harder, I think, than anything else. From the standpoint that our marker is produced by a basic biological process that I mentioned goes back, maybe even back to bacteria, but certainly back to yeast. Evolutionarily, it’s such that it’s hard to imagine, for me anyway, how a cancer cell could evolve around such a basic biological process and come up with something different. Even shifting: for example, some cancer cells conduct more oxidative phosphorylation than others, and so, rather than relying on glycolysis for any ATP, they just do more mitochondrial respiration; however, mitochondrial respiration is a source of reactive oxygen species and oxidative damage. As it turns out, our marker and our antibody would still get them. I don’t mean to belabor all the different ways, but it is a good point, and we have thought about it because it is, as you correctly state, a common feature of cancer to be able to work around drugs, but I think, at least, it would be much harder.

Has your therapy caused a reduction in senescent cells in mice?

Misty: It’s in animal studies that we’ve done, and we’ve shown binding in vitro, which means that the cell is compromised.







Lewis: There’s a reduction of senescent cells in vivo.

Misty: In vivo is where you find that there’s an actual reduction.

In what tissues?

Lewis: In that particular case, we were looking at inguinal adipose tissue and muscle tissue.

Misty: Well, the way that we did a milestone that was the very first thing we did, the first one we looked at was whether we could reduce senescent cells. So we got from a provider, very, very old mice that had not been involved in drug tests, but had been involved only in maze testing and things related to psychology. We took groups: we had very old mice, and we had very young mice. We took two different dosage levels of our antibody, the mouse homologue, and we injected it, and what we found was that there’s a marker called p16Ink4a, which is on senescent cells; everybody’s talked about it, more or less. We showed that in the very old mouse with our upper level of dosage, we reduce the level of p16Ink4a all the way down to the very young mouse controls. We also then looked at a particular muscle tissue to see if we can regenerate muscle tissue because Lewis’ concept was that by removing senescent cells associated with the muscle tissue, the muscle tissue can regenerate. Stem cells were still there, and they do corrective maintenance. In that study, we also got a regrowth of the muscle back to that level. That was the very first study.







Lewis: Also, Mayo Clinic has observed that, even with small molecule senolytics, removing senescent cells can lead to muscle regeneration.

Was that in humans?

Lewis: That was in mice. In humans, we haven’t really been working on that. We’re now using humanized mice, and we’re working toward a clinical trial.

Misty: The benefit of the humanized mice is that we can use the humanized antibody.

Lewis: Since the humanized monoclonal is what we’ll be using in clinical trials and for our pharmaceutical product, we’re anxious to demonstrate that it’s effective in doing the different things that we want to do. We’ve been working with a major institute on cancer studies. They’re looking at a variety of features in the humanized mice, including not only killing the primary tumor cells and senescent cells associated with the tumor but also looking at regeneration of tissues, the formation of desmoplasia, which is scar tissue, and others.







Traditional biomarkers for senescence cells are typically beta-gal and p16Ink4a, but these implementations, so what other ways are you measuring the presence of senescent cells in tissue and any changes to their levels?

Lewis: Well, we have looked at both p16 and beta-gal, and wherever we find them, we find binding of our antibody.

Misty: So, those are confirming our antibodies.

Lewis: We’ve also looked at the large, flat morphology; we look for cells that morphologically look senescent, as well. The final way is that we put them in situations where the histone H2AX is present. We’ve looked for beta-gal, p16, H2AX, and the morphology.

One reason we age is the inhibition of our stem cells due to inflammation, which prevents regeneration of tissue. Do you believe that the SASP from senescent cells plays a key role in stopping healthy tissue regeneration, and what studies do you feel support this?







Lewis: As far as the supporting students are concerned, we could certainly provide those; we have something like 800 pages to maintain. It’s also true that oxidative stress is involved with inflammation. In fact, it has been considered as a cause of inflammaging, which has been related to senescent cells as well. So what we’re looking for is that our antibody removes cells that are promoting inflammation. There’s senescent or not, but presumably they would be senescent cells, and, again, I have seen papers support what you’re saying.

Misty: Even the Mayo Clinic looked at, in the normally old animals, muscle regeneration, and what that involves is removal of senescent cells; the way those muscles regenerate would be if the stem cells were allowed to start regenerating the tissue again, so that has been done in vivo in that sense.

Lewis: In terms of interefering with stem cells.

Misty: The stem cells were limited by the senescent cells: that’s the general theory of us and others who have done the same tests.

Lewis: We do have papers in our bibliography.







You’ve been testing your senolytic approach to combat sarcopenia in naturally aged mice. What have your results been so far?

Lewis: Well, as Misty mentioned, the result was that we had regeneration of muscle tissue in the mouse model that we use. I should qualify; you mentioned that we were senolytic. We certainly are senotherapeutic, we certainly remove senescent cells, but the reason I’m cautioning you is that, at least in some papers, senolytics are defined as small molecules, not biologics.

You’re biologics, purely. Xenobiologics, is that a good term?

Lewis: I think we make senotherapeutics, which can also though be blockers, but the bottom line is that I would certainly qualify it as something that can remove senescent cells but not call it a senolytic. I don’t know if it fits the strict definition that was proposed in some of the early studies.

Do you expect cancer or senescent cell human trials to begin first?







Lewis: That is tough because we are working with this major institute. They’re very far along in the pancreatic cancer model and are working with humanized mice, so they could be the first prepared. We’re separately doing toxicology and other studies so that the combination could mean that we could go into the clinic with them.

Misty: They have the safety studies and dosing already done.

Lewis: And they have organized clinical trials before, so they’re expressed an interest in doing so.

You can’t say what the group is?

Misty: No, we have a confidentiality agreement.







Lewis: It’s an educational institution, and in my career, I’ve represented a lot of educational institutions, and they’re very nervous about having anyone use their name. It’s not just this particular one; in general, I’ve found that they don’t like that. In our case, we do have a contractual agreement where we are not supposed to use their name.

If you do make it to trials, either for senescent cell removal or cancer, is there an approximate time frame you’re looking at right now?

Misty: Probably 12 to 15 months. Part of the issue is we have to keep making the antibody, and we’re still doing relatively small batches, we haven’t yet moved to large batch amounts, so that was a little bit of a limitation.

Lewis: That’s the phase that we’re at now. We have a large contract organization that makes very large quantities for pharmaceutical companies as well.

Misty: Which we’ll switch to when we get closer to this, but right now we’re using small quantities.







Lewis: We’re about ready to switch over.

Do you pronounce that “see-wa”, is that right?

Lewis: Yes. Actually, we’re named after an oasis in Egypt. It was the location of the oracle of the god Amun where Alexander the Great went in Egypt to ask questions about his descent from a god, which they confirmed, conveniently for him. One thing I like to point out is that these ancient oracles, not just Siwa, the Delphi and a lot of the well-known ones, people think of them as places of religious inspiration, but, because they had customers from around the ancient world, they were really intelligence services collecting information. The reason that our company’s named after them is that we look at ourselves as being like them, as being collectors of all the information and providing the best synthesis of that into a satisfying answer.