Di Yu, Senior Lecturer in Immuno-oncology at Uppsala University, started his career in the Shaanxi Normal University of Xi’an, the city with the famous Terracotta Soldiers. He then received a scholarship from the Chinese government that allowed him to earn a Master’s Degree in biotechnology in Sweden. Yu joined Professor Magnus Essand’s group and took his first steps in virus engineering, an experience that gave him the momentum to start his Ph.D. at Uppsala University. He transitioned from viruses into CAR-T cell research, and soon after became involved in a project that would lead to the founding of Elicera; a biotech company specialized in fighting cancer, where he currently serves as the head of Translational Research and Technical Operations. Recently, LifeScientist had the opportunity to talk to him and discover the latest projects and developments he is working on.
You recently published some very exciting findings about treating solid tumors with your group in the Nature biomedical engineering journal. Can you explain why such discoveries have so much potential for improving patient treatments?
The current available CAR-T cells rely on recognizing the antigen expressed on the cancer cell surface and thus kill it. Therefore, one of the major challenges is how we can stop the tumor cells from escaping recognition by the CAR-T cells. For example, targeting CD19 for treating B cell lymphoma exerts selection pressure on the tumor and can result in the growth of CD19-negative tumor cells. In addition, although the initial overall response rate is good, only 30% to 40% of leukemia or lymphoma patients have long-term responses. However, when it comes to solid tumors, the response rate is not promising at all. So to address these challenges, we had the idea of arming the CAR-T cells with a bacterial protein called NAP, which stands for Neutrophil-Activating Protein, taken from Helicobacter pylori. These NAP-armed CAR-T cells can induce a so-called bystander endogenous T-cell response against cancer cells, which is independent of the CAR-T targeted antigen. In this case, even if the cancer cell escapes recognition by CAR-T cells, it will be killed by the endogenous T cells.
We believe that arming CAR-T cells with such bacterially derived factor provides a therapeutic advantage by guaranteeing that all T cells stimulated by NAP can secrete cytokines and chemokines in a “natural” way as a response to the “bacterial factor” and thus also revert the otherwise immunosuppressive tumor environment.
That’s a very innovative approach that has stirred your career in a totally new direction. So, I have a question that I’m sure many of our readers may be thinking about already. How have you been able to balance your academic career, your job as a co-founder of a start-up, and your personal life all together?
I do research from nine to five, take care of the kids from five to eight, and later focus on company work during the night. Currently, it is mainly the documentation for setting up our first clinical trial. To be honest, it’s a lot of work, but the good thing is that we have a great team with experts in all aspects. Personally, I don’t have to deal with the “business part” of the company as our talented CEO Jamal El-Mosleh takes care of this part . I only take care of research and science, and it is mainly translational research, which largely overlaps with what I do in academics as well.
As a researcher and co-founder of a startup specialized in biotech solutions, I would like to ask you how well equipped you think Sweden is to encourage biotech innovation and research. Do you think the country has good policies in this area?
In my opinion, Sweden is a fantastic country for that as it has a policy called “the researchers’ privilege,” which stipulates that the researcher, instead of the Department or University, owns the Intellectual Property (IP) of their invention. As far as I know, Sweden is the only country that has this policy, and this means that as a researcher, I can take my invention and develop it freely with no restrictions. This policy has made Sweden a very attractive country for those who have great ideas and want to make them a reality, an excellent environment for start-ups. Besides that, there are a lot of support sources; for example, the VINNOVA funding agent, settled by the Swedish government, is dedicated to funding start-ups with new technologies and ideas. At Uppsala University, we have an innovation center, UU Innovation, that helps researchers in the early commercialization phase. I got support for patent search and writing, and lawyers are available to help with company set-up and regulatory affairs discussions. I also received funding support to perform some proof-of-concept studies and for patent costs. There is also a business incubator at UU Innovation that helped me with business setup. To my knowledge, this is one of the best university technology transfer offices (TTO’s) in the Nordic countries and the best in Sweden.
And regarding innovation in Sweden, I would say that if it’s not number one, it is in the top three.
That’s great. Let’s go back to when you transitioned from virus engineering to CAR-T cell therapies. What triggered your interest in this area?
It was kind of a coincidence, and lucky for me that it happened the way it did. It was around ten years ago while I was doing my Ph.D., working with an oncolytic virus, and also at that time working with the NAP protein to modify it. At that time, CAR-T cells had just started becoming popular and publicly noticed, especially after Dr. Carl June cured Emily Whitehead in the US. One of my colleagues Dr. Angelica Loskog, now the CEO of Lokon Pharma AB, brought the CAR-T cell concept back to Sweden and started the first CAR-T cell therapy clinical trial in Europe along with the clinician Dr. Gunilla Enblad. Since one of the obstacles in CAR-T cell therapy is how to tackle the harsh tumor microenvironment, and from my experience, I knew that NAP could do the job, I started thinking, “let’s try to put NAP into CAR-T cells and see how they get along”. Of course, there were many technical barriers to overcome, but with effort over the years, we solved them and finally realized our CAR-T cell therapy.
What a challenging journey. Could you talk a little bit about how Elicera was founded and about its innovative technology?
Sure, Elicera’s founding is quite a fascinating story. Around 10 years ago, I joined Professor Magnus Essand’s lab (co-founder of Elicera) and developed an oncolytic virus for the treatment of neuroendocrine cancer. Later, a British journalist, Alexander Masters, read our publications and realized that our group, as academic researchers, lacked the money to test this potential drug candidate in a human clinical trial. He then started a crowd-funding campaign, and a businessman and philanthropist, Vince Hamilton, heard this story and decided to donate. With Vince’s contribution and donations from more than 2,000 people worldwide, we started our first clinical trial with an oncolytic adenovirus developed in a research lab. Along the same timeline, my invention to modify the virus surface also resulted in a US patent, and we successfully out-licensed this technology to an Immuno-oncology company, Immunicum. The out-licensing also generated upfront payment, which we used to cover the patent costs for other inventions resulting from my Ph.D. studies. As I mentioned previously, in Sweden, we as researchers own the IP derived from our research. At this time, we realized we have enough inventions/drug candidates with therapeutic potential to merit testing in human clinical trials.
Furthermore, I have always felt a great sense of responsibility to carry through findings from translational studies. Therefore, feeling that it was only ethical to bring our government-funded discoveries to human trials rather than settling with scientific publications, we decided to establish a company and seek grants to develop these drug candidates from bench to the bedside. Again, luckily, we met Jamal El-Mosleh, who teamed up with us to found Elicera. We successfully raised enough money through IPO, and I am proud to say that we recently got a large amount through an EU grant as well. Now we have enough funding to start a clinical trial testing our CAR-T cell therapy, which hopefully will begin early next year.
So you have a stake in the science and business parts of the Elicera story. Regarding this, can you tell us three main challenges you encountered while developing the CAR-T cell therapy that go beyond just science? For example, in manufacturing?
The manufacturing process is challenging, especially for Elicera as a start-up company, since we cannot afford a fully equipped GMP lab to produce both the viral vectors and CAR-T cells. Therefore, we are partnering with BioNTech for virus production and will seek collaboration with Vecura for CAR-T cell production. As a researcher, I don’t have any experience with the manufacturing process, especially regarding the regulatory guidelines that apply. It is a completely new world to me, but luckily, we have experts alongside helping us from BioNTech, Vecura, and our CRO unit. Before starting clinical trials there are many details to be tested to achieve a GMP-complaint CAR-T cell production. For example, whether to use fresh or frozen starting materials and how cells should be transported from the clinical to the manufacturing site. We received a VINNOVA grant to set up the manufacturing process. I would say ,currently, everything looks fantastic, and we can establish a seamless CAR-T manufacturing pipeline. Of course, there are a number of other practical and regulatory-related issues to consider as well, but I hope we can start the trial early next year.
“I have received a lot of help from GenScript, especially regarding DNA synthesis. A lot of artificially designed DNA regulatory elements could be synthesized and tested efficiently with GenScript’s help. I also received help with GMP-grade plasmid preparation, which made our human clinical tests possible.”– Di Yu, co-founder, Elicera AB
Want to know how GenScript Biotech can help your research?