A variety of adoptive T-cell therapeutic strategies has shown a remarkable remission rate exceeding 80 percent in certain areas of blood cancer treatment. However, innovative cell therapy has not made much progress in treating solid cancers.

This is because, unlike blood cancers, solid cancers still have a lot of problems to overcome, such as antigenic diversity, migration to target organs, and hostile tumor microenvironment.

While adoptive cell therapies (ACT) include tumor-infiltrating lymphocytes (TILs), endogenous T cells (ETC), and T cells engineered to express a CAR or T cell receptor (TCR), a U.S. expert has suggested that ETC may potentially be an optimal

Korea Biomedical Review met with Professor Cassian Yee from the University of Texas MD Anderson Cancer Center during the “Current and Emerging methods for Immune Cell Therapy Symposium,” sponsored by CancerRop, MJCellbio and Myongji Hospital’s New Horizon Cancer Institute.

Questions focused on the current status and obstacles of ETC treatment development and future goals of Professor Yee in using ETC to treat solid cancer.

Professor Cassian Yee from the University of Texas MD Anderson Cancer Center explains what endogenous T cells are and how they can be useful in treating solid tumors, during the Current and Emerging methods for Immune Cell Therapy Symposium at Myongji Hospital in Goyang, Gyeonggi Province, on Thursday.

Question: Can you briefly describe what ACT and ETC are?

Answer: ACT is a form of immunotherapy that involves the isolation and expansion of immune cells in the lab and uses them to infuse back into cancer patients.

Unlike conventional chemotherapy, surgery, or radiation, the therapy uses the body’s own immune system. Therefore, it provides multiple ways of killing cancer cells and enabling long-term protection against recurrence.

ETC therapy is unique in that it does not require a tumor as a source of T cells or genetic engineering. ETC relies on naturally occurring tumor-reactive T cells in the peripheral blood, which is one of the essential advantages of this technique.

However, these cancer-killing T cells are exceptionally rare and require labor-intensive methods to isolate and expand before re-administering to patients.

Q: Were there any challenges associated with researching ETC therapy? If so, how did you overcome them, and what are some future obstacles that the therapy needs to overcome?

A: I started in T-cell therapy more than 20 years ago, and since then ETC is probably still not considered as a mainstream approach to T-cell therapy.

In the past, most people believed that the concept was not feasible to do. I was fortunate to be in the right place at the right time and being a little bit stubborn.

Back then, we had to screen 10,000 clones to get what we wanted, and even then, we were not able to treat patients. However, over the years, they were overcome due to technology and maybe some creativity and a lot of good luck. Moving to MD Anderson has also allowed me to treat the patients that the team wants to treat for ETC development.

There always are obstacles in research, and I think it is important in a new field or any field to have the stamina to continue to work what you think is the right answer.

Q: What is the current status of ETC development? Is it in preclinical trials? Or has it gone further than that?

A: Right now, we are in clinical studies or phase 1 and 2 clinical trials to be exact. We are conducting trials for melanoma, ovarian and pancreatic cancer, and sarcoma. However, the studies are in the early phase, so the results are not ready for general eligibility.

Q: What about the efficacy and response of the treatment in the trial?

A: We first have to stress that a small number of patients participate in the trials, but if we put all the numbers together, the response rate is around 30 to 35 percent.

However, we have to be careful with that number as it is not a real significant number that we can publish as the patient pool is so small, and we had to group different trials together to obtain the number. I hope that we can do a much larger study in the next two or three years to confirm the efficacy of the treatment.

Q: Controlling toxicity is as important as the treatment itself. Do you believe that we can control toxicity when using ETC?

A: Yes. I think because we use natural occurring T-cells, we do not have a problem with toxicities seen with CAR-T (chimeric antigen receptor T-cell) therapy. These T-cells will recognize their targets in a more physiologic fashion. Therefore, the targets are very tumor-selective.

Q: You previously mentioned that the T-cells used in ETC are very rare, and your team had to expand the cell from 0.001 percent to 1010. However, is it okay to enrich and expand by that much? Won’t the cells be damaged?

A: The concern is that if out take a T-cell and expand it to many times, it will become exhausted, or it may be not available to divide anymore. However, because of the way we grow the T-cells, they are memory cells, and not everyone expands to 10 billion because we have many cells to start with. As it has previously been confirmed that memory cells continue to expand and divide in the body, they can protect the body for many months or years afterward.

Q: How long does it take to extract ETC from the patient and multiply it and inject it into the patient again?

A: From vein back to the vein, it takes about six to seven weeks, but we are now in the process of decreasing that to four to five weeks with some new technologies. Some of these new technologies involve using artificial antigen-presenting cells to stimulate T-cells.

Recent technology allows us to develop a system where we might be able to isolate T-cells from a chip. That way, we can use far fewer cells and speed up the process. This can also lead to true automation and remove the need for manual labor.

However, this is all in the development stage and is not currently available.

Q: What plans do you have for expanding the use of ETC in treating other cancers?

A: The first possible answer would be when we find new antigens, it can give us an opportunity to treat that cancer, which may have its unique mechanism to suppress the T-cell response.

The second would be ETC may allow us to treat rare cancers, and I think this is important as currently, there are very limited options for rare tumors. It also allows us to see relatively quickly whether we can see a response or not in a rare tumor.

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