T Cell and Tumor Immunotherapy: The Next Nobel Prize Hot?

T Cell and Tumor Immunotherapy: The Next Nobel Prize Hot?

March 23, 2015 Source: Bio Valley

Dong Chen (Professor, Institute of Immunology, Tsinghua University)

In recent years, good news about cancer immunotherapy has continued to come. The emergence of a series of results made the US Science magazine in 2013 to promote tumor immunotherapy as the biggest scientific breakthrough of the year.

Several advances have been particularly eye-catching: following the US Food and Drug Administration (FDA) 2011 approval of anti-CTLA4 (cytotoxic T cell antigen-4 antibody) for the treatment of melanoma, PD-1 (programmed cell death 1 Antibodies were also approved for use in similar tumors in 2014, and the phase III clinical trial of lung cancer was terminated early; CAR-T (chimeric antigen receptor T cell immunotherapy) technology has also been a great success in the treatment of leukemia.

For a time, many insiders believe that the success of this field may have won the Nobel Prize in recent years. So who should win the prize? More importantly, what is the scientific basis for these developments?

T cell therapy is in the ascendant

The T cells in our body are mainly a class with αβ T cell receptors, and there are two kinds of CD4 and CD8 molecules. CD4 T cells primarily secrete cytokines to regulate the function of other immune cells and are therefore referred to as helper T cells. CD8 T cells are called killer T cells, and they specifically recognize and kill virus-infected cells.

Immunologists have long wanted to use vaccines to trigger the function of tumor-specific CD8 T cells, thereby destroying tumors. Vaccines against viral antigens have a good preventive effect against tumors caused by human papillomavirus (HPV) and hepatitis B virus (HBV). However, therapeutic tumor vaccines, including vaccines that use dendritic cells, have not been as effective as they are today. Dendron, a biopharmaceutical company based in Seattle, USA, has a dendritic cell vaccine for prostate cancer. It has been FDA-approved and its stock has soared, but it has recently closed down due to poor treatment.

Another idea in the immunology community is to reinject the T cells of a tumor patient into the patient, but the tumor-specific T cells in the patient's blood are generally less. Dr. Steven Rosenberg of the American Cancer Institute has discovered a new approach. He is also a surgeon and has access to a large amount of tumor tissue for experimentation. His laboratory amplifies T cells in melanoma tissue with a T cell receptor activator and growth factor-interleukin 2. Many T cells in tumor tissue are treated for treatment. These T cells are returned to the patient and have a better therapeutic effect. According to what I know about MD Anderson, about 50% of melanoma patients have a treatment response using this treatment called "Adoptive T Cell Therapy." .

However, for other tumors, especially non-solid tumors, it is not necessarily as strong as melanoma, or it is difficult to collect T cells with strong tumor specificity. Some scientists have thought of adding surface receptors for tumors to the general CD8 T cells in the patient's blood so that they can also attack the tumor. CAR-T is a method of recognizing a receptor for a CD19 molecule expressed by all B cells with a signal transduction region capable of causing T cell activation to form a so-called chimeric artificial receptor. This receptor-expressed T cell can attack and destroy all cells expressing CD19. Now this technology is in the ascendant, has significant efficacy in the treatment of leukemia, and is being tried for solid tumors. Many CAR-T biotech companies are hot.

An important "brake" of the immune system

Since many tumors, especially melanoma, have tumor-specific T cells, this suggests that the immune system can recognize tumors and try to control them, but why can't they destroy them? Do we still have a way to promote the function of these T cells?

T cells have a strong lethal effect on virus-infected cells, but there are many ways in which our body can make CD8 T cells attack their normal tissue cells without misjudging. This involves the theory of co-stimulatory factors in immunology. Ronald Schwartz, a scientist at the National Institutes of Health (NIH), discovered that T cell activation requires not only the first signal of the T cell receptor, but also the second signal, mainly from the CD28 receptor. ICOS (inducible costimulatory molecule) is another co-stimulatory receptor. The author's laboratory has done a lot of work at the beginning of this century. Recently, Mr. Bohai, a professor at the Institute of Immunology, Tsinghua University, has made a new breakthrough. Only two signals are available, and T cell proliferation and function are the strongest. The CD28 receptor is expressed in T cells, while its ligands CD80 and CD86 are derived from antigen presenting cells. Under normal conditions, or when there is a tumor, CD80/CD86 expression is relatively low. Therefore, the body does not develop autoimmune diseases, and the immunity to the tumor is not strong. But according to Professor Charles Janeway of the former Yale University, activation of the innate immune system leads to high expression of CD80/CD86 and T cell function is very strong. In view of this consideration, many scholars are also thinking about how to enhance the second signal to tumor-specific T cells, such as OX40 and 4-1BB through the tumor necrosis factor TNF receptor family. The chimeric receptor of CAR-T combines the first and second signals.

Dr. James Allison, who is currently in the Department of Immunology at MD Anderson (the former department head of the author), has taken another strategy. In addition to CD28, CD80/CD86 has another receptor, CTLA4, which is expressed after T cell activation. Chinese scholar Tak W. Mak and Professor Arlene Sharpe of Harvard University, through the study of CTLA4 knockout mice, found that these mice died of autoimmune diseases shortly after birth. Therefore, CTLA4 is a vital "brake" in the immune system. Dr. Allison thought of blocking CTLA4 function by antibodies to enhance the lethality of CD8 T cells on tumors. His research team proved that this method is feasible through the study of mouse tumor model. Mederax Biotech, which was later acquired by Squibb, produced humanized CTLA4 antibodies based on these results and conducted clinical trials for melanoma treatment. Approximately 20% to 30% of advanced patients have a response, but the most encouraging is that the two-year survival rate is quite good. The FDA approved the drug very smoothly.

Regarding the mechanism of action of CTLA4 antibodies, Dr. Allison recently found that its role may not or not only block the binding of CTLA4 and CD80/CD86, but remove a class of CD4 T called regulatory T cells. cell. These T cells were discovered in 1995 by the famous Japanese scholar Shimon Sakaguchi. There is increasing evidence that regulatory T cells play an integral role in maintaining immune tolerance in the body, they are also abundant in tumors and highly express CTLA4. Therefore, CTLA4 antibodies may enhance tumor immunity by removing regulatory T cells. This also explains why patients with CTLA4 antibodies often develop autoimmune diseases.

Looking for better antibodies

The PD-1 molecule was discovered in 1992 by the famous Japanese immunologist Professor Tasuku Honjo. From 1998 to 1999, his team reported that PD-1 is expressed in both B and T lymphocytes and plays a negative regulatory role similar to CTLA4.

They found that PD-1 gene-deficient mice developed autoimmune disease, but were much slower and lighter than CTLA4-deficient mice. PD-1 has two ligands, all of which have amino acid sequence similarity to CD80/CD86 molecules. The first ligand, PDL1, was first discovered in 1999 by a Chinese immunologist, and was proved to be a ligand for PD-1 in 2000 by the laboratory of Benedict. Another ligand, PDL2, was reported in 2001 by the Arlene Sharpe Laboratory, a professor at Harvard Medical School.

PDL1/L2 is expressed in antigen-presenting cells, and PDL1 is also expressed in various tissues. The display flat laboratory first discovered that PDL1 is highly expressed in tumor tissues and regulates CD8 T cells in tumors. In 2006, Professor Rafi Ahmed of Emory University in the United States discovered that PD-1 controls the "depletion" of CD8 T when chronically infected with viruses, so that T cells do not function well.

Due to the success of CTLA4 antibodies, several companies have also produced PD-1 antibodies. The Japanese company Uno and Squibb, who are co-operating with Prof. Benedict, have produced PD-1 antibodies. In addition, Merck, Roche, and AstraZeneca have antibodies to PD-1 or PDL1. Squibb and Merck have first achieved breakthroughs in the clinical trial of PD-1 antibody against melanoma. They have better therapeutic response than CTLA4 antibody and have lower side effects. They were officially approved by the drug regulatory authorities in Japan and the United States in 2014. Various cancer treatments such as lung cancer, lymphoma and kidney cancer have good effects. In addition, CTLA4 combined with PD-1 antibody is far superior to single antibody in terms of melanoma treatment response and multi-year survival rate.

In addition to CTLA4 and PD-1, there are other negative-regulating co-stimulatory factors, such as Display Flat, B7-H3, which our laboratory and Tak W. Mak have studied, as well as Display Flat, James Allison, and our laboratory. B7-H4/B7S1/B7x and so on. The function of these molecules on tumor immunity is unclear. In the treatment of melanoma, drugs that target these molecules may be less toxic than CTLA4 antibodies, or better than existing drugs in the treatment of other tumors. I think this field will once again become a hot spot in immunology.

Immunotherapy enters a new era

For cancer diseases, we have entered a new era of immunotherapy. Immunotherapy is achieved by modulating the immune system, especially the function of CD8 T cells, which is significantly different from previous surgery, radiotherapy and chemotherapy for tumors.

The breakthrough in immunotherapy is inseparable from the basic research of immune tolerance. Overcoming the body's immune tolerance mechanism will be the main goal of future immunotherapy. New approaches and combinations will continue to emerge.

The biggest contributor to this field is generally considered to be James Allison. For more than a decade, he has been committed to transforming basic research results into clinical treatment and is the standard bearer in the field of cancer immunity. Others who may have won the Nobel Prize together are Dr. Benedict and Dr. Shimon Sakaguchi, who is often referred to by immunologists, but Shimon Sakaguchi may also be awarded another prize for discovering regulatory T cells with other scholars.

Tumor immunotherapy is a "revolution" for human health and the bio-industry. There are so many cancer patients in China, what should we do?

The author thinks that there are still many opportunities in this area. The best treatment plan for various tumors has yet to be finalized, and we can catch up. However, we must vigorously develop basic research. Only when China develops a number of world-class oncology immunization laboratories (I don't think there is one now), we may have original drugs appearing constantly, so that we can have the chance to win the Nobel Prize 10 years later. Otherwise, our cancer patients can only rely on foreign pharmaceutical companies for treatment. (Bio Valley Bioon.com)

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