Collection: History of human tumor immunotherapy: from history to the future.

.
cancer is a typical multicellular proliferation out-of-control disease. It is generally believed that life on Earth occurred in multicellular life 600 million years ago, and the existing sponge-like porous animal gate is the earliest multicellular animal. Human diseases are somewhat related to congenital underdevelopment, while others are related to acquired injuries. there are only four major systems in the

the human body: metabolism,
immunity
, endocrine and nerves, all diseases associated with these four mechanisms. Physiological regulation and pathological function of the human body are also often associated with these four conditions.

catalog


, history of immunodevelopment

second, immunology principle

THIRD, major anti-cancer immunotherapy

IV, immunotherapy
V, immunotherapy toxicity and efficacy assessment

VI, the interpretation of ICIs resistance

7, clinical application

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immune system is a multicellular animal specialization system The primitive basic mechanism sexist in single-celled animals is the basis of complex mechanisms after multicellularization, and such as the molecular system CRISPR-Cas system in single-celled animals is an immune mechanism that maintains single-cell stability.


. In 1909 Paul Ehrlich proposed the theory of immunosurveillance, arguing that the immune system can contain the occurrence of tumors, and that immune dysfunction is one of the basic causes of cancer.

1959 Frank Macfarlane Burnet and Lewis Thomas (former MSK President) put forward the "tumor immune surveillance" hypothesis that the immune system can recognize and remove malignant tumors, thereby inhibiting the development of tumors.

in 2002 Gavin P Dunn and Robert D Schreiber first proposed the
Tumor Immunology
editing theory, which systematically describes the three-stage relationship between cancer and the immune system.


. Second, the basic principles of anti-cancer immunology

more than 100 years of human immune system unremitting research, has been the main problems in this field have some shallow understanding.
Professor Showing summed up the human understanding of anti-cancer immunity as a summary of the three basic questions: Is there any? What is the state of immunogenicity? The relevant factors that initiate anti-cancer immunity.
:

. (a) Is there an immune response to remove cancer cells from the human body?answer is yes!

1868, a man named William. For the first time, Doctors at Wilhelm Busch reported a significant reduction in tumors after infecting
cancer patients
with Danvenom. In 1891, William J. William B. Coley (1862-1936) began treating cancer by injecting bacteria into tumors, creating the "Coli toxin" therapy. This method is not yet effective and can lead to death from infection; improved mixed heating bacterial fluid becomes safe, and many people with malignant tumors in this method are indeed alleviated, even long-term, without cure. The exploration of early immunotherapy, once suppressed, has been recognised today and named the highest prize in the immune world. Collie Award.

such as cytokine therapy, pass-through immunocellular therapy and immunodot inhibitor therapy have been proven, including ICIs, which has a certain percentage of patients in most cancer species to obtain efficacy, and previous chemotherapy and
molecular targeting
the mechanism of treatment is completely different.

(ii) is there a specific antigen to trigger a specific immune response to remove cancer cells?

the source of cancer cells and human cells themselves, the existence of antigens, but after the immune editing of cancer cells antigen is weak, it is difficult to effectively stimulate the immune response. In addition, there are complex immunosuppression or immune escape in the tumor microenvironment, resulting in the immune response can not be effectively completed.

antigen segeny is the starting point for stimulating immune response, and this issue needs to be fully studied in the future. Professor Thierry Boon of Belgium has been studying cancer cell antigens for a long time. Is there an antigen unique to cancer cells for a cancer lesions that have entered the clinical phase and are progressing (continuous proliferation or metastasis in situ) ? Does the progression of the disease have a substance that human cells have not expressed at any time of antigen properties (immunogenicity)?

currently look at the field of cancer antigens have the following point of view:

cancer cells have unique antigens? Or shared? For example, some CEA/AFP proteins from human foetus are now unclear. After cancer, these genes, which should have sunk, are reactivated and heavily expressed. It is not known whether cancer cells are disorderly or functional expressions. Are there genes specifically expressed by cancer cells? At present, there is, very little, either less expression, either has been immune, or immunogenicity is insufficient.

Belgian scholar Thierry Boon, who has long studied cancer anti-cancer antigens, says the antigens of cancer cells are the main problem. The deficiency of antigen is an important reason that the current release of TME immunosuppression/escape can only solve some of the problems.


. BOX: Cancer antigen problem: no antigen, no immune response

antigen itself factors

foreign

the relationship between antigen and the body's species, the greater the difference, the stronger the immunogenicity. 1) Interspecies: pathogenic microorganisms, animal immune serum is good antigen to humans.

2) Substances interthestical: ABO blood type antigen system on the surface of human red blood cells and tissue compatibility antigens on the skin and organs of the isosome. 3) self-antigen: its own substances are generally antigen-free.

a: the
of their own substances (such as crystalline proteins) that have never been in contact with lymphocytes

b: changes in their physical physical and chemical traits (trauma, infection, drugs, ionizing radiation, etc.)

physical and chemical traits 1) molecular size

generally speaking, the greater the molecular weight, the stronger the antigen. Substances with antigens, molecular weight is generally more than 10.0kD, individual more than 100.0kD, less than 4.0kD generally does not have antigen.

2) the complexity of chemical structures

. Protein, aromatic amino acids are the main, especially tyrosine-containing proteins, strong antigens, non-aromatic amino acids are the main, antigens are weak.

3) Molecular conformation and accessibility

. 4) Physical state,

general polymerization state of the protein is stronger than its monomer immunogenogenic, particle-borne antigen is stronger than soluble antigen.

immune pathways and antigen doses

antigens with the above conditions can be immunized differently depending on the route and dose of the body.

artificial immunity, most antigens are non-transverse into (intracutorin, subcutaneous, muscle, vein, celiac injection) before the body has antigen.

the relevant factors in the body

1) the evolutionary relationship between the host and the antigen source

2) the genetic background of the host

3) the health and nutritional status of the body

the above factors are to some extent mutually constrained. How does

(iii) stimulate the anti-cancer immune response?

stimulate the immune response involves many complex aspects, if you have the time and energy to do a frame like Daniel Chen, as things stand, we are still in the darkroom, only occasionally found a few molecular switches, more complex networks have not yet been discovered.


.Writing in the journalChristian U Blank of the Netherlands describes seven factors that affect the immune response to cancer and is mapped in radar. It can be classified into several categories:

(1) cancer cells themselves: if there is anaerobic solution level LDH, antigen load on the surface of the cell membrane, MHC expression, negative feedback effect of PD-L1 expression.

(2) in the blood: chronic inflammatory levels reflected by CRP, IL-6; Just as the physiological autoimmune response is to remove aging waste metabolites in the body, the IgM rapid removal mechanism is used, and if the pathological autoimmune response requires the use of chronic inflammatory response mechanism, IgG system. Another is the number of immune cells circulating in the blood, which reflects the host's immune system state.

(3) microenvironment: Til in TME reflects whether immune cells can enter the final stage, which stops with local immunosuppression or immune escape.

it's worth noting that Blank didn't discuss the value of microecology in anti-cancer immunity, perhaps because of the lack of detectable standards. Microecology is an important direction, and the Science Journal's Cancer Immunotherapy album has been specifically published.

Three, major anti-cancer immunotherapy

a long history of anti-cancer immunotherapy, first in 1868, a named William. For the first time, doctors at Wilhelm Busch reported a significant reduction in tumors after intentionally infecting cancer patients with danpoison. erysipelas is an infection that affects the seofi-skinned lymphatic tubes, mainly caused by group A beta-hemolytic streptococcus. Induced factors are surgical wounds or nostrils, outer ear canals, lower earlobes, anus, penis and toe fissures.

1891, The American Memorial Hospital, The Osteopathic Dr. William. William B. Coley (1862-1936) began treating cancer by injecting bacteria into tumors, creating the "Coli toxin" therapy. This method is not yet effective and can lead to death from infection; improved mixed heating bacterial fluid becomes safe, and many people with malignant tumors in this method are indeed alleviated, even long-term, without cure. As more safe and effective radiotherapy began to become available in the early 20th century, Colitoxin therapy was banned by MSK hospitals until it was later banned by
ASCO
, although THE ASCO eventually lifted the ban. Later, Corrie's daughter inherited her father's legacy and invested heavily in cancer immunotherapy research. The exploration of early immunotherapy, once suppressed, has been recognised today and named the highest prize in the immune world. Collie Award.

based on known immunology principles, it is speculated that the mechanism of treating cancer with bacterial infection is to increase the body's response to tumors by bacterial antigens, and that both congenital and acquired immunity are active. Bacteria and auto-aging damage cells, i.e. cancerous cells, are removed by the same immune mechanism, there is no strict boundary between them, and even a considerable number of functions are overlapping.however, humans have not found reliable immunotherapy for a long time due to the limitations of human cognition of this mysterious system in their small universe. Until two immunotherapy methods appeared:






1. Antibody treatment for cancer cells

there are some special antigens in cancer cells, humans use the principle of immunoasory antibodies to remove them for the purpose of treating cancer, these treatments have achieved some efficacy.

herceptin seinita: growth stimulation factor for cancer cells, i.e. human epidermal growth factor receptor-2, HER2). The gene, the c-erbB-2 gene, is positioned on chromosome 17q12-21.32 and encodes a transmembrane receptor-like protein with a relative molecular mass of 185,000, with tyrosine kinase activity. The receptor is blocked and lags, and the growth and metastasis of cancer cells is inhibited. But because cancer cells have more than one growth stimulator, even if the cancer cells initially express the receptor, only about 50 percent of the patients initially are effective at this treatment, and almost all patients will be resistant to the antibody treatment within a year.


.

. 2. Intercytic matter, such as
blood vessels
is a necessary for cancer lesions and is a treatment for intercellular themes in cancer lesions.

. AVASTIN (Beva monovirus): Antibodies against VEGF, a cytokine, can trigger an antibody reaction to remove this cytokine, block ingesttheon of new blood vessels in the body to block the progression of cancer, at the expense of the body's normal vascular rebirth physiological processes are also disturbed.

. 3. Immune detection point inhibitor (ICIs)


immunotest point refers to some activation and inhibitory receptor regulation switches located on the effect T cell, the use of activated antibodies can activate the function downstream of the receptor (activation or inhibition), activation can make The T cell in an attack state, inhibition.