Jenny

Welcome to today's episode of the HealthTree podcast for CLL, a show that connects patients with CLL researchers. I'm your host, Jenny Ahlstrom. 

Now a little bit about HealthTree. HealthTree is a global nonprofit using innovation to save lives. We provide lifetime personalized support and education, meaningful patient-to-patient connections, and a powerful patient data portal. Our cutting-edge technology empowers patients to better manage their health and engages them as critical contributors to lifesaving research. The trust of our patient community allows HealthTree to provide continually updated, real-world patient data to researchers who seek to advance clinical care and find cures for blood cancers. 

Now, before we get started on our show today, we'd like to highlight a program you can use to learn more about CLL called HealthTree University. This is a full curriculum organized by topic. They are animated videos taught by expert faculty. To date, we have three introductory units with over 40 classes taught by 16 CLL specialists on a variety of topics. You'll see this program expand and grow as we perform more interviews to answer your key questions. Additionally, we have webinars coming up in the month of May. So you can check out our CLL events under our community tab on the main menu. 

Now for today's show, we're living in an age of immunotherapy in blood cancers, including CLL. We are seeing CAR T-cell therapies come out, antibody therapies, checkpoint inhibitors, and other types of immunotherapies really become staples in CLL care. Vaccines are yet another immunotherapy option that we will learn about today. For today's program, we would like to welcome Dr. Inhye Ahn. 

Dr. Inhye Ahn

Thanks so much, Jenny. I'm Inhye Ahn from Dana-Farber, and really happy to join this program. 

Jenny

We are thrilled to have you. Let me give a short introduction for you before we get started. Dr. Ahn is an Assistant Professor at Dana-Farber Cancer Institute, specializing in the care of patients with chronic lymphocytic leukemia, or CLL. She earned her medical degree from the Catholic University of Korea and completed residency at the Methodist Hospital combined with laboratory research training at MD Anderson followed by a hematology and medical oncology fellowship at the NIH. Her research focuses on genomic analysis to improve the identification of high-risk CLL and the development of new treatment strategies that can change the course of the disease. So Dr. Ahn, let's just get started on the topic of vaccines. Can you share broadly how vaccines are being used in cancer care? What's the purpose of some of these? 

Dr. Inhye Ahn

Totally. So as you said earlier, Jenny, in the introduction, a cancer vaccine is a part of immunotherapy. The key concept of immunotherapy in cancer is to harness the immune system to fight against cancer and there are two parts to it. Number one is to stimulate the immune system so that it can attack cancer properly. The second part is to reduce the immunosuppressive effect of the cancer cell itself. So it's a two-fold strategy actually. The cancer vaccine is one way to harness the immune system.

There have actually been successful attempts, mainly in solid tumors. For instance, there is an old type of vaccine called BCG vaccine developed for the treatment of or the prevention of tuberculosis but can be used in early-stage bladder cancer with effect. So this is a strategy where the stimulatory vaccine can help attack the cancer cell. The second type of vaccine that is FDA-approved is a sipuleucel-T (Provenge) prostate cancer vaccine. And this is actually approved for metastatic prostate cancer. This cancer vaccine is actually targeting a specific protein expressed in the vast majority of prostate cancer. 

Jenny

Those are two great examples. When you think about vaccines for blood cancers and CLL specifically, do you think about them as being able to actually kill the cancer? Are they strong enough to kill the cancer? Or is it’s function to prevent progression in early disease or to maintain a response after initial therapy? When you think about vaccines, you've got the prostate cancer example that is to treat the cancer. But in some of the others, I've heard people say that maybe it's to prevent progression or maintain a response. Do you want to share a little bit about your overarching view, seen in general in cancer? 

Dr. Inhye Ahn

Absolutely. This is actually a great question and a scientific question in the field. I think what you're asking, Jenny, is about the true part of the immune system. Immediate immune response against the vaccination and also the long-lasting, what we call memory immune response. So in the lab and with scientific experiments as well as with the infection controlling vaccines, there have been precedents of immediate immune response as well as recall immune response. We want to recapitulate that in a cancer vaccine. This is very early data, but there is evidence of recall response to vaccination in cancer. I think that's a feasible strategy. I think the big question is how long would it last and can that be not restricted, meaning that when the cancer evolves to a slightly different type of cancer, can the vaccine still work during that evolution of cancer? 

Jenny

Yeah, you would think that certain cancers have different types of genetic, mutational changes over time, right? If you're going to talk about this vaccine in terms of being customized for each patient, maybe we jump into that topic. What is the difference between an off-the-shelf vaccine in blood cancers or CLL versus a personalized vaccine? 

Dr. Inhye Ahn

Off the shelf means that you have a shared, basically a common ground that runs across different types of patients and cancers. One example would be the prostate vaccine that I just mentioned. That prostate antigen is actually expressed in almost all prostate cancer cells. And therefore you can use this vaccine off the shelf. The personalized vaccine ideally means that you individualize therapy for each patient's cancer. So what we try to do in the NeoVax form is to actually use individual patients' cancer genetic state to make a really one-of-a-kind patient-specific vaccine. 

Jenny

So, it's customized for each patient? 

Dr. Inhye Ahn

It is, that’s right. 

Jenny 

That is amazing. Can you share a little bit about the history of this product that you're going to talk about NeoVax because it really didn't begin in CLL, or did it? Maybe I'm wrong. 

Dr. Inhye Ahn

Personalization started in melanoma first. I think the whole story began when we were able to do more precise sequencing of the cancer genes. Previously, it was very expensive, it was slow, and it hasn't been feasible to turn around the sequencing data into a scalable form. Now, that is possible. We now have a computational pipeline that uses genomic data to predict the antigen that is specifically expressed on the cancer cell, and that can be presented by the immune cell and therefore immunogenic. 

So this pipeline has been really developed by people at the Center for Cancer Vaccine at Dana-Farber led by Dr. Catherine Wu and Dr. Patrick Ott. It's been a decade worth of work.
Finally in 2013, the team launched the first study in melanoma patients. It was a very small study, six patients with advanced-stage melanoma had been involved and treated. Eventually, in 2017, they reported the outcome in a paper called Nature and really a successful outcome. They did a really deep science with individual patient samples and found out that not only can you make the vaccine out of melanoma cells, but you can also make the melanoma be controlled in a durable manner. So six, seven years out, these patients are still alive, despite the fact that some of the patients had stage four diseases. 

Jenny

That's incredible with a vaccine. I have a question, so if you are targeting the specific genetics of the patient, what type of genetic testing do you do prior to the manufacturing of the vaccine to be able to make this personalized version? 

Dr. Inhye Ahn

We do a lot of sampling to make an accurate prediction of what is really expressed on the cancer cell and not on your regular cells. If you develop a vaccine that targets the antigen on the regular cell, it can create toxicity. So you want a precise cancer-specific target. To achieve that, we get a blood sample from our patients. CLL is actually beneficial in a way because there are a lot of circulating cells for most CLL patients. We can use blood samples for the cancer-specific sequencing. For the regular, what we call germline information, we use saliva that has very little contamination from blood, and therefore it represents the normal cell. Then, we overlap those genomic data from the cancer cell with the regular cell, and you subtract. That leads to the cancer-specific information. 

Jenny

What is the test called? Is it like a next-generation sequencing genomics test? 

Dr. Inhye Ahn

Precisely. There are many types of it, but we mainly use full exome sequencing. We also use RNA sequencing to validate the transcription of this genomic and predict how these cells bind to an immune cell. It's called HLA typing. So we use multiple tests to validate these are really targets from cancer cells and also being expressed on the immune cells. 

Jenny

Is HLA typing what you typically do if you're trying to go to transplant? Patients might be very familiar with that type of type test. 

Dr. Inhye Ahn

That's right, it's a clinical test too. 

Jenny

It's fantastic that it's not a bone marrow test, that this is a blood test. Is this a commercially available test or is it just used in research or just at Dana-Farber? 

Dr. Inhye Ahn

It's currently a Dana-Farber platform. To predict the antigen, you actually require a dedicated computational biologist looking into individual patient data. We fortunately have a platform that has been developed by a team. Right now, it's not commercially available. 

Jenny

Okay, that's exciting and good for you. This is amazing research. To me, this is why you see a specialist and why the work you're doing at Dana-Farber is really important. Let's follow up on the history. So, they tried it in melanoma and it worked. Has it been used in any other cancers? 

Dr. Inhye Ahn

Yes. We were very excited with melanoma. The NeoVax program has expanded into other cancers including CLL, as well as other other solid tumors. We have a successful program in glioblastoma, a form of brain cancer, as well as a kind of women's cancer, called ovarian cancer. There's also a program in kidney cancer, specifically renal cell cancer. 

Jenny

Wonderful, let's talk about it in CLL. Why is CLL an attractive target for this particular vaccine? 

Dr. Inhye Ahn

I'm very biased for CLL, that's what I do for research. I think CLL is a great disease for understanding cancer in general for two reasons. Number one, you have an accessible disease from blood and other diseases are not able to do those simple blood tests. You actually need surgery in the sense of cancer samples or even on their own, I see for many of the blood cancers. I think CLL is a wonderful disease to really study the cancer evolution and serially test the patient sample to better understand how individual therapy affects the disease. The second part that is very interesting about CLL, is it has a very long disease course in general. The patients are not treated right away. We wait until the patients meet the treatment indication, meaning they have to have a symptomatic disease that meets the treatment indication defined by the International Workshop for CLL. That creates a window of opportunity where the cancer cell grows without any intervention. We are specifically trying to target what we call the watch-and-wait period with the vaccine. 

Jenny

Okay, so you're in that pre-treatment phase when using the vaccine for this particular clinical trial? 

Dr. Inhye Ahn

That's right. 

Jenny 

As the vaccine is personalized to each CLL patient, from the time you begin testing to the time you have that profile, how long does that take? And then how long does the manufacturer take for the actual vaccine? 

Dr. Inhye Ahn

I have to say it is getting better, not as fast as I wish it would be. It's currently approximately three to four months from the initial testing of the sequencing to the actual having the vaccine at our pharmacy. It takes delivery, sequencing, identification of the peptide, and synthesis of the peptide. There are actually a dozen steps in between those four that we go through. 

Jenny

Plus you need to make sure that the vaccine is safe. I'm sure that is part of that process too, you go through a safety protocol to make sure that everything is clean and safe before giving it to any patients. I mean, we see that with CAR-T, so we know that sometimes these things take longer than we'd like, but when they're safe, it's good. And if you're in that watch-and-wait season, that's still okay. 

Dr. Inhye Ahn

Yes, precisely right. 

Jenny

Since patients are in watch-and-wait, I had asked that question, is this vaccine given following any type of CLL treatment? But the answer to that would be no, right? 

Dr. Inhye Ahn 

It's no. Because of the fact that some CLL patients do not ever require therapy during that period. We don't want to target those patients who would do well, regardless of what we do. We specifically want to target the CLL that is expected to grow steadily over time. These are the patients who have unmutated immunoglobulin chain mutation cells. It's approximately half of the CLL population. So it's actually a pretty strong diagnostic marker in CLL that predicts any disease. There is an important exclusion criteria for this trial which is deletion 17p. It is a marker that predicts a faster disease growth. Typically, patients get treated within a year or two of diagnosis. So the timeline is so short that we don't want these patients to be treated with the vaccine and not have enough time to follow up how the vaccine works. 

Jenny

Yeah, that makes sense. Across many cancers, deletion 17p is known to be a very high-risk feature and it's usually associated with that mutation called TP53, which is this master regulator of cells. If you have that mutation, it's very challenging. I can see why you might want to exclude that from this part of the clinical trial while you're testing this new. 

Dr. Inhye Ahn

Del(17p) in the untreated CLL population is a very small fraction of the patients. In general, it's 5%. We're hoping that the vaccine is still applicable for many patients, and we're excluding a small proportion of patients who may benefit more with subsequent established disease in CLL.

Jenny

That makes sense. Let's talk about the dosing and frequency. How many doses are created? Do you receive multiple doses over time, or how do you do the dosing? 

Dr. Inhye Ahn

Yes, so it's multiple doses. It's actually five priming doses plus two booster doses. The five doses are spread out across three weeks and then there are two booster doses at week number eight and 12. The reason for it is that we have learned so much from the COVID-19 pandemic that CLL patients require multiple doses. People have shown graphically that you need five, six, seven doses to really escalate the immune system's response to the vaccination. So, we're following the notion that more vaccination is actually needed to teach the immune system. 

Jenny

Is there long-term dosing? This is currently a very short period of time, like three weeks and then week eight and 12. But following that, would you see in the future the need for an annual dose? I would come to the clinic for an annual vaccination if I knew my CLL was not going to come back. Have you seen that in these other cancers? Is that something that you would consider at a future time point? 

Dr. Inhye Ahn

Great question. We haven't implemented an annual vaccination strategy in cancer, but that's definitely something that we should investigate. I think the first question is does the memory response come down over time? Can we boost that by doing annual vaccination, just like flu, for instance? That's an excellent question that we haven't answered yet. 

Jenny

That spurs another question. Are there tests that allow you to see if there is still a response happening for the vaccine? In the example of titers, if you get vaccinated you can still see if some of those titers exist for vaccinations that you might have had as a child. 

Dr. Inhye Ahn

We don't have a clinical test that measures the immune response, but we do have a very powerful tool in the lab that helps answer some of those questions. We're actually collaborating with a lot of lab investigators, including Dana-Farber's tumor immunogenetics laboratory, as well as Dr. Catherine Wu’s lab. In those lab settings, we're trying to understand the immune response, namely the T-cell response as well as B-cell response. We're doing single-cell genomics to really break down the immune cells. We're doing a lot of work to answer those questions. But right now, we don't have a simple lab test in the lab that says, yes, the vaccine is working. 

Jenny

Another reason to join a clinical trial and go to a center like yours. In other vaccines, sometimes they'll give an adjuvant or some kind of booster with the vaccine that might help increase the response of the immune system, or amp up the immune system that helps with progression-free survival or extent of length of life with that vaccine. Is one being used in this situation? 

Dr. Inhye Ahn

This is also a really good question. It is also very common to include an immune stimulating agent within the vaccine. The NeoVax program actually incorporated an adjuvant called Hiltonol within the vaccine. So, it's given with the vaccination, there's no separate injection. This is about stimulation with the adjuvant, but also we need to suppress some of the immune suppressive signals in the human and therefore, we are trying to combine the vaccine with an additional immunomodulatory agent. Specifically, we use a drug called cyclophosphamide or Cytoxan, as well as a checkpoint inhibitor called pembrolizumab. 

Jenny

Okay, and cyclophosphamide is a chemotherapy, basically. I mean, you might call that an alkylating agent, but it's basically chemotherapy. Tell me again, break it down for us. What does cyclophosphamide do? 

Dr. Inhye Ahn

Absolutely. Many of the listeners would be familiar with the cyclophosphamide. It's actually one of the very commonly used chemotherapy agents. Many people consider it as a chemo. So why do I call it an immunomodulatory agent? Well, it is a chemo. It kills the B-cells at high doses. But what we're using is not an IV cyclophosphamide that we mix in in a lot of chemotherapy regimens. We actually use a very low-dose oral cyclophosphamide. So typically in the chemotherapy, for instance, FCR (fludarabine, cyclophosphamide, and rituximab) that they used in CLL in the past, the dose that people use is 250 milligram per meter square with three consecutive doses per cycle. So it's a lot of doses. As opposed to that, we use 50 milligrams of oral cyclophosphamide pills twice a day. And then we use it for four alternating weeks rather than getting high peaks of cyclophosphamide. What that can do, instead of killing the cells with chemotherapy, it can actually affect the regulatory T-cells that are known to protect the cancer cells from being attacked and stimulating the immune system. It's actually an immune modulator that has been shown to be effective. This strategy actually has turned out to be hugely successful in the setting of stem cell transplant to sort of tamper down the immune system so that you get less graft-versus-host disease or GVHD. So it has been used right after the transplant setting to reduce that immune related fighting. The second drug, pembrolizumab, is a very well known drug in solid tumors. It is actually used in multiple different cancers, lung cancer, kidney cancer, and even lymphoma like non-Hodgkin lymphoma. The way it works is that it actually causes the brakes in the immune system to let go. So you're making the immune system more stimulated and more cognizant of the cancer cells so that they can attack. 

Jenny

Okay, that's wonderful. Can you explain how it's a little bit different from the antibodies that patients might be familiar with like obinutuzumab? You explained how pembrolizumab works by taking the brakes off. 

Dr. Inhye Ahn

Obinutuzumab is a type of antibody that specifically targets the B-cells. The cyclophosphamide and pembrolizumab are geared toward attacking or not attacking but modulating the T-cells. It works really differently. One way to think about obinutuzumab is that it is working against the CLL cells. While the cyclophosphamide and pembrolizumab, these are not specifically addressing the CLL cells. These are more for the immune micro-environment rather than the CLL cells. 

Jenny

In some of the documentation, it said patients need seven neoantigens on their CLL cells. Can you explain what this means and break it down for us? 

Dr. Inhye Ahn

It's not lucky seven. We actually need a sufficient number of antigens to make the vaccine. We also wanted to have various antigens rather than just a few exactly because of the evolution of cancer that can happen. So just to back off a little bit is that the cancer cells are not static. They move and they change over time. This is called clonal evolution. What we sample in the very beginning of the course of the disease may be different from several years from now because cancer cells move and change and therefore the antigens that are expressed from the cancer cells can change as well. So to prevent cancer cells from becoming a different type of disease and therefore escaping the target that we're trying to attack with the vaccine, we want to include as many targets as possible. Seven proved to be a feasible yet sufficient number. We actually applied this platform of screening with the sequencing in CLL patients and found that the vast majority of the patients with unmutated IGHV actually have more than 7 neoantigens. So, we selected seven. It's feasible, it's good enough. 

Jenny

What percentage of CLL patients do you think will meet that criteria? 

Dr. Inhye Ahn

Unmutated IGHV is approximately 50% and then when we applied this platform to 11 patients, 9 patients had more than 7. 

Jenny

So the majority of people who may want to consider this will probably be able to join this trial? 

Dr. Inhye Ahn

That's right. 

Jenny

Let's talk about the trial details a little bit. Is the trial currently open? 

Dr. Inhye Ahn

Yes, it's been open for a while, but we had to move one by one because of some of the safety concerns in a very early stage trial. So since then, we have moved on quite a bit and we have accrued to the third stage of the study. Initially, the trial was structured to have three different arms. Arm one is testing the vaccine only, arm two is testing the vaccine and the low-dose cyclophosphamide and arm three is combining the vaccine, low-dose cyclophosphamide and pembrolizumab. We have now identified patients up to the second arm and then the third arm including pembrolizumab will be open very soon this year. 

Jenny

Well, that's nice to know that all three of the arms include the vaccine. 

Dr. Inhye Ahn

That's right. 

Jenny

If you're joining, there's no placebo comparator arm. How does it work for patients who want to travel to Dana-Farber to join the study? Because this is only open at Dana-Farber, correct? 

Dr. Inhye Ahn

That's right. It's currently a very small study and we want to do deep studies using individual patients. So we haven't been able to open the study elsewhere. In terms of the travel, unfortunately we have limited resources, so we do not have any dedicated support for the travels for patients. 

Jenny

When you give those first doses over that three-week period, if I were traveling out of state or something like that, when would I need to be there for those different doses over that three-week period? Or would you want me to just come for three weeks, stay, get the doses and then come back for my eight-week and my 12-week dose? 

Dr. Inhye Ahn

The first three weeks would be pretty busy as the patients will be coming in on day one, two, and then weekly thereafter for three weeks. It may be just logistically difficult to travel back and forth every week from different states. It might be reasonable to stay just nearby or at least on a drivable distance rather than doing air travels every couple of days. But after that three week period, it should be doable to commute from different states because it's only two more vaccinations. Pembrolizumab is given every three weeks. I've seen many patients traveling from different states to get that infusion. It's actually a relatively simple infusion given over about a 30 minute period. It's not a long infusion either. 

Jenny

If a lot of patients in CLL have this watch-and-wait time period, what are your, and maybe you want to explain what clinical trial endpoints are for studies and how you're going to compare the different three arms in terms of your overall outcomes. What are your overall outcomes? Keep it simple so patients understand clinical trial endpoints, but maybe we can understand what you're trying to learn from the endpoints of this study. 

Dr. Inhye Ahn

In terms of the clinical trial endpoint, this is a phase one study. We're testing it for the first time in CLL. First we want to make sure we can make the vaccine, deliver them to the patient and make sure it's feasible. Feasibility is the number one point. Then, we want to make sure the trial regimen is safe. We do know that NeoVax is safe. It's actually very well tolerated, minor reactions at best, but we don't know yet whether the combination is safe. We want to prove that. In terms of the patient relevant outcome, I think, disease reduction is our ultimate goal. CLL cells are present in three compartments of the body: blood, lymph nodes, and bone marrow. We would like to show that we can control the disease or even reduce the burden of disease with vaccination plus immunomodulatory therapy. We'll be measuring the blood counts, we will be doing CT scans to look at the lymph node disease, and we plan to get bone marrow biopsies to see what had been changed before and after vaccination.

Jenny

Let's talk about phase one studies because you can take a drug that has been used effectively for example, in melanoma, kidney cancer, and other cancers, and still need to run a phase one study in a new disease just because you're using it in a new disease, and you're using it in new combinations. So patients sometimes hear, oh, this is phase one, maybe it's just testing for safety and maybe I don't want to join a phase one study. But that only means that you're using it for the first time in CLL and with some of these other treatment combinations. So that's why you're testing for safety like you said, how is it going to respond with the cyclophosphamide or pembrolizumab. I think that is an important point for patients to know, that this vaccine has already been tested in other cancers and being used effectively. That might just encourage additional patients to consider it as a treatment option during watch-and-wait. Let's talk more about side effects. I know vaccines typically don't have a lot of heavy side effects, but do you have any data so far about that in this trial? 

Dr. Inhye Ahn 

Sure. So based on a few patients that we have treated in the CLL trial, we did see minor rash, low-grade flu-like symptoms like achy muscle and low-grade temperature. One patient had a mild elevation of the liver enzyme that was temporary. All of these side effects eventually resolved without any intervention for many patients. Some of the side effects like injection reactions were expected. We see it in other vaccination programs, just like COVID and flu. We see some of the common side effects there as well. So overall, the side effect profile seemed to be consistent with other vaccinations and consistent with what we saw in other solid tumors. 

Jenny

Do you get any pre-meds, like any Benadryl during the trial or not? 

Dr. Inhye Ahn

No. If the patient develops reactions then we're willing to give it. That's something we didn't need. 

Jenny

They're getting it in the clinic, so they're right there and you can watch them and that's the safety portion. When you think about genetic evolution, let's say a CLL patient goes in and gets the vaccine and it significantly prolongs any time until disease progression or to the beginning of a need for treatment. Could you redo it and go back and say, okay, your disease is now different, you have different markers. Could you feasibly run the process again? 

Dr. Inhye Ahn

I think that would be a fantastic followupn trial for this CLL study. Yes, genetic evolution does happen in CLL. Sometimes that can drive drug resistance in CLL as well. Because treatment can select certain diseases, certain characteristics of a disease that is stronger against certain types of treatment. Therefore, yeah, definitely the sequencing result we get from day one of CLL may be very different from, you know, year number 10 of CLL. Therefore, doing this pipeline of vaccine generation again in the future is a really interesting idea that we should test. We're not quite at that stage, but this idea may be feasible as we move forward with the vaccination in cancer and make the vaccine platform a little bit more scalable for a larger patient population. 

One research that has come out in the melanoma world, is that they're now using mRNA information. You may have heard about this before in the COVID vaccination field. There's peptide vaccine, but there's also mRNA vaccine from vendors like Pfizer and Moderna. We use those preferably for immune-compromised patients because they work so well. Therefore they are now trying to use that platform for cancer vaccines. They were first tested in melanoma. It was very scalable. It was individualized yet because it was based on the sequencing cluster in terms of generation of the vaccine. They showed in a very large scale trial effectiveness. So, it's moving on to a big phase three trial setting in melanoma. I envision this approach could be one way to move the vaccine forward first to a larger population, but also in the multiple disease core setting.

Jenny 

Interesting. So what type of vaccine is NeoVax? 

Dr. Inhye Ahn

NeoVax is a peptide vaccine, unlike the mRNA vaccine that has been tested in melanoma. 

Jenny

Okay, great. As you look at the landscape just overall with CLL in this watch-and-wait scenario, how does this trial compare with other watch-and-wait strategies for patients? 

Dr. Inhye Ahn

It is very different. We're doing something, we're doing an intervention and an intervention targeted at the immune system rather than CLL cells. I think this trial really stands out from many other trials in clinicaltrials.gov. There are actually trials doing early intervention in CLL but the vast majority of them focus on targeting CLL sites by using approved treatments for CLL. For instance, BTK inhibitor, BCL2 inhibitor, moving it up front so that you could use it early on in the absence of symptoms. So we're very different from that approach. 

Jenny

Well, I like that approach because really, when it comes to cancer, your immune system is probably seeing cancer cells in a normal person on a regular basis, and it's able to tamp those down just like it would with a viral infection or a bacterial infection, and it's eliminating those cells because it's working properly, right? Then there's something that happens in CLL that triggers that mutation that no longer allows that cancer cell to be repressed. Then it ends up 

being present and over time potentially growing. So we have to think about that. It's a great approach in my opinion to think about going after the immune system to bolster the immune system to recognize the CLL cells and go after them. What an amazing thing to enable your immune system with that potential killing power. 

Dr. Inhye Ahn

Thanks, Jenny. We're very excited about this approach too. I believe the watch-and-wait CLL population really has the best chance of responding to the vaccination strategy, as opposed to patients who have gone through multiple lines of CLL therapy. For a couple of reasons, their burden of disease may be lower and therefore their chance of a vaccine working against them may be better. Their immune system may be a little bit more competent than patients who are on active therapy. We do know from COVID data that CLL patients on active therapy have hampered immune response to COVID vaccination. Therefore combining CLL-directed therapy with this NeoVax didn't seem like a compatible idea. I think untreated patients may be a few years out or even before the CLL targeted therapy might be the best population to get the vaccine. 

Jenny

It sounds like a wonderful prevention strategy. So prevention and progression. What an amazing thing. It's so exciting. Now I want to include a couple questions that we received as a write-in. You may have answered some of these before, but maybe we can kind of summarize what they said. Charlene was asking, since I live out of state, do all of my follow-up appointments and tests need to be done at Dana-Farber? 

Dr. Inhye Ahn

Yes. 

Jenny

Yes, you do. Because when they come back, you don't have any in-between tests that you're doing like between week eight and 12, you're just doing all the testing when they're receiving these different doses, correct? 

Dr. Inhye Ahn

That's right. So, I mean, there's no in-between visits, but all of the planned visits should be done at Dana-Farber. 

Jenny

Mike was asking, are all watch-and-wait patients eligible or just people with certain characteristics? 

Dr. Inhye Ahn

Sure, so two things. We are looking for patients with unmutated IGHV, which is a marker that predicts a steady growth of the disease. We do not want to have patients with deletion 17p. It's a relatively uncommon, yet high-risk marker that predicts patients to be treated in a few years of their diagnosis. We want the vaccines to work in a sufficient period of time and therefore excluding these patients. If you're unsure about your marker status, it might be best to first talk to your doctor about whether these two have been tested. If not, maybe get a test locally, because these are actually well-established, well-accepted prognostic markers that can be tested even when you're not being treated for CLL. 

Jenny

Okay, wonderful. How long do you think it will take to complete this phase one study? And then, what are your next steps after this? This is a very exciting option for patients. 

Dr. Inhye Ahn

We have already accrued the six patients to the first two cohorts. We have five spots left for the third cohort. I anticipate the study would complete accrual in late 2025. Hopefully we can release the results at the end of 2026. The next step would be really to expand this trial to a larger CLL population. It's a very small trial right now, but once we have proof of the concept and feasibility, I believe this can move forward to a larger patient group, as Jenny said, as a preventative strategy. 

Jenny

That's a really interesting question because when you have a disease like CLL, where you have a lot of patients that don't progress or a long period of time in watch-and-wait period. How do you run those clinical trials when you start getting to these comparison arms or things like that? Because these are taking years. How do you compress that time period to find the results that you need, but in a disease like this, that's challenging, right? 

Dr. Inhye Ahn

Yes, Jenny, you're talking like a scientist. That was the main topic at the meeting that we attended together in Portugal. I think that the key point here is to focus on the population. The population who would benefit most from the preventative strategy. The population of interest in CLL are those with relatively higher risk of getting treatment in a few years of time. Relatively higher risk of having multiple lines of therapy down the line. So focusing on high risk can be an effective strategy to show that immunotherapy or vaccine strategy works as a quality of life improving option, disease slowing or disease control option for these patients. 

Jenny

Another question, there are different diagnostic tests that can test for these lower levels of disease, like minimal residual disease testing. I know in some of the other blood cancers, some of the researchers are asking, can we use MRD testing as a clinical trial endpoint and not maybe wait because, maybe you want to explain this, but for patients, when people are living longer and some of the clinical trial endpoints are progression-free survival or how long you take to relapse or overall survival, that's decades, right? So could you foresee using MRD testing as a clinical trial endpoint? I know in some of the blood cancers, they're actually asking the FDA to approve this so it can be used because they're having the same problem. It's just taking too long to get through these studies. Then by the time you wait 10 or 15 years for the study results to come out, the whole treatment landscape is completely different. That's a long time to wait for study results.

Dr. Inhye Ahn

Right, we have the same conundrum. I guess that's a good thing, because we have great options, making patients live longer and better. Yet to determine which drugs are working the best and move the field forward, we need a surrogate marker that is other than overall survival. MRD was developed to fill that gap. In certain settings, it works really well as a prognostic and predictive biomarker in CLL. For instance, the German CLL-14 study demonstrated that at the end of treatment, achieving undetectable MRD was predictive of favorable outcome relevant to progression-free and overall survival. So, it can work well. However, on the flip side, when the patients get a continuous BTKi-based therapy, the MRD did not matter that much. And in fact, the vast majority of the patients did not get to MRD at all. Over 90% don't get to MRD with about three years of treatment in the beginning. What it tells us is that it really depends on how the drug works and the duration of therapy too. The BTK inhibitor, for instance, makes the disease slowly go down over time and it controls the disease in a very excellent and durable way. But, it's not a very quick and deep response with those continuous BTK inhibitor therapies. In contrast, venetoclax based therapy makes the disease go into a very deep remission and therefore MRD has a value in predicting the outcome. So, yeah, so we need to study more how these surrogate endpoints work in what treatment, in what setting, and at what time point. We're still learning to use this test. It is clinically available, but whether it adds to the treatment, that decision is still something that is less clear. 

Jenny

In those other two treatment arms, you're only using cyclophosphamide and pembrolizumab when you're giving the doses, right? There's no follow on pembrolizumab or cyclophosphamide over time. It's just given with the doses, correct? 

Dr. Inhye Ahn

Cyclophosphamide actually starts a little bit before the vaccination. So it starts two weeks before the vaccine, and then the patient would alternate one week long of oral cyclophosphamide every other week for four hours, so four weeks in total. And then once the patient starts the vaccine, we start the pembrolizumab together and give it every three weeks for a total of 17 cycles, so approximately one year. So yes, there is a long tail of immune checkpoint inhibition to sort of stimulate the immune system as the vaccine responds and matures. 

Jenny

How often do patients have to come back during that year's time point? Because you're giving that vaccine at week 12. And then what are the requirements for the patients to come and get the remainder of those things? 

Dr. Inhye Ahn

So during the pembrolizumab infusion, we would have the patient come to the infusion center and get it. So every three weeks, it would be a follow-up in the clinic as well as the infusion. 

Jenny

So I think that's important for patients to know because patients are wondering what kind of travel, do I really need to be close to the center to participate? Am I willing to do a lot of flying? And that's always a question for patients in terms of participation. So that's good to know. 

Dr. Inhye Ahn

There are a lot of visits. I understand it requires a lot of travel, especially for patients living in different states. I'd be happy to talk to the patients who are interested in the trial, how to make this trial as smooth as possible. I have treated patients on a different pembrolizumab-based trial in CLL who are willing to come to our center to get innovative therapies. So it's not for all, but for some patients it can work and it is feasible.

Jenny

I agree, and you only have a very few number of spots available. So to me, this is a fascinating approach and if there's something like that, it would be amazing if it works well. It's exciting to see the research that you're doing. I just want to thank you for the amazing work you're doing in CLL to have this discovery be made for CLL patients. What a breakthrough, it's incredible. These immunotherapies are just so fascinating and so exciting for patients so it's thrilling. We are grateful for everything you're doing. 

Dr. Inhye Ahn

Thanks Jenny, thanks for the kind introductions and for your time.  

Jenny

Thank you again Dr. Anh, for participating. It's been incredible having you. We'd like to thank our listeners for listening to this HealthTree podcast for CLL. We invite you to join us next time to learn more about what's happening in CLL research and what it means for you.