Hello, everybody, and welcome to Crowncast, the podcast from Crown Bioscience that aims to discuss the emerging trends and viewpoints in oncology drug discovery and development. I'm today's host, Johnny McMichael, and it's my pleasure to bring you conversations with scientific experts from around the globe. Thank you very much for joining us today. We really do appreciate it. To introduce myself briefly, I'm Crown's VP of client experience and enablement. Today, I'm delighted to be joined by Crown's director of immuno oncology, Kara Hoversa, who's based at our site in Leiden. Tara did her PhD at Amsterdam University Medical Center. She then postdoc at KU Leuven. Eight years ago, she joined, the company in Leiden known as Oselo, which is an expert, CRO in organoids research and high content imaging, overrules from senior scientist to head of myeloid cell biology. For the last four years, in fact, maybe three years, Hara has been director of immuno oncology with Crown Bioscience Netherlands since the merger of Acelo with Crown Bioscience four years ago. Welcome. And how are how are you today? How is... I think you're in Amsterdam today. Right? Hi, Johnny. Yeah. Thanks so much for the invitation. Hannah, thank you so much for joining us. It's great to to speak with you, and I always enjoy working with you in our conversations together. So please tell us a little bit about your background and the scope of your role with Crown Bioscience. So I'm a trained immunologist and actually I'm trained in mucosal immune system. That was where I did my PhD in and also followed up with my postdoc. And that actually means that then at that time, within the mucosal environment, within the gut, you would like to actually suppress your immune system because you don't want to have an, let's say allergy response or any kind of inflammation in your intestines upon eating something or several other reasons. So we were always trying to look for the suppression of the immune system. And then actually, when I moved my career from academia to indeed Ocello within The Netherlands at that time, instead of suppressing the immune system, we want to actually activate the immune system, trying to fight cancer. So actually activating immune cells to fight cancer. So can you please tell us a little bit about what is meant by the term immuno oncology? So within the immune oncology field, we are looking in how can the immune system of the person itself help to actually fight the cancer within the patient itself. And in your time working in this field, have you seen a large change in the field? So last year in 2024, there has been an FDA approval of Till therapy. And on the other hand, also of a bispecific antibody that actually targets the immune cells directly. So those have been very exciting developments now, again, within the fields, which I think will further boost again the fields to put energy in the development of these two. And on the other hand, another big trend I think that we see in the field is that there's a lot of combination now. So in the first beginning when ICI was released, the idea about it and the thought was that you would just give the immune checkpoint inhibitors to the as a single treatment. And nowadays, it has actually been completely shifted. And actually, the immune checkpoint inhibitors have now been are now used in the clinics either as an adjuvant during chemotherapy or target therapy, or even as a new adjuvant. So the approach is literally changed, I think, within the field. And I think that's very exciting. Yeah. Are there any other sort of current and future trends in immunotherapeutic development that you're seeing? Things like thinking of things like CAR Ts, for example. The combination, I think, and it can be a combination of multiple IO type therapies or in combination with standard of care. That's definitely the way to move forward. And I think that also completely makes sense because if you want to suppress or no, you actually want to release the suppression of the immune system which is done by an immune checkpoint. Then you also want to make sure that for example either a tumor antigen is released. So actually the T cells that are potentially in the tumor microenvironment are also able to actually recognize the tumor. So for example, if you have a damage during chemo or then those antigens will be more released. For the CAR T cells, there has been developments regarding to prevent, for example, exhaustion. So this is another way where what can happen with an immune cell if they become multiple rounds activated. In the end, the immune system is built in such a way that it will go in an exhausted state. But that actually means that then those immune cells will not be able to perform their inflammatory or cytotoxic effects. So that's one of the things, but also that can be done, for example, by changing or having new approaches with the signaling domains within the CAR T cells. And actually today I saw a new paper, which I also thought was very exciting. So most of the CAR T cell products at the moment are based on autologous, meaning that it would be personalized. It would be from the same patient. But on the other hand, of course, there's also benefits if we can have more allergenic off the shelf type of therapy for everyone. The downside of the allergenic approach, of course, is that there's a high risk for graft versus host type of response within the patient. And I noticed this new paper that they actually described to make use of virus mechanisms like HIV. And for example, proteins that's normally HIV are using because HIV is actually also suppressing your immune cells. So actually these proteins can reduce the HLA expression. And so they are now trying to incorporate this in allogeneic CAR T cells. So you still have a functional CAR T cell that can recognize the antigen on the tumor of the patient and thereby kill hopefully all the cancer cells. But by actually this reduction of the HLA expression on those CAR T cells, they would not be recognized either by the T cells, the cytotoxic T cells from the patient itself or other immune cells. How challenging is it for the design of preclinical models and platforms to try and mimic some of these really quite intricate interactions? Most of researchers often also have been done in animals, But this is very tricky because in the end, to make sure that the mice, if you would be testing on a mice, has a correct immune system that is reflecting the human immune system, that's already a challenge. We do generate those mice. But of course, it does take more I would say, more technology and more expertise to run those type of models. And thereby, they are also a bit more costly and maybe not available for everyone. How key role does the tumor microenvironment play in IO research? Altogether, I think the TME already plays a major role to determine whether cancer can be either what we call hot or cold. Meaning either it does have immune cells inside infiltrated already or there is barely any like what they also call immune desert type of environment. And if you have any this cold or immune deserts then it's very difficult or it doesn't really make sense to come directly only with an immune type of therapy because if the immune cells are not entering the cancer environment and there are no immune cells. So who are going to stimulate or activate? So then you would need a trigger to make sure to break that barrier. So you can target either, for example, fibroblasts that often generates such a physical barrier. It also can suppress the immune system very well. So this is another indeed major factor. And that I think is, yeah, what we all like to reach is that the immune cells are not suppressed in the cancer environment. And I think most important is again, as I just mentioned, if you have a cold tumor, it doesn't really make sense to come with an IO type of therapeutic alone. So you need to think about combinations. What excites you the most about the future of the immuno oncology field? And then there's another FDA approval actually of a combination of a bispecific. So we have been testing these bispecifics in our in vitro assays. And this bispecific is now FDA approved indeed to combine with ICI therapeutics in head and neck squamous cell cancer. So that is another exciting example of indeed combinational type of approaches. But, yeah, it's also very exciting that those combinations are showing more success now. What advice would you give to companies, research groups out there who are developing novel immuno therapeutics? Don't get stuck in your bubble, maybe. You know, think also outside the bubble and definitely indeed understanding which type of patients you are aiming to target for, what is try to make sure that you characterize this correct so that you also can model them correctly. And then you have better chances of success because if you have a better understanding of your model, then you can better test which modifications you might need to make to make your therapeutics a success. Do you have any, closing thoughts, to share with those listening in? Indeed, reach out to, your scientific surroundings and share your knowledge or experience with each other to make the most out of it. And indeed try to avoid to be in your own bubble, but definitely reach out to others for advice and support as well. Yeah. Absolutely. Absolutely. Well, thank you, Hera. I've enjoyed the conversation very much. Always worth spending time in your company. Thank you to everyone who's listened in today. I hope you've enjoyed this episode of Crowncast. If you have, please subscribe on YouTube, Spotify. Also, you'll find us on the Crown Bioscience website, crownbio.com. And I'm... We're hopeful that you'll be able to join us on a future episode of Crowncast. Take care. Thanks, everyone. Goodbye.
