Cancer Vaccine May be Effective for Melanoma Patients

The Chief Scientific Officer at IO Biotech, Muhammad Al-Hajj, Ph.D., discusses new clinical data on cancer vaccines and the tumor microenvironment with Pharmacy Times. Tune in as Al-Hajj discusses its safety, efficacy, role in treating melanoma, and the future of cancer vaccines for multiple cancer types.

Q: What are the safety risks of current cancer treatments on the tumor microenvironment?

Muhammad Al-Hajj, Ph.D.: Good. Thank you for having me. Thank you for the question. So the thing with the tumor microenvironment (within the tumor), you have normal cells that have just been hijacked, or brought in by the tumor cells, and then you have the tumor cells. When you try to modulate the tumor microenvironment, you’re trying to modulate cells that are more or less normal, but they’ve been a little hijacked. You must be careful if you want to block certain pathways, because they’re present in normal cells elsewhere outside the tumor. This is where the challenge is. If you have a super serious, potent therapy that’s going in and modulating this key normal pathway (or key normal target), it could have serious safety implications. That’s where this vaccine approach is turning out to be really needed—[because] it changes the threshold, but very, very nicely without these major safety concerns. And so for every single vaccine that the company and its collaborator have tested, they’ve been very safe, which is really exciting.

Q: So how does this method of delivery impact safety and efficacy?

Al-Hajj, Ph.D.: The safety of the mode of delivery of the vaccine is not clear. There are many factors that impact any vaccine, not just a cancer vaccine. The feature of the vaccine itself (the immunogen and design that you have, the vaccine type, or the formulations) all these have impact. Also, you have the variations among patients. So depending on the patient—and so what just like what we have with the COVID— when you have people get a serious reaction, when they get their boosters, and others don’t, so you will have these variations. And the type of administration parameters also vary.

So, you have to take all these into consideration. And this has been taken into consideration with the development of our current vaccines— and they've been tested. And clearly you test these in many preclinical models. You assess safety, etc. And then once you get to a point where it is worth going, then the regulator's satisfied, “Okay, now it's worth trying then just go in and it is tested in the in the human setting.”

Q: Could you explain how this mode of treatment is unique from previous modes of treatment?

Al-Hajj, Ph.D.: All previous vaccines (at least most of the studies that have been done), the vaccine approach has been around for a long time—it's really an attractive way of doing it. You get your immune system, and the patients get their immune system, to go after the tumor. But all these previous attempts have been designed with neoantigens, basically antigen service can modify, be modified, mutate it into the cancer cell—and then prevent it. So, you’re going after changes in the cancer cell.

What IO Biotech is doing (and, to our knowledge, nobody else has actually done something like this before) is not go after these antigens. Take, for example, a therapy like programmed cell death protein 1 (PD-1), the checkpoint blockade. This empowers T cells, takes the brakes off of T cells. Now the T cells go to the tumor—a lot of patients respond very well, some patients do not. One of the main reasons that a lot of the patients don't respond to the therapy is that the therapy empowers T cells. The T cells go to the tumor, the tumor has these suppressive mechanisms blocking these T cells from getting in.

So instead of vaccinating something that kills T cells—which are still in an environment around them that is just so hostile to T cells—It's not going to work so well. That is one of the reasons a lot of these new antigen vaccines don't work so well. What we did is say, “Okay. Why don't we vaccinate against key elements that are driving this immune suppression?” That takes the defensive level down, and then you have a therapy that is combined and has the checkpoint blockade.

Now the T cells don't have enough resistance to get inside, and then you see a dramatic response. We're eliminating the key suppressive mechanisms for that tumor type. We're eliminating those, and then you have an empowered T cell therapy and…boom! Now it has a more dramatic response. So, in melanoma patients (if you give them this) the anti-PD1 checkpoint blockade creates responses in the mid-40%. And the trials we did—when you combine it—goes up to 80%. What you have now are these T cells might work in more patients and we are doing a longer trial to confirm these early findings.

Q: How do tumors "hide" from the immune system?

Al-Hajj, Ph.D.: There's multiple mechanisms when tumor cells evade the immune system. One of them, they express things. Typically, your immune system scans for things that are hostile and foreign and gets rid of them. Now the tumor cell is part of ourselves. It's just mutated. But now it must evade this immune system so it expresses molecules that say, “I'm normal.”

For example, programmed death-ligand 1 (PD-L1) they are upregulated in cancer cells. PDL-1 tells the T cell, “Look. I'm fine here, don't touch me.” That's why a blockade of anti-PD-L1/PD-1 to drive efficacy. That's why we vaccinate against PD-L1.

Another way they do it is to bring other cells into the environment that secrete things to make it physiologically not nice for a T cell. For example, indoleamine 2,3-dioxygenase (IDO). We go after IDO and you convert this mechanism. So, the nutrients in the tumor microenvironment do not become permissive for a T cell— so the T cell gets to the tumor to penetrate but it is not going to survive because the pH is not optimal and the nutrients are not optimal. So, you see, what the T cell does it put out a signal that says, “Don't touch me.” You need to block that signal.

And then next is bring other cells to do more things that make it hostile for these immune cells to get to. So, we're trying to eliminate these factors so the T cells can get in to do their job. We try to eliminate this defense so that the cancer cell cannot hide, or just enable the immune cell to get to it and eliminate it.

Q: Is this treatment being explored for other disease states aside from melanoma?

Al-Hajj, Ph.D.: We're not exploring anything outside of cancer yet ourselves. Although the basically the mechanisms or the approach itself makes sense (it can be applied to other diseases), but we have not explored it yet into other disease settings. But theoretically, you should be able to apply it in a setting where an immune cell having issues to overcome a certain setting and then you could vaccinate against and then change that environment from a repressive to a permissive setting. For example, what we do with the with the PD-L1 or IDO You have cells that express IDO in the tumor microenvironment. We vaccinate.

Now the T-cell therapy, for example (the checkpoint therapy) is not working so well because, like I said, there are T cells that express IDO that push these T cells from entering, although they're empowered. Now, when you vaccinate to drive this subset of cells to really go and then eliminate these IDO-positive cells, you get rid of these cells. So now you don't have this IDO function and other functions of IDO within that tumor setting. And what happens now, these empowered T cells outside, which you’ve already given them the checkpoint blockade therapy to can come in and just kind of do the job. So, you shifted it from “Okay, it was repressive, the cell was not coming in,” where now it's like “Okay, the cell is coming in, and then you do drive this efficacy.”

Q: What is the significance of cancer vaccines in the future treatment of melanoma or other cancers?

Al-Hajj, Ph.D.: This is a good question. If you look at right now, like in the oncology clinical trials, there's been research done with checkpoint blockade, or any other T cell therapy, that is powerful. There's over 3,000 trials done in combination of elements to control (to basically empower) these cells further— some of them are toxic, some of them are an efficacious.

There's a lot of issues, so people are trying to figure out how to do it. If you have an empowered cell like a chimeric antigen receptor T cell (CAR T cell) that you put a checkpoint inhibitor or you put a bi-specific, a T cell engager on, and we know they work in minimal areas. But they don't work in the majority of cases because of this repressive tumor microenvironment. A lot of agents to modulate the tumor microenvironment are being developed—that comes with toxicities and challenges that come with a lot of things. For it to work, it has to be safe. It has to be able to go after multiple elements that are suppressive— because you don't have only one suppressive element in the tumor microenvironment, you might have 1,2,3 different elements in every tumor setting.

If you combine multiple drugs with the checkpoint therapy, it ends up being very toxic. So, this is what's so neat, you know, actually knows what attracted me to this place in the first place. I worked in the cell therapy space before, and we faced these challenges. We had these super powerful T cells that we engineered, and then tried to apply them in a tumor setting but they were not very efficacious because of these defense mechanisms. To overcome them 1 by 1 (individually), it becomes a problem and sometimes it’s very just not safe.

The vaccine— so far and at least it’s showing from what we've tested ourselves— is very safe, versus this systemic kind of treatment with an agent that modulates 1 of these. It has been very safe because you can do repeat treatments. So, you have an impact, another impact, until you really have this dramatic efficacy and then ease up And then you can treat the patients and not have serious issues from the modulating agent by itself. So far, it's been really nice that you don't see these major issues, we see it safely. And on top of that, you can put one, or a couple, together and it's still safe.

We targeted IDO, PDL-1, and it's still safe. Targeting more than 2 together, it's still safe. This is what's attractive about it—it changes the environment to a threshold, low enough to empower the T cell come in and do its work.

Q: Closing thoughts?

Al-Hajj, Ph.D.: Thanks, I appreciate it. I'm looking forward to basically finish this trial and just getting going to see the same results in the other trial. And apply it in other indications— then develop new agents that are going to be applied for other indications that may, or may not, work with the current vaccines that we have here.