Targeting CLL With Cancer Vaccines

Transcript:

Dr. Catherine J. Wu: Well, it’s a pleasure to be here, and to share with you some of our ongoing, exciting research. The title of my talk is “Targeting CLL with Cancer Vaccines,” and this is a very exciting ongoing area of work. Recently, together with Dr. Wierda, Dr. Kipps, Michael Hallek, John Gribben, Nick Chiorazzi, and Federico Caligaris-Cappio, on behalf of the International Workshop in CLL, we put together a special report that is coming out soon in blood, about the research priorities in CLL. How can we get to a cure?

And what this image is trying to depict, which is part of the article, is that we’ve made a lot of progress at this point in 2026. And we’ve gotten to a place, shown on the left bank, where we’ve made so many strides in terms of how we think about the therapies that are available for CLL, how patients can be treated. But we really want to cross over to that next stage, which is, how can we precisely know what are the right therapies for which individuals with CLL, and how can we get there better and faster?

Together, we started to brainstorm, and we really think that the next frontiers are as labeled in the steps. Really understanding the, what we call the molecular taxonomy. So, how do we classify the different subtypes of disease? We have to understand what are the dependencies and vulnerabilities of CLL, and the basis of therapeutic resistance?

We have to also go back fundamentally, and understand, what are the origins? How do we get here? How did a normal B cell become a CLL cell, and even transform into Richter’s? And finally, the fourth part is understanding that interaction between the CLL cells and the immune system.

And so, really, I want to highlight that this kind of immune interaction is something that we’ve known a lot about in CLL for some period of time. But with the better tools that we have, how can we precisely get to, what are those critical interactions? And in doing so, could we actually get to intervention at an early stage, so we can change the natural history of what happens when a patient has CLL? And so, that’s just kind of a backdrop, and some understanding of where we are in the landscape of everything else going on.

This is a complicated image, but I want to note that we are in a very exciting time in general, in the therapy for cancer. Because immunology has really come to the fore. And there are, as noted here in the different quadrants, many different modalities of immune therapy that there might be.

There might be adoptive cellular therapy, there might be vaccines, there might be immune checkpoint blockade, or there might be T-cell antigen-directed antibodies. But at the center of all of this is some understanding of what is being displayed on the surface of CLL cells, that distinguish it as a malignant cell, not as a normal cell. And if we could understand what those so-called surface-expressed peptides, we call them antigens, are, that is the sharp point of the spear. That is how we launch our immune attack.

And so, in the vein of thinking about, how do we harness immune responses? How do we do it in an antigen-specific fashion? Well, cancer vaccines are really front and center of that effort. And cancer vaccines have been around the block for a long time, and they’re very unique in their ability to modulate immune systems.

Because on the one hand, going from 9:00 to 12:00, they’re really focused on the antigen, and trying to foster immunity in a very precise and potent fashion against those antigenic determinants. And if you target enough of them, maybe this can address whatever kind of variability is within the cancer population, so that we can avoid the subsequent arrival of resistance, which can happen when tumor heterogeneity is not addressed.

Going from noon to 3:00, we know that vaccines are a potent way to increase the quantity and quality of T cells. Going from 3 to 6:00, we also know that they can stimulate inflammation and the driving of interactions with the immune microenvironment. And we are always cognizant of how we can best deliver and manufacture these vaccines.

But I think a key takeaway for vaccines is, it is an opportunity to expand the T-cell reservoir and promote immune surveillance and memory. And so, they really have the ability to amplify pre-existing anti-tumor T-cell responses, but also prime and expand new anti-tumor responses.

And so, I alluded before to this roller coaster that we’ve been on. Vaccines have been interrogated over the decades, and sometimes, there’s been a lot of excitement. Sometimes, there’s been a disinterest. But we are in a very exciting time, because the new technologies that have come upon the scene have really been transformative.

And I would say that in the past decade, we’ve observed a convergence of transformative technologies that have yielded new immune targets that we can go after. And this is what we call neoantigens. And this has really been a result of next-generation sequencing, so, NGS. This is because we have better neural network-based prediction algorithms that allow us to take that sequence information, and start to tile around mutations, and start to predict which ones out of the whole array are the ones that we want to go after.

And for more than a decade now, we’ve had FDA approvals of immune checkpoint blockade antibodies. And I like to talk about that as kind of like the Obi-Wan Kenobi moment, if you follow Star Wars. Think we all remember that moment when Obi-Wan Kenobi goes into the Death Star and goes, “Hmm.” And then, the whole Raiders shield goes down, and suddenly, the Death Star becomes more vulnerable to attack. And that’s really what I think immune checkpoint blockade antibodies have done for us.

And in terms of launching the attack, really, I think our fighter pilots are going after the neoantigens. And so, what are neoantigens? Well, these are targets that arise because of DNA mutations in tumors. And mutations are part and parcel of the identity of what a tumor is. We’ve learned so much from next-generation sequencing about finding and discovering what those mutations are, which proteins do they come from, and which ones are the ones that are really driving the generation of that type of cancer. Including for CLL, and in previous talks, I’ve talked about our work discovering DNA mutations in CLL.

But in this case, those DNA mutations also provide us with a new therapeutic opportunity. Because some of those mutations can lead to, from the DNA level, to a change in the RNA, a change in the protein level, so that we have altered peptides.

And at least some of those peptides have the ability, as they go through processing and presentation within the tumor cell, they can have the possibility of being bound to a patient’s own HLA molecules. And HLA is the vehicle from which these peptides are seen by the immune system. So, when they hit the surface, at least some of those mutated peptides that are presented have the ability for, then, the T cells to come and recognize them.

And so, the concept of a neoantigen is not a new one. It’s just that we never had the way to actually systematically find the mutations on a patient-by-patient basis. Now, problem solved with next-generation sequencing. And when this started to happen more than a decade ago, myself and other groups started to wonder, “Couldn’t we just, in real time, start to analyze, at the DNA and RNA, level those tumor-specific mutations? And couldn’t we use the HLA typing information, and those fancy epitope prediction tools, and start to ask for a patient’s own set of mutations? What are the mutations that could generate these so-called neoantigens?”

“And if we could identify the personal neoantigens for each individual, then could we not prepare a vaccine that could be directed and given, administered to patients, to mount T-cell responses against those neoantigens?” And this was the concept that we and others really started to test.

And so, what this graphic is showing is the immense progress that we’ve made over the last seven or so years in this area. Our first study, Ox Nature 2017, was the first of its kind that we co-published together with our colleague, Ugur Sahin, back in 2017. The way this graphic is organized, the left lane is for synthetic long peptides, SLPs. So, these were peptide vaccines. The middle lane is for RNA vaccines, and the right lane is for other types of vaccines. And what you can see is that, initially, we were focused on, can we even do it? Is this safe? Is this feasible? Answer is, for sure, yes.

And the next-level question was, in the blue font, “Were these actually able to stimulate a strong immune response?” And across many different tumor types, the answer, again, is for sure, yes. And since then, we and others have been able to show that we can demonstrate that such vaccines actually hit tumor and are able to target tumor.

What’s been very exciting in the recent couple years is that the studies have become sophisticated enough, so that we can start to detect whether or not there’s clinical impact. In the green font, what you can see is, in diseases as tough to treat as pancreatic cancer and high-risk renal cell carcinoma, that, in fact, when we give these vaccines, patients have a less chance of recurring after getting the vaccine. Been super exciting.

And that’s the top of the road in the yellow, is that there’s been a 150-person study, which is in a randomized open-label Phase II study in melanoma, that demonstrated benefit of adding a vaccine together with anti-PD1 therapy, compared to anti-PD1 therapy alone. And this is that information here.

So, on the red line is those patients who got both the mRNA vaccine that targeted 34 different targets, neoantigens, together with pembro. So, this was entirely a personalized vaccine. Each and every one of those tumors were analyzed in real time, and a personal vaccine devised for them. And those patients had less recurrence than those patients in blue, who received the antibody alone.

And this type of activity has really spurred a lot of excitement in the field. There are a lot of clinical trials right now, spearheaded by different companies. And what I want you to notice is that the original clinical trials that we and others did were in the academic settings, and they were studies of eight, 10, 15, 30 patients. But look now, we’re getting to hundreds to thousands of patients that are being treated. And I do think that for these solid tumors, we’re going to hear about the readouts, probably in another year or so.

For CLL, this is what we call a lower mutation burden tumor. And so, there, the number of neoantigens that we can target are understandably less, based on the DNA structure of the malignancy. So, what do we do, then? Is it so easy to find neoantigens that we can include in vaccines?

And certainly, there are challenges in T-cell immunotherapies for blood malignancies, and also, for chronic lymphocytic leukemia. We have to think about what are the right tumor antigens to go after? We’re always dealing with cancer heterogeneity. And we think about the lack of knowledge of the properties of anti-tumor T cells associated with effective responses.

And then, we also think about the absence of effective, sustainable strategies to reprogram T cells for optimal persistence trafficking in the tumor, and ability to eliminate tumor cells. And so, I come back to that concept where it’s really important to think about what the antigen is.

What this graphic is trying to show is that, in the current day and age, where we’ve really been is above the surface of the water in this iceberg. So, I talk to you about neoantigens, which are here on the left. Tumor-associated antigens is a class that we’ve thought about for decades. Not necessarily effective, but certainly out there. Some cancers are also generated by viruses, and there have been some promising work there.

But look at what’s beneath the surface. There are so many parts of our genome that have not been heavily cataloged or characterized. We call it the “dark proteome,” because when we look at the protein level, there is a lot of junk stuff that we haven’t fully analyzed. And we and others have started to look at what is in the tumor immunopeptidome and trying to understand what the dark proteome is.

And I’m not going to go about this in detail, only to say that there are nascent efforts that are pretty interesting that are already going on in our groups, trying to understand this dark proteome, and to see what type of immune responses they can generate. And I do hope that in the future, in the not-too-distant future, actually, I think that what we have down here in the linear line on the bottom is what we are currently doing for our vaccine trials. Which is starting from tumor, and analyzing DNA and RNA, and then coming up with a set of neoantigens to put in our vaccines, to give to patients.

But what if we instead first did a mass spec characterization, which allows us to directly physically see, what are the peptides that are being produced by tumor cells? Which we can analyze directly with what we call this – by mass spectrometry. And then, this could help us inform what to put in our actual vials.

And so, this general excitement about where we are in the vaccine field has led us to partner together closely with the National Institutes of Health. They tapped myself and other colleagues to put together a vaccine roadmap, so that we can really bring vaccines out to patients more broadly.

And I had the privilege back in December of assembling a fabulous team of experts in the field, represented across the country. And together, we started to identify what were the key questions that have been missing that we still need to address, in order to make cancer vaccines more broadly available. And on St. Patrick’s Day, we were able to go to the National Cancer Institute, and this proposal was met with great enthusiasm. And there’s an effort right now to raise 200 million in a public-private partnership, to fund clinical trials of vaccines.

And so, I do hope, and I’m quite optimistic, in the not-too-distant future, with all our bank of knowledge that we’ve learned from our research studies over the past one to two decades – especially since I do think that sequencing is, and should be part of, the routine diagnostic tests that patients get when they are first diagnosed with cancer. That we can then work with our primary oncologists and order up a cancer vaccine to be given. And that the pharmacies at our hospitals can say, “Sure. These will be ready in a few weeks.”

So, aspirational for sure, but I don’t think unrealistic. Thank you for your attention, and I hope we have the opportunity to be in contact in any time in the future, should you have questions.