20 18 What's the difference between traditional cancer treatment and Nobel treatment? What is tumor immunity?

Cancer immunotherapy is a technique to eliminate tumor cells by enhancing autoimmune function. Cancer immunotherapy can be divided into four categories: nonspecific immune enhancers, vaccines, adoptive therapies and immune checkpoint inhibitors.

Nonspecific immunopotentiator

Non-specific immune enhancers do not specifically target tumor cells, but achieve better anti-cancer effect by up-regulating the overall immune function of the body. As the earliest immunotherapy for cancer, non-specific immunopotentiators have been used in clinic as early as 1990s. The most common nonspecific immune enhancers include interleukin and interferon. Because the human immune system plays the role of identifying "friend or foe", the nonspecific up-regulation of its function will often cause unexpected harm to the body, resulting in more serious side effects such as flu-like symptoms, rash, leukopenia and so on. Therefore, the use of non-specific immunopotentiators is limited, and they are often used as auxiliary drugs in combination with other immunotherapy or chemotherapy.

As the representative of emerging tumor immunotherapy, tumor vaccine, adoptive therapy and immune checkpoint inhibitors have attracted more attention from researchers and the market. In this field, the technical iteration is changing with each passing day, and the emerging participants gradually form a separatist situation, and capital is pouring in, which is isomorphic with * *, and builds the forefront of the battlefield between human beings and cancer.

vaccine

At present, there are four kinds of vaccines approved by FDA for cancer treatment, namely Gardasil and Cervarix for preventing cervical cancer, hepatitis B vaccine for preventing liver cancer and Provenge for treating advanced prostate cancer.

Human papillomavirus (HPV) is considered to be the cause of more than 90% of cervical cancer, among which seven subtypes with high pathogenicity (16, 18, 3 1, 33, 45, 52, 58) can be prevented by vaccination with nine-valent HPV vaccine. Similarly, more than 90% of patients with primary liver cancer in China are HBsAg-positive patients with hepatitis B. Vaccination with hepatitis B vaccine can greatly reduce the probability of developing liver cancer.

Unlike the preventive cancer vaccine, which saves the country by preventing cancer-related virus infection, the therapeutic cancer vaccine Provenge is the first real cancer vaccine. Dendritic cells isolated from patients with this vaccine were co-cultured with prostate acid phosphatase PAP*** which was highly expressed in prostate cancer cells in vitro, so that dendritic cells could learn to recognize this specific antigen. After transfusion to patients, dendritic cells processed PAP antigen and presented it to T cells, which then found prostate cancer cells expressing PAP in vivo and put them out.

In addition to conventional cancer vaccines, some researchers also classify oncolytic viruses as a branch of cancer immunotherapy. The original "evil" virus can specifically infect tumor cells after genetic modification, and kill tumors by replicating in large numbers in cells. The principle of drug resistance of tumor cells released in this process can cause immune response and strengthen the therapeutic effect of oncolytic virus. The biggest obstacle to the application of oncolytic virus is that it is also one of the goals of immune system, so it is often necessary to use intratumoral injection or combined immunosuppressant. However, in some early clinical oncolytic virus products, intravenous injection has been tried, hoping to further expand the application prospect of oncolytic virus.

Adoptive cell therapy

From 65438 to 0984, Linda Taylor came to the National Cancer Institute to seek a cure for her advanced metastatic malignant melanoma. Cancer immunologist Steven Rosenberg received her. After a part of Taylor's lymphocytes were isolated, the researchers used a large dose of IL-2 to stimulate the lymphocytes, and the obtained lymphokine-activated killer cells (LAK cells) were transfused back into her body. Taylor's condition gradually stabilized and recovered.

In the past 30 years, history has also witnessed the technological transformation of adoptive cell therapy from the first generation LAK therapy, cytokine-activated killer cell CIK therapy, tumor infiltrating lymphocyte TIL therapy and cytotoxic T lymphocyte CTL therapy to the fifth generation chimeric antigen receptor T cell CAR-T and tumor-specific T cell receptor genetically engineered cell TCR-T. The phase I clinical results of Juno Therapeutics' CAR-T candidate therapy JCAR0 15 show that 9 1% of adult patients with acute lymphoblastic leukemia have achieved complete survival. Although the overall survival time has not been significantly prolonged, everyone has high hopes for this new technology which combines genetic engineering and cell therapy.

T lymphocytes' recognition of tumor cells depends on the combination of T cell receptor TCR and MHC- antigen complex on the surface of tumor cells. Many tumor cells have formed the ability to escape T cell recognition by reducing MHC expression in the process of continuous evolution. In view of this dilemma, on the one hand, researchers hope to find a genetically engineered TCR with high affinity for MHC- antigen complex through gene mutation and screening. On the other hand, they try to "anchor" T cells to tumor cells by allowing T cells to express receptors, bypassing MHC and directly binding to tumor cell surface antigens. These two different research directions gave birth to TCR-T and CAR-T respectively.

As an extension of traditional adoptive cell therapy, the ability of TCR-T technology to identify tumor antigens depends on the major histocompatibility complex (MHC) expressed on the surface of antigen presenting cells, which limits its application breadth and overall effect in different populations to some extent. But the biggest advantage of TCR-T is that it can not only recognize the surface antigen of tumor cells, but also recognize the antigen in tumor cells through MHC transmission, which makes the tumor types it targets much wider than CAR-T.

Although the light of the fifth generation adoptive cell therapy is dazzling, it still cannot shake the dominant position of surgery, chemotherapy and radiotherapy in the field of tumor treatment. In clinical trials, CAR-T has also exposed many problems and sticking points that need to be improved, such as unexplained disease recurrence and fatal cytokine storm.

Monoclonal antibody immune checkpoint inhibitor.

Anti-programmed death protein 1 (PD- 1) antibody is a kind of immunotherapy with the most research and the fastest clinical development. PD- 1 plays a role in the effective stage of immune response and is expressed in activated T cells, B cells and myeloid cells. It has two ligands, namely programmed death ligand-1 (PD-L 1) and PD-L2. PD-L 1/L2 is expressed in antigen presenting cells, and PD-l1is also expressed in various tissues. The combination of PD- 1 and PD-L 1 mediates the inhibitory signal of T cell activation, inhibits the killing function of T cells, and negatively regulates human immune response. China scientist Chen Lieping's laboratory discovered for the first time that PD-L 1 is highly expressed in tumor tissues, which regulates the function of tumor infiltrating CD8+ T cells. Therefore, immunomodulation targeting PD- 1/PD-L 1 is of great significance in anti-tumor. ?

PD- 1/PD-L 1 inhibitor can specifically bind to PD-L 1 on tumor cells, inhibit its expression, and make the inhibited T cells recover their recognition function to tumor cells, thus achieving anti-cancer effect through the autoimmune system.

In recent years, in the clinical research of tumor immunotherapy, a variety of PD- 1/PD-L 1 monoclonal antibodies have developed rapidly. At present, PD- 1 inhibitors Pembrolizumab and Nivolumab have been approved by FDA for advanced melanoma, non-small cell lung cancer, Hodgkin's lymphoma and head and neck squamous cell carcinoma, and Nivolumab has also been approved by FDA for the treatment of renal cancer and urothelial cancer. In addition, monoclonal antibodies such as PD-L 1 inhibitors Atezolizumab and Durvalumab have also entered several phase III clinical studies, covering many tumor species such as non-small cell lung cancer, melanoma and bladder cancer.

Cytotoxic T lymphocyte antigen 4 (CTLA-4) is a transmembrane protein expressed on the surface of activated T cells. CTLA-4 acts on the initial stage of immune response, and its activation can inhibit the initiation of T cell immune response, thus leading to the decrease of activated T cells and preventing the production of memory T cells. It is found that tumor cells can activate CTLA-4 and inactivate activated T cells, thus realizing the immune escape of the tumor itself.

Many preclinical studies have found that blocking CTLA-4 can restore the activity of T cells and prolong the survival time of memory T cells, thus restoring the immune function of the body to tumor cells and improving the tumor control rate. Therefore, specific monoclonal antibodies against CTLA-4 have been developed. ?

At present, two CTLA-4 inhibitors, Ipilimumab, have been approved by FDA for the adjuvant treatment of stage III melanoma and the treatment of advanced melanoma, while the clinical research of Ipilimumab and Tremelimumab in renal cancer, prostate cancer and lung cancer has been widely carried out. Early clinical studies showed that these two monoclonal antibodies were safe and effective whether used alone or in combination with IL-2, PD- 1/PD-L 1 inhibitors or chemotherapy.

Other monoclonal antibodies, such as OX40 and 4- 1BB monoclonal antibodies of tumor necrosis factor TNF receptor family, are still under development.

At the end of 20 14, Science magazine predicted an important breakthrough in science and technology in 20 15, and combined immunotherapy was among them. As early as the last century, people realized that cancer is far from a gene of normal cells or the change of protein, and combination therapy is the key to cancer treatment. Shanghai Dunfu Hospital is the first hospital in Shanghai to carry out tumor immunotherapy. At present, 2,500 people have been provided with tumor immunotherapy. Please contact us if you need tumor immunotherapy >>

The cornerstone of medical development is life science. With the deepening and breakthrough of the research on the phenomenon of tumor formation and development, the treatment methods for diseases will be more abundant and diverse. In the near future, the research and development of drugs with high efficiency and low toxicity for new tumor targets, the transformation of the safety and economy of cell therapy, the combined drug regimen to overcome drug resistance, and the precision medical care that focuses on prevention and early detection will be the most attractive directions in the field of tumor treatment. And immunotherapy is precisely the most promising key point!