In Pursuit of CAR T 2.0 Technology

Since last year’s personalized immunotherapy success story surrounding Emily Whitehead, CAR T cell therapy has embarked on a new era. There’s an exciting surge of scientific effort toward understanding chimeric antigen receptor (CAR) technology and its potential to advance cures. Enter Dr. Yu, equal parts medically trained surgeon and astute researcher. His cross-cultural efforts between China, the US, and Canada are driven by a passion for translational medicine rooted in gene therapy research. While recounting his endeavor to bridge the gap between the bench and the clinic, Dr. Yu reflects on the promise of an innovative CAR T cell therapy 2.0 and why he continues to pursue a more precise immunotherapy.

You have an impressive résumé—it starts in medicine and branches out into basic research. What inspired you?

After conducting cardiac surgery on many patients, I noticed that almost every patient has to go back to the ICU. Infection and sepsis are hard to control within patients undergoing this type of surgery. It led me to the study of how to control and prevent these infections in the hospital.

Can you take us through your scientific journey?

Helping patients was my motivation so I applied for a PhD in medical microbiology and immunology at the University of Alberta [Canada]. My focus was vaccine research. After graduation, I thought, what next? At that time, gene therapy was quite hot. I applied to UCSD, Theodore Friedmann’s lab. Professor Friedmann is a pioneer of gene therapy and he coined the “gene therapy” term in 1972. We used genetic engineering to increase safety in the design of viral vectors. Afterward, I studied gene delivery with Professor Sam Wang Kim. As I continued to develop gene therapy technology, I partnered with a Japanese company to set up a location in Oceanside, California. We started with five employees and have grown to 115.

It sounds like you are really driven to help patients. Also, your work carries across multiple countries; can you please tell us how your work in China and the US impacts translational research?

In China, they have many patients and also they have a faster clinical trial process. In the US, sometimes we’re waiting for patients and the process can be long and slow. [So] I’m back in China to set up training for more of the scientists within translational medicine. I try to make the technologies get to clinic faster. This is the reason why I’m in basic research and translational medicine and pharmaceutical development.

Your approach is from a number of perspectives. Why is that?

I feel this is helping me to be multidisciplinary. Currently, many of the life science technologies need more and varied scientific knowledge to design and to reduce the risk of failure. Also, the industry as a whole challenges me to think more systematically, like a systems engineer. You cannot just take care of one part and forget another. You need to consider the big picture to move ahead. I feel this gives me a greater chance of success for helping people.

What’s your proudest moment so far?

Working at a hospital, you see very sad scenes. That motivates me to research gene therapy technology—gene therapy from the vector part, the gene part, the genetics part, and also the clinical part. Gene therapy has been around for 30 years. CAR T cell therapy is a form of gene therapy. This is why I say it’s the right timing for us. I’ve worked with a patient who was close to death; but after the infusion of the CAR T cells, the patient was very much alive and was even able to stand. This is why I try to do my best, and have branched out from lymphoma and myeloma to leukemia and solid tumors. So many patients are waiting, and there are many lives to save. I’m so happy with what I do because almost 87% of my patients have been saved.

You’ve mentioned CAR T cell therapy. What’s CAR T 2.0?

I think of the first CAR T cell therapy as version 1.0 because usually they just modify CAR T molecules. This has already proven to be successful. However, even though we can continue to improve their therapeutic effect, we cannot prove their safety. How do you balance it? This is why we think about how to go about making the T cell more fit for reduced risk by increasing safety. You cannot just modify the CAR T molecules because if you modified the CAR T molecules you may reduce risk but also you’ll reduce efficacy.

For solid tumors, they have a microenvironment that is not good for the activity of CAR T cells. We consider how to make CAR T cells that can ignore inhibitory effects present in the tumor microenvironment (TME). For example, PD-1 is mainly expressed by the T cell. PD-L1 is mainly expressed by the cancer cell and also the TME. Even though you have a lot of the PD-L1 in the tumor tissues, if we can reduce the PD-1 expressed on T cells, then they can go into the tumor uninhibited and keep functioning. This is why we are also using silencer RNA to study this as we continue to genetically engineer T cells that are better fit for their environment. This is what we call 2.0.

What are the biggest challenges you face as you work toward CAR T 2.0?

Lots of issues here. Many of the current manufacturers producing modified CAR T cells are simply from basic research backgrounds. For industry, I think we require more of a single-use technology so we can avoid contamination. Second, simplification of the process is important. Third, cells from each patient are different so it’s challenging to make controls. In this case, you have to have a very experienced scientist observe cells to make a judgment call. Or, using AI is promising because that sort of system will remove variability. In Chinese medicine, for example, an experienced doctor who is very old and with lots of experience would like to pass down knowledge to their student. However, it’s difficult to pass down personal intuition and feeling. But if you can tell a machine to “understand” by accumulating data, you can design this machine and make the passing on of knowledge easier by modern methods.

What is your perspective on the future of CAR T and its impact?

I think safety is still a problem. It’s hard to reduce the risk and make CAR T therapy more benign so you can treat the patients, but also not harm them. This is still a clinical bottleneck or pain point. Another challenge is finding the right targeting molecule. It’s important to distinguish exactly what the CAR T is fighting. Biomarker discovery is challenging because you have to look at the specific cancer, numerous biomarkers, and the TME. For example, you have to look at overexpression. It means a cancer cell can make 100 times more biomarkers than a normal cell because the normal cell is still healthy. Also, neoantigens: these antigens change so frequently. Once you hit the right target, you may hit 100 cancer cells but another 100 will change. This is why it’s quite difficult. I really think this is where T cell receptor (TCR) therapy in combination with CAR T therapy could help. This is maybe where the future lies.

Is there anything outside of the science that really drives you and motivates you?

I like reading, swimming, and walking. This is also my time to think. I’ve read and written lots of kung fu stories about teaching someone how to fight a bad guy and helping weaker people. This is the same as a doctor or scientist: the goal is to treat the patients, to save the patients. This can be summed up in two purposes: one purpose is to try to make the people live longer; the second is to try to make their quality of life better. In other words, to make patients happy. Healthy, happy. This is why I use my knowledge and greatest effort to reach this goal one step at a time.

Read more about CAR T cell therapy research