Dr. Vincent Lam at ALKtALK
Dr. Vincent Lam , Johns Hopkins Hospital
Director, Esophageal Cancer Research Program, Assistant Professor of Oncology
Expertise: Esophageal Cancer & Lung cancer
Dr Lam: I am so excited to join your conversation tonight on a Sunday evening. I’m scrolling through five pages of people on the zoom call. It’s just amazing to see how committed and engaged you all are. That’s a big reason why I focus on ALK lung cancer: It’s YOU!
A little about myself. I am from the West coast and grew up in Seattle. I started my career as a computer science major and a software engineer. I worked in Silicon Valley for almost five years and then for some reason had this epiphany that I needed to do medicine. So, I did. My medical school was in San Francisco and then I ended up coming to the East Coast for training and oncology. My first faculty job was actually at MD Anderson in Houston where I met Amanda and some of you on this call. I’m really pleased to be able to get back to the East Coast and so I am at Hopkins where I focus on lung cancer. I also lead the esophageal cancer research program here at Hopkins because in the thoracic oncology group we see both lung and esophageal cancer.
Question: Recently, you have been testing ALK patients’ blood. What are you doing?
Dr. Lam: We’re trying to do several things. First, our main focus at Hopkins is to leverage our expertise, that is immunotherapy. Why doesn’t ALK respond to immunotherapy well? We are trying to lay out what they call the tumor micro-environment and other factors involved in your immune response in ALK. We really try to sort out the specific reasons why immunotherapy just doesn’t seem to work well in this particular disease. Then, on the therapeutic side, you know, we are trying to develop novel immunotherapies. Because as you all know well, the current immunotherapies such as Keytruda and Opdivo really do not illicit responses, or don’t treat ALK lung cancer well at all. We feel there’s really just a strong need to figure out better treatments that can better engage the immune system to get us to where we really want to go. In terms of treating ALK, we want to turn it into this chronic, long-term disease, if not find a cure.
Question: Can you talk about and describe your specific ALK vaccine?
Dr. Lam: One of the novel immunotherapy strategies that we’re looking at has been a vaccine. Back at MD Anderson, I lead T-cell therapy trials for lung cancer and I really have a strong focus and interest in trying to figure out different ways to introduce newer immunotherapies to “immune-cold” tumors like ALK. We are still in the early stages. That is why I’m so grateful for Amanda and many other patients who have really taken it upon themselves to help us get the funding so the project can progress onward. Just very briefly, you know vaccines are really meant to teach your immune system about the cancer itself. Vaccines have been used to teach the immune system about Covid and other infectious diseases. So, leveraging that paradigm, we have been working on a vaccine but with a slightly different twist. You know Dr. Awad and Dr. Chiarle are doing a great job in their project. We are really trying to develop a possible vaccine for the huge unmet need of ALK patients who are really doing well on their TKI. Unfortunately, they’re sort of sitting on a ticking time bomb as some of you have described to me. Because we do know that, unfortunately, cancer can acquire resistance and progression on a TKI. This situation does happen more often than not. So, with our vaccine approach, we are really trying to leverage this novel immunotherapy for patients in that situation.
Question: Can you describe a little more in detail how your vaccine is complementary and/or how it is different from other vaccines that are currently in the works?
Dr. Lam: If I take a step back in terms of just introducing the concept of vaccines, I know Dr. Awad and Dr. Chiarle have talked to the group, so you have some knowledge about this already. Cancer vaccines are not new. The field has been developing over the past few decades. Of late, particularly in melanoma, there have been some really exciting advances in terms of using a vaccine to educate your immune system about your cancer so that it can serve as a different way to basically wake up your immune system. “Hey, you need to take care of this cancer.” Unfortunately, we haven’t made a ton of progress with cancer vaccines, although, as I just mentioned, about melanoma. The reason is that cancer as you can imagine is an extremely hard problem and it is a hard proposition to present the proper information to your immune system through a vaccine. You want to set up all of the cascades of immune events that are needed to affect a substantial immune response that is done well. These tasks will lead to tumor shrinkage. Our solution is really aimed at trying to take a smaller bite of that apple. We are trying to circumvent some issues and challenges that are involved with building a vaccine for the progressive metastatic setting (for patients who are stage 4 and have progressed on a TKI or chemotherapy). Though there is exciting progress made by groups like Dr. Awad and Dr. Chiarle, we are circumventing some of those challenges by bringing the vaccine earlier into a patient’s cancer journey. Cellular therapy and vaccine work that has already been done have taught us a lot of important lessons. That’s why I’m really optimistic about making progress in a T-cell therapy or a vaccine for lung cancer and other cancers such as ALK lung cancer. One lesson that has been very consistent is that immunotherapy works best when there is not a lot of tumor. It can work when there’s a lot of tumor but it works best when there’s minimal tumor burden. The other thing that we’ve learned is that the immune system can actually ignore signals that are presented to it. Often, it is because the immune system thinks that the presentation may look too much like a normal healthy tissue. Obviously, you don’t want an autoimmune process and so that’s one of the hypotheses about why potential ALK may not be as immunogenic as some other tumor cancer types are, like melanoma. In general, in melanoma, your immune system goes crazy. Moving the vaccine up earlier in a patient’s cancer journey can actually solve at least a couple of these main issues that have been holding back vaccine progress in the metastatic setting. No 1, if we treat people who are doing well on their current TKI and have very little disease if at all, fortunately this takes care of the issue of having to rely on or generate a robust immune response so that it has to shrink a ton of tumor. No 2, your immune cells can actually get exhausted. There’s an exhausted phenotype that is well described. So, it is probably playing a role in why immunotherapy does not work well when there’s a lot of tumor. No 3, to my best knowledge, this has not been done before. We are actually using the vaccine in a prophylactic sense and not a therapeutic sense. The distinction is that we are putting in the vaccine and we are trying to teach the immune system about it. We are again drawing upon the successful experience of our infectious disease vaccines for coronavirus and the like, so our proposal and what we are working on is actually for patients who are doing well under a TKI treatment and for whom have not acquired any resistance yet. We’re going to teach the immune system about the acquired resistance mutations beforehand, before the patients attain these resistance mutations. With our vaccine, you will know the specific mutations that were included and we will able to capture around 80 to 90, probably 90% of the acquired resistance mutations that are seen after Alectinib or Brigatinib such as G1202R. G1202 is a common one. So, in a nutshell, we’re trying to educate your immune system about these bad mutations in advance so if the TKIS start breeding these mutations, your immune system has a memory about it from the pattern we have shown it from the vaccine. Your immune system should spring into action to keep it down. Hopefully, that means you can stay on your Alectinib or Brigatinib for a longer period of time.
Question: What is the requirement for taking this vaccine? Is it NED? Or is it to be stable?
Dr. Lam: I want to stress that we’re in the early stages. This is called pre-clinical data. These are data in test tubes. This approach does elicit a really strong immune response. As you probably know, clinical trials can come about with novel therapeutic approaches. It is often that you have these pre-clinical studies that include this kind of data. Once you see those results you can open a clinical trial. One of the nice things about our vaccine product is that it actually has been used in overall general vaccine constructions. This similar vaccine has been used in multiple studies and has been demonstrated to be quite safe. The exact components are actually in clinical trial now with my colleague Dr. Mark Yarchoan for liver cancer at Hopkins. Along with my senior co-collaborator, Dr. Liz Jaffee, who has been working on vaccine for over decades, I strongly believe that this presents a really nice opportunity to bring the vaccine to the clinic at the same time as we are working on it. As you may know, we have made some really amazing improvements in terms of mice models but there is still a lack of a good model that can truly recapitulate what the human immune system is going to do with the vaccine. We strongly feel that the only way to see if it works is to put it into people. That’s how we can actually accelerate the development of vaccines and other cellular therapies. From your initial question about how it may be complementary to Dr. Awad and Dr. Chiarle’s vaccine, I think that the data we generate from putting our vaccine into patients and comprehensive scientific analysis on the biospecimens of patient who are in the trial will help to inform all cellular therapy and vaccine efforts. Hopefully, this will be able to facilitate Dr. Awad and Dr. Chiarle’s efforts as well. Any information that they get from their efforts definitely would be helpful to us as well. They are aimed at a different patient subgroup and they are aiming their efforts during a different part of the cancer journey than us.
Question: Does this vaccine pass the blood brain barrier?
Dr. Lam: We don’t know. That is why I hope you won’t get sick of me saying that. For us to know, we have to start putting it into people. If we have a product that we believe is safe, we’re going to do a parallel study of the mouse phase and get the result from people. To do my study, it will actually take a couple of years. My study is so critical because it will help us optimize the vaccine in terms of dosing and kinetics.
Question: You said immunotherapy is not known to help ALK patients but what you are studying is immunotherapy. Can you describe a little more about it?
Dr. Lam: I was sort of colloquially referring to immunotherapy in the sense that it is currently approved in US by the FDA. Immunotherapies like Keytruda or Opdivo are immune checkpoint inhibitors that really aim to release the brakes on the immune system. So, if the tumor put the brakes on the immune system, you are taking those brakes off. The brake in this case is a protein called Pdl-1, which some of you may be familiar with. Maybe you have looked at your pathology reports and it says Pdl-1 is like 100% or 90%. Maybe your oncologists have been tempted to actually start Keytruda or Opdivo. But, we know through retrospective studies and registries, the response rate for these types of immune checkpoint inhibitors for ALK patients is very close to zero, if not zero. So, we don’t use immune checkpoint inhibitors in ALK NSCLC of course. There have been studies done where we combine them with TKIs and the issue is toxicity. So, that is why it is not a standard of care at this moment. Immunotherapy is such a big umbrella. It basically refers to any treatment that can enhance your immune response to ALK or any other cancer. So, the vaccine is different because it tries to enhance your immune system’s awareness about ALK cancer in a much different approach.
Question: Many of us had significant tumor burden at time of diagnosis, would your recommendation then be to shrink tumors with TKI first and then administer your vaccine?
Dr. Lam: Absolutely. However, right now, we don’t have any vaccine experience in people to definitively guide us. However, that is what we are trying to do. Based on other cellular therapy and vaccine studies, I strongly believe that these novel immunotherapy strategies are best deployed in the context of minimal tumor burden. In fact of note, at least one of the melanoma studies has actually shown really promising results. I think they only treated 8 patients or so but 4 years out many of those patients are still doing relatively well, no recurrence. The authors just published a paper not long ago that showed they were able to demonstrate memory T cells in those patients that came about from the vaccine that they were given. One notable thing about that study is that it was done in patients in the adjuvant setting, meaning these melanoma patients actually got surgery and they were generally not metastatic stage 4. So, this approach is a curative approach. They received the vaccine as sort of an insurance policy, if you want to think like that.
Question: How would you know if you qualify for the vaccine?
Dr. Lam: The eligibility criteria for the clinical trial will be disclosed when the trial is posted. We’re still working out the details of the clinical trial. As noted earlier, we are trying to get this funded so we are not quite there yet. With the heroic effortsd you and others have put in, we are really getting close. I think initially, it will be for patients who are on their TKI. It does not have to be first line. Actually, it can be patients who are on chemotherapy as well. These patients will have to have stable disease for over 4 months. We don’t have that set in stone yet but that’s what we are thinking. You do not need to have measurable disease. You can be NED (no evidence of disease). In fact, it would be better if you were NED because we are not actively treating progression. So, we don’t really have to measure your disease progression in terms of scans.
Question: What about disease progression that developed from a bypass mechanism? Will a vaccine work for that situation?
Dr. Lam: No. The vaccine does not directly address that. The coverage will only be about half of the acquired resistance. For a patient on Alectinib or Brigatinib, for example, an interesting thing about vaccines is because it is more of a “live” drug. It is not a static drug like a TKI. To combat the trickiness of this cancer and how it gets acquired resistance, you have to understand this concept of epitope spreading. Even though you are not directly targeting a part of the tumor, over time, the process of the immune system responding to that part of the tumor eventually can lead to the immune system learning other parts of the tumor. So, in fact in the melanoma study, one of the key things that they were able to demonstrate at the 4 year mark, was that indeed those patients had evidence of epitope spreading so that their T-cells can recognize part of the tumor that they did not get originally vaccinated for.
Question: About people on Lorlatinib that are stable, does that mean they meet your criteria for the vaccine?
Dr. Lam: Yes. They are eligible. However, I forgot to mention one of the other criteria. The only other thing is that you cannot have one of the several known acquired resistance mutation. For example, the G1202R that we are vaccinating against. If you are on Lorlatinib, chances are pretty good that you did have one of the acquired resistances that we will be vaccinating against. However, there is a minority of patients that may not so these patients will be eligible. The reason why we are doing this is because we hope there may be some epitope spreading. The vaccine will be able to cover parts of the tumor that are not being vaccinated against, so we look at this as a pilot study. We really have to be very crisp about our hypothesis and how we are measuring success. It is very limited. So, it is a very narrow scenario of patients who don’t have what we are vaccinating against. We will see if the vaccine actually worked if we don’t find disease progression. Hopefully, you can get vaccinated against G1202R before you get it so hopefully you will never get it. That’s where it’s amazing that ALK Positive has funded this amazing effort by Dr. Awad and Dr. Chiarle where you can get on their clinical trial. I want to pause just a little bit to think about how truly amazing it is to have two bona fide vaccine efforts underway for one single disease. I don’t actually think even EGFR has this type of a set up.
Question: How do you know that a vaccine stops working or responding? How do you know if it worked or not?
Dr. Lam: In contrast to the setting where we are vaccinating against patients who are progressing, in our setting our initial measurement of success is when we check patient’s blood. We hope to find and measure patients who have been vaccinated to see if we can find immune response. We will be looking at a particular type of T-cells that have arisen and check for specific levels of cytokines or chemicals your immune system releases when it gets activated. That is the first measure of success in this earlier setting. Secondary success would be in a clinical setting where you look at the patients and see how long they stayed with their TKI. We would expect they will be on the TKI for longer than expected. Also, if or when they progress, what does the molecular profile of the progression look like? Did they progress on G1202R, something we vaccinated against? Or it is an alternative bypass mechanism?
Question: Why do you vaccinate specifically against resistance mutations rather than all ALK protein in general?
Dr. Lam: That is a wonderful question. Probably step two. Science is an iterative process (repetitive). It is a fine balance that I’m trying to achieve in terms of trying to ask a focused narrow question that can move the field forward as quickly as possible and to generate data to share with you and other groups that may be working on similar things. The quickest way and the cleanest way to learn about “how this is going to work in humans” is to actually focus the question on acquired resistance. What you are asking is very intuitive next step because you know what works along the lines of what’s been done in other disease groups. We should vaccinate against the ALK wild type, a protein without acquired resistance. I mentioned earlier in terms of challenges for vaccine strategies that have come before us. So, vaccinating against acquired resistance mutations is really appealing because you know theoretically this is a completely foreign thing to your immune system. You should not have G1202R mutations for example. We have some data that show it is actually more immunogenic than vaccinating the ALK fusion protein itself. A basic way to look at it might be your immune system has likely seen your ALK fusion protein before and there’s a reason why it became metastatic. So, your immune system either hasn’t seen it at all which is supported by another group or that the immune system decides to ignore it or is unable to mount a significant response to it. So, this all just complicates the question a little bit more. I feel that we can actually demonstrate this in a clinical trial for a highly immunogenic sequence that you know would be a great starting point as a proof of concept.
Question: You mentioned that you need to be stable for NED for 4 months for this trial. Can you talk about the difference between stable and NED?
Dr. Lam: So, there’s a third term that you may have heard before is disease control. This just means that you are not progressing. So, it could be that you have zero response to your first line TKI but as long as it’s not getting worse, then we are good.
Question: Would this be applicable to other cancers such as ROS1 since it is so closely related to ALK?
Dr. Lam: I don’t think anybody has done a prophylactic (intended to prevent) approach and so you can imagine that we know ROS1 has a very similar acquired resistance landscape. ROS1 is a known analog to ALK so if we can demonstrate that this works in ALK, I think it would apply to potentially other disease types and even outside of lung cancer.
Question: Do you see the vaccine strategy evolving or leveraging mRNA as a delivery method?
Dr. Lam: So, for the broader audience, there are different ways to deliver the information to the immune system. There’s a vaccine that is a peptide based. That is what we are using. Our group has a lot of experience with this form. There’s DNA and there’s mRNA. Covid vaccine by Moderna and Pfizer uses the mRNA-based method. There are technical differences between the three types of vaccine. We don’t really have any clear evidence that suggests one is better than the other at this point. One thing that is nice about peptide-based vaccine is that there are many advantages from using peptides. I believe Dr. Awad and Dr. Chiarle are also using a peptide vaccine. They had looked at DNA-based vaccines, I believe.
Question: Most of us on this call have ALK. Is there anything that you can offer to provide some hope for us? Something you think is coming down the pipeline in the next few years that can help us?
Dr. Lam: I mentioned earlier that I’m really optimistic that we’re going to make some significant headway in the novel immunotherapy space and that includes vaccines and T-cell therapy. There are different way to approach treating ALK and I firmly feel that to get to where we really need to go in terms of achieving a long term durable response we will continue to find a better way to engage the immune system. In the meanwhile, we are grateful for all the TKIs and the small molecules. We will continue to lean on those. On the front end, there is progress being made. There’s a lot of lung cancer that does not respond to the current immune checkpoint inhibitors so it’s not a new issue that the field hasn’t been grappling with for the better part of this past decade. We can leverage a lot of progress that’s already being made in non-small cell lung cancer that’s immune cold such as ALK is. Then, in terms of non-immunotherapy strategies there are combinations (ALK plus SHP2, TKI plus SHP2, combinations with MET) and these are all great. These clinical trials are already pushing the ball forward until we can get to a really long-term sustainable immunotherapy strategy. On the further horizon, there’s been some progress made in the whole protein degrader area of drugs. So, instead of a TKI to stop the activity that’s downstream of this fusion protein that is causing all these issues, a drug can actually goes and tag your fusion protein and dispose of it using your normal garbage collecting mechanism. There are a lot of challenges still but in that space there are already companies that are working on similar things on RET, for example.
Question: For those that are progressing on Lorlatinib, are there any clinical trialz that you can recommend for immediate need? Do you have recommended trials that you suggest for your patients that are progressing on Lorlatinib?
Dr. Lam: Yeah, that is the million-dollar question. Currently after you are post-Lorlatinib, we do have TPX-0131 coming. TPX-0131 is a more potent TKI that can address some of the compound resistance mutations that happen as a result of another potent TKI. It is not quite ready yet for clinical trial enrollment. What’s ready now? I would say I am very enthusiastic about Dr. Dagogo-Jack and colleagues’ combinational trial using Lorlatinib with a MEK inhibitor or SHP2, although it is not specific for ALK patients. I have had patients who tolerated that fairly well so I think that would my sort of go-to trial right now. Then, outside of TKI specific trials we’ve seen some interesting results in a class of drugs called Trop2 inhibitors or antibodies. This is a non ALK, non EGFR specific trial. There’s actually several of them and they are actively enrolling in clinical studies now. I have had some patients who are EGFR or ALK but primarily EGFR who have responded to Trop2 inhibitors on these trials. So I actually think that may be something worth looking into. Finally, a little more of a stretch, we had some initial results for gastroesophageal cancer in MD Anderson before on cellular therapies.
Question: When the TPX0131 trial is open for enrollment, you mentioned you may be the point person at John’s Hopkins? Can you elaborate on what you know about TPX-0131?
Dr. Lam: TPX-0131 is the next potent TKI that we hope can help our ALK patients specifically in the post-Lorlatinib setting. It has been demonstrated to be effective in pre-clinical data against the compound mutations that are the cause of Lorlatinib resistant (both solvent front and gatekeeper mutations). We are quite excited about that. In fact, I know it is starting in early phase clinical trials in Australia right now. Soon, they will be bringing it to start in US hopefully by the end of this year.
You can watch the recording of this ALKtALK here: https://www.youtube.com/watch?v=bDJsOvPbfV0
The questions have been organized and may not appear in the same order as in the recording.
Compiled and transcribed by: Alice Chou