James Allison talks about tumor immunotherapy in the interview
As the chair of immunology at the M. D. Anderson Cancer Center, James Allison is one of the founders of modern tumor immunotherapy. He has made significant contributions to mechanisms of T-cell development and activation as well as the development of novel strategies for tumor immunotherapy. Recently, Biodiscover is honored to interview James Allison.
The Cold Spring Harbor Asia conference on Precision Cancer Biology: From Targeted to Immune Therapies was held in Suzhou, China on September18, 2017 and will last four days. James Allison is invited to deliver a keynote speech, and later he receives our interview.
Prior to the interview, we firstly make a brief introduction to James Allison. We are familiar with the emerging tumor immunotherapy. James Allison is one of the founders of tumor immunotherapy.
Allison has made significant contributions to mechanisms of T-cell development and activation as well we the development of novel strategies for tumor immunotherapy. What’s more, he defined the structure of the T-cell receptor and found CD28 is important co-stimulatory receptor that leads to functional activation of native T cells or inactivation of T cells.
He resolved the major dispute in research and showed that： LA-4 inhibited T cell activation by fighting CD28. This blockade of CTLA-4 could enhance T cell response, resulting in the elimination of tumors in animal models. The discovery lays a profound foundation for the emergency of the tumor immunotherapy. In addition, it is conducive to the development of ipilimumab, the antibody of CTLA-4 and the first approved immune checkpoint inhibitor.
As one of the famous scientists, Allison is a member of the National Academy of Sciences and the Institute of Medicine. In 2015, he received the Lasker-DeBakey Clinical Medical Research Award. Now, he is devoted to improving the current immune-checkpoint blocking therapy and defining the new target to release the immune system and then eradicate cancer.
Interesting story in the discovery of CTLA-4
The questions that we put forward are based on the discovery of CTLA-4
Allison said, there was an interesting story in the discovery of CTLA-4. Previous studies proved CTLA-4 was a positive regulation of T cells, but the research result of his team confirmed that CTLA-4 had a negative regulatory effect on T cells.
In fact, Allison wondered if he could use the immune system to attack cancer a long time ago -- finding a mechanism for tumor cells to evade the attack of immune system, and if it prevents the immune system from shutting down, tumor can be removed. This is the source of the idea that CTLA-4 is applied to the treatment of cancer. The subsequent experiment is successful because after injecting antibody CTLA-4, almost all of the mice recover from tumors.
But clinical trials did not begin quickly. Before CTLA-4 was found, clinical trials on applying immunotherapy to treat tumors were not successful because they failed to remove the tumor forever. Therefore, even some people said that the immune system was no effect on the treatment of tumor.
Allison spent three years finding a small company that had an idea to conduct clinical trials of ctla-4 antibody. Eventually, only in the first clinical trial did he successfully remove tumor. However, there are still problems that need to be further researched if we want to apply immune system to treat all kinds of tumors.
CAR-T and prospect of immune checkpoint inhibitors
We are interested in the further development of tumor immunotherapy in the future. In the interview, Allison also shares his opinions with us.
Allison believed the CAR-T and immune checkpoint inhibitors will eventually be combined to treat disease. CAR-T has made a great success in the treatment of leukemia, which can only kill cancer cells rather than all cells at certain stages of leukemia. But it is a challenge to apply CAR-T to solid tumors because the tumor cells and normal cells have a cross-reaction, and most antigens expressed by solid tumors don’t have tumor specificity. Therefore, we still make efforts to do further research.
Several checkpoints inhibitors have made some breakthroughs. For example, in the beginning of conducting the research about five years ago, the original median survival time of melanoma was 11 months. But after the checkpoint inhibitors currently employed, 75% of the people live for three years. However, Allison said that checkpoint inhibitors are only a part of immunotherapy and cannot replace all immunotherapies. If checkpoint inhibitors are applied to treat other cancers, they maybe don’t work. That is to say, there's a lot of work to be done in order to help more patients out of cancer. In addition, patients’ responses to checkpoint inhibitors are unpredictable, so it is still a challenge to research how to use drug. For example, some patients have a strong immune response, and antibodies can quickly identify immune checkpoint molecules, but for some patients with less effective immune response, checkpoint inhibitors have little effects.
Allison said reducing the side effects of immunotherapy is far from a major problem in the treatment of cancer. Although it is impossible to remove all the side effects, we are trying to reduce side effects based on the concept of early identifying and dealing with problems. In addition, several methods used to reduce side effects have taken effects, such as adjusting the amount of antibody to conduct local delivery.