Significantly different from traditional methods such as surgery, radiotherapy and chemotherapy, immunotherapy of tumors is a "revolution" for human health and the bio-industry. Many industry insiders believe that the success of this field may have won the Nobel Prize in recent years. So who is the hero in the field? What is its scientific basis?

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

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 had much therapeutic effect to date. 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.

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 ways 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.

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. This type of T cell was discovered in 1995 by the famous Japanese scholar Professor 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 antibody/anti cd86 antibody 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 perform well in antiviral function.

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.

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 immunotherapy in the future. New approaches and combinations will continue to emerge.

The biggest hero in 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.