An Era of Promise for Cancer Vaccines

ASCO Daily News

Dr. Pedro Barata and Dr. Lillian Siu discuss recent advances in cancer vaccines and biomarkers, including the potential of the neoantigen and immune modulatory vaccines and the challenges surrounding cancer vaccine development.

TRANSCRIPT

Dr. Pedro Barata: Hello, I'm Dr. Pedro Barata, your guest host for the ASCO Daily News Podcast today. I'm a GU medical oncologist at the University Hospitals Seidman Cancer Center in Cleveland, Ohio, and an associate professor of medicine at Case Western Reserve University School of Medicine. I'm also an associate editor of the ASCO Educational Book. And today we'll be discussing a timely article that was recently published in the Educational Book titled, “State-Of-The-Art Advancements on Cancer Vaccines and Biomarkers.”

I'm delighted to welcome one of the article's co-authors and a world-renowned oncologist, Dr. Lillian Siu. She is a senior medical oncologist and director of the Phase 1 Program at the Princess Margaret Cancer Center and a professor of medicine at the University of Toronto.

Welcome, Dr. Siu.

Dr. Lillian Siu: Thank you, Dr. Barata; it's great to be here.

Dr. Pedro Barata: Wonderful. Dr. Siu will discuss new tools for cancer vaccine development, strategies for combating the immunosuppressive and tumor microenvironment. She will also address cancer vaccine guidelines and patient recruitment strategies to optimize patient selection and access to cancer vaccine trials. I should say that Dr. Siu and her co-authors also addressed this topic during an Education Session at the ASCO 2024 Annual Meeting.

Finally, our full disclosures are available in the transcript of this episode.

So again, Dr. Siu, great to be speaking with you today. I'm looking forward to our discussion.

Dr. Lillian Siu: Thank you, Dr. Barata. And before I begin, I want to acknowledge Dr. Jeffrey Weber and Dr. Inge Marie Svane, who both presented during the ASCO session you mentioned. They gave excellent presentations related to the topic of neoantigen vaccines and immune-modulatory vaccines, which we will talk about later.

Dr. Pedro Barata: Wonderful. So let's get started. Cancer vaccines are among the most promising frontiers for breakthrough innovations and new strategies in the fight against cancer. The successes in vaccine development during the COVID-19 pandemic, I think, inspired further research in this area. Why do you think it's important that we harness these recent successes and technological advances to really accelerate progress in vaccine development?

Dr. Lillian Siu: Absolutely. I think all of us who have lived through COVID really appreciated how important the COVID vaccine development was to all of us. It saved millions of lives. And I think we witnessed a paradigm change in drug development that none of us thought was possible, that we're able to actually bring a concept to a drug from bench to bedside within an extremely short time. That timeline is not something we would ever imagine to have happened, and it did. And I think it gives us hope that perhaps this is not just limited to the COVID vaccine; it's also extrapolatable to other therapeutics – that we can bring promising medicines to our patients in a really expedited timeline, obviously without compromising their safety.

We now know that cancer vaccines have entered a new, or maybe I should say, renewed era of promise. And it's holding promise on many fronts, Pedro, if I may. It's very exciting in the area of molecular residual disease. In other words, a setting where the cancer is treated definitively by surgery or radiation, plus adjuvant treatment. And we know some patients will relapse because we know they're at high risk. And now we also have different ways to detect these microscopic risks, such as by ctDNA, circulating tumor DNA, or biomarkers. And we know that having some therapeutic that can eradicate these cancers at such microscopic levels would be very attractive, especially with low toxicity, and I think cancer vaccine is such a candidate. And of course, we can even look further into the future of using such treatment in cancer prevention, especially in those with high risk of developing cancer, for example, those with hereditary syndromes like lynch syndrome. We're not there yet, but I think it holds that promise.

So I think, going back to your original question, if we can develop such a therapeutic that is showing promise in a very short period of time, it brings the timeline and the hope to a much shorter timeframe to really deliver to our patients in a very timely manner while safeguarding all the important parts, such as safety and tolerability.

Dr. Pedro Barata: Wow, those are such important points. I couldn't agree with you, more. It’s really exciting. As I think through this, and as I was reading through your piece, I was thinking it would be great if you could highlight some of the novel approaches to personalized neoantigen vaccine development that are driving progress in this space.

Dr. Lillian Siu: Absolutely. And during the session, Dr. Weber spoke about the neoantigen vaccine, and he's a pioneer in this space. So I can only try to iterate some of the points he had delivered during his talk. Neoantigen is a very exciting space for immunologists because we know that tumors express these neoantigens. Many of these are unique antigens that are only expressed in tumors, so-called tumor specific antigens, that we can use as our targets, including vaccines, but not limited to vaccines. And with these altered sequences in DNA in different forms, they could be mutations and splice alterations, etc. We expect that we have modified proteins that are expressed by tumor cells, and these become targets for our drug development of vaccines. And now we can have very specific strategies, very sophisticated algorithms to figure out which neoantigens are more so called immunogenic, more likely to stimulate or activate the immune system, and they can be recognized by T cells. So leveraging this knowledge and technology, we have been able to develop especially mRNA vaccines that are deliverable to our patients through different mechanisms, for example, in lipopeptides, etc., so that we can deliver to the patients in a safe way, such that we can use it to deliver vaccines, such as in the MRD setting that I mentioned earlier, as well as in the advanced disease setting.

So Dr. Weber, in his presentation, highlighted one of such vaccines that have been tested in a randomized controlled trial that is KEYNOTE-942, which randomized 157 patients to the mRNA vaccine plus pembrolizumab versus pembrolizumab alone in patients with advanced melanoma. This is a vaccine against 34 mutated neoantigens, and it showed a significant difference in the recurrence free survival with a hazard ratio of 0.56. And if you look at the 18-month relapse free survival rate, it was 78.6% versus 62.2%. Obviously, these are still fairly early data and numbers are still small. I think we would definitely look forward to the randomized phase 3 study of neoantigen vaccine in melanoma and other cancers.

Dr. Pedro Barata: No, absolutely. And I agree, it's really exciting. Dr. Weber did a fantastic job going through some of that data.

So let me ask you Dr. Siu, as you think about this cancer vaccine field, what are the limitations that you'd highlight when you think about cancer vaccine development? What challenges do you encounter, obstacles do you encounter?

Dr. Lillian Siu: There are many, many potential challenges. And to some extent, that's probably why cancer vaccine development has been somewhat slow for the many decades until more recently. We know first of all; the target has to be recognized. So we need immunogenic targets. So I think a lot of the effort has been put into trying to understand which antigens expressed by cancer cells are immunogenic, able to activate the immune system. They're obviously assay based methods. You're going to try and see if you can ex vivo stimulate immune cells on dishes and models, etc. But we need to also develop in cyclical computerized algorithms, and now with AI, I think that makes it even more tangible and exciting that we can actually understand through a large number of neoantigens or other antigens, whether we can choose the ones that are most likely going to actually stimulate T cells to be activated. And I think that is one area that there is a lot of interest in development, how to really develop ways to select out the most attractive antigens.

I would also want to highlight that the platforms, which is how we deliver the vaccine, can also pose significant challenges. For example, vaccines can be delivered using peptide-based formulation, cell-based formulation, nucleic acids and viral vectors. For some of these formulations, for example, the peptides very often are restricted to HLA. They can be rapidly degraded in the body, such that they become not really visible to the T cells anymore. Some of the formulations can be very complex. For example, the cell-base; it may need to have cells isolated from patients, cultured, stored and transported to the site of delivery, which can be very complex. For some of the nucleic acid vaccines, they can have very low transfection efficiency. It could be at risk for also having, for example, DNA vaccines integrated into the host genome. And then lastly, there's also the immune suppressive environment in the TME, such that it does not really have the effect when you give it repeatedly. It becomes attenuated and no longer effective. So these are some of the challenges associated with cancer vaccines.

Dr. Pedro Barata: Thank you for that summary. I think it's really important for folks out there, including researchers getting into this field, to be aware of potential obstacles they might encounter.

So let me ask you the opposite question as we see more compelling preclinical and clinical data emerging in this field of vaccine development, what is really exciting you the most about the newest technologies that are shaping the future of cancer vaccines, in your opinion?

Dr. Lillian Siu: I think one I want to highlight is the immune-modulatory vaccine that Dr. Svane, Dr. Inge Marie Svane had presented during the presentation at ASCO. This is a completely different strategy from the neoantigen vaccine. It targets antigens in the tumor microenvironment. And we know that in the tumor microenvironment, we have tumor cells, we have immune cells, and there are many types of cell types, including, for example, macrophages, cancer associated fibroblasts, regulatory T cells, etc. And using these particular cell types, we know that we can really develop vaccines that can stimulate the body's immune system to attenuate, to downgrade some of the negative factors in the tumor microenvironment. And this is what Dr. Svane and her group is trying to do. For example, they have an IDO vaccine that is able to actually target these antigens in the tumor microenvironment, and by that, not just suppressing the negative forces, so to speak, but also activate T cells to help attack cancer cells. I think that's a very interesting area. Very early promise has been seen already in non-small cell lung cancer in early phase trials using the immune-modulatory vaccine.

But going back to your question, what kind of advances; I mentioned earlier about having novel ways to select our antigens that are most immunogenic. There are many algorithms that are being developed, and I think we can try and leverage that kind of knowledge from artificial intelligence, machine learning. So I think that's definitely very exciting. There are also new vaccine platforms coming out. For example, there's recent data using modification of peptides, so called amphiphile vaccines, that already show very early promise in colorectal cancer, microsatellite status, colorectal cancer, as well as in pancreatic cancer in the molecular residual disease setting, where these long peptide vaccines targeting KRAS mutants together with adjuvant oligonucleotide DNA, combined together, can actually be given to patients and reduce the chance of cancer relapse in patients with resected colorectal cancer, as well as pancreatic cancer, with endpoints such as ctDNA or biomarker being downregulated. I think that's a very exciting example.

Another very exciting example is cell-based vaccines that are being developed in Europe by the NKI Netherlands Cancer Institute Group, where they are looking at plasmacytoid dendritic cells that are loaded with peptides from different tumor associated antigens and then given to patients, which, again, in non-small cell lung cancer, together with pembrolizumab, has yielded very high response rate. And we will almost certainly see more trials coming out using that particular platform with the dendritic cells. So that's just some of the examples of exciting things that are happening in the vaccine field.

Dr. Pedro Barata: Thank you. I’m wondering if you can share with our listeners about what really are the existing guidelines for using these new tools for discovery, methods of treatment, and perhaps optimizing patient selection to access trials.

Dr. Lillian Siu: To be honest, the latest guideline that was published from the FDA that I can find is almost 13 years ago in 2011. So I think it is time for a new guidance, or at least a draft guidance, to give some additional support and guidance in terms of what to do with these new treatments from the FDA and perhaps other regulatory agencies as well. I think we're now entering a very exciting time that cancer vaccines are no longer an ineffective therapeutic. It is now showing evidence of efficacy, not just in the advanced setting, but also in the molecular residual disease setting. There're so many questions to be answered, like how to develop these trials in early disease; what's the end point? Can we incorporate them into the neoadjuvant setting, and if so, how do we give these drugs before surgery, and do we give them maintenance after surgery? I think guidance from the regulatory authorities would be extremely helpful and informative to guide academic groups as well as the pharmaceutical sector to develop these agents in the right way.

Dr. Pedro Barata: Dr. Siu, this is a fantastic summary, and we certainly are on the cusp of a new dawn of discovery and development in cancer vaccines, and super interesting to hear from you talking about it. Before letting you go, do you have any final thoughts that you'd like to share with the listeners, with all of us about this topic?

Dr. Lillian Siu: I think as a drug developer like you are, I'm extremely excited because we now have yet another way to leverage the host immunity as a cancer therapeutic, and it is going to be opening a new door to combination therapy because we can imagine combining these treatments with other immunotherapeutics such as bispecific molecules such as CAR Ts and even vaccine plus vaccine combination is feasible. That came up actually during the session as a question from the audience. Can we combine neoantigen vaccines and immune-modulatory vaccines together? And both of our speakers who presented felt that it was possible. Obviously, we have to understand the sequence question and the endpoints question, but the fact that it opens a new door to combinatorial therapy, not just with immunotherapeutics, but perhaps with other therapeutics as well, antibody drug conjugates, etc., really, I think, is very exciting for this field to become further explored.

I mentioned earlier in the podcast that the whole area of cancer prevention is something that we have not been tapping into for the last decade with vaccines because it has not been very effective. Viral vaccines, of course, HPV and other vaccines targeting viruses, but targeting cancer cells is not something we have been successful using vaccines to prevent cancer from developing. I think we would be very interested to see if this will become a reality in the next decade. I think we would start off with patients with high risk of developing cancers such as, as I mentioned earlier, those with lynch syndrome, those harboring BRCA alterations, for example. Can we use these vaccines to actually prevent the cancers from developing in such high-risk individuals? I think the field is definitely open to that consideration.

Dr. Pedro Barata: Definitely. And I'd like to thank you, Dr. Siu, for sharing these great insights with us today on the ASCO Daily News Podcast.

Dr. Lillian Siu: Thank you so much for your time.

Dr. Pedro Barata: And thank you to all the listeners for your time today. You'll find a link to the article discussed today in the transcript of this episode, and I encourage you to check out the 2024 ASCO Educational Book. Finally, if you value the insights that you hear on the podcast, please take a moment to rate, review, and subscribe wherever you get your podcasts. So again, thank you so much for your time and see you soon.

Disclaimer:

The purpose of this podcast is to educate and to inform. This is not a substitute for professional medical care and is not intended for use in the diagnosis or treatment of individual conditions.

Guests on this podcast express their own opinions, experience, and conclusions. Guest statements on the podcast do not express the opinions of ASCO. The mention of any product, service, organization, activity, or therapy should not be construed as an ASCO endorsement.

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Disclosures:

Dr. Pedro Barata:

Honoraria: UroToday

Consulting or Advisory Role: Bayer, BMS, Pfizer, EMD Serono, Eisai, Caris Life Sciences, AstraZeneca, Exelixis, AVEO, Dendreon

Speakers’ Bureau (Inst): Caris Life Sciences, Bayer, Pfizer/Astellas

Research Funding (Inst.): Blueearth, AVEO, Pfizer, Merck

Dr. Lillian Siu:

Leadership (Immediate family member): Treadwell Therapeutics

Stock and Other Ownership Interests (Immediate family member): Agios

Consulting or Advisory Role: Merck, AstraZeneca/MedImmune, Roche, Voronoi Inc., Oncorus, GSK, Seattle Genetics, Arvinas, Navire, Janpix, Relay Therapeutics, Daiichi Sankyo/UCB Japan, Janssen, Research Funding (Institution): Bristol-Myers Squibb, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Pfizer, AstraZeneca, Boehringer Ingelheim, Bayer, Amgen, Astellas Pharma, Shattuck Labs, Symphogen, Avid, Mirati Therapeutics, Karyopharm Therapeutics, Amgen