Research progress of global tumor immunotherapy

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Tumor immunotherapy has unique advantages in cancer treatment and is favored by more and more research institutions and pharmaceutical companies. Given the complexity of the immune system, cancer immunotherapy covers a variety of mechanisms of action and drug forms, with varying developments. This paper analyzes the development stage, mechanism of action and research and development institutions, and aims to explain the overall trend and direction of tumor immune drug development, and provide a basis for anti-tumor drug research and development.

1. development process

The continuous innovation of science and technology has brought about the transformation of tumor treatment mode. With the deepening of research on tumor immunology, cell biology and molecular techniques, tumor immunotherapy has flourished in laboratory research and clinical applications, and has become the fourth effective treatment method for tumors after surgery, chemotherapy and radiotherapy.

Figure 1 Development of tumor immunotherapy

Source: Based on publicly available information

2. mechanism of action

Tumor immunotherapy is a treatment method that makes the body produce tumor-specific immune response by active or passive way, and exerts its function of inhibiting and killing tumor. Tumor immunotherapy mainly includes immune checkpoint inhibitors (ICB), adoptive cell transfer therapy (ACT), tumor-specific vaccines, small molecule immune drugs and so on. Tumor immunotherapy has the advantages of specific and efficient, and can make the body free from harmful treatment. With the in-depth study of tumor immunology theory and the continuous progress of technology, it is expected to achieve a new breakthrough in the radical cure of cancer and become the mainstream method of tumor treatment.

(I) immune checkpoint inhibitors (ICB)

Immune checkpoints are inhibitory pathways that are critical for controlling the duration and magnitude of the immune response, which tumors can use to counteract immune action. Checkpoint inhibitor drugs have the ability to interfere with the immune mechanism of tumor resistance and enhance the body's immune response to tumor cells. Immune checkpoint inhibitors include the first generation of anti-CTLA-4 antibodies, the second generation of anti-PD-1 antibodies and anti-PD-L1 antibodies. The second generation of ICB is more selective and safe than the first generation of ICB. Clinical results show that the actual benefit population of ICB therapy accounts for a very small proportion of patients, and the study of ICB in combination with chemotherapy or targeted drugs to treat tumors, as well as the development of biomarker criteria for screening potential benefit populations are the key directions in the future.

(II) adoptive cell transfer therapy (ACT)

ACT is an individualized tumor treatment method, which can inhibit and kill tumor by isolating immune active cells from patients, inducing differentiation, transformation and amplification in vitro, and then returning to patients, targeting antigen-specific tumor cells. At present, CAR-T therapy (chimeric antigen receptor T cell therapy) and TCR-T therapy (T cell receptor chimeric T cell therapy) are the most effective therapies. The main side effects of CAR-T are cytokine release syndrome (CRS) and unexplained neurotoxicity. It has shown strong and lasting lethality in the treatment of malignant hematological tumors, and some progress has been made in the treatment of solid tumors.

(III) tumor-specific vaccine

Tumor-specific vaccine is a kind of therapeutic active immunotherapy, which is based on the antigen generated by tumor mutation. The tumor antigen is introduced into the patient's body to activate B cells and T cells to produce immune response and act on specific types of tumor cells, so as to prevent tumor occurrence and eliminate tumor. Compared with monovalent vaccines, the efficacy of polyvalent vaccines is relatively more secure, and the combination therapy with other immunotherapies can better reflect the value of vaccines.

(IV) small molecule immune drugs

At present, macromolecular drugs occupy a dominant position in tumor immunotherapy, and some small molecule immune drugs have made some progress due to their promising prospects. The results show that CSF1R,IDO,ALK-5,CXCR1/CXCR2 and so on in the tumor microenvironment of the cell expression, set off the research and development of the above targets. At present, CSF1R inhibitors, IDO inhibitors, ALK-5 inhibitors are in the late stage of research and development, and more basic research will be carried out in the future to complete the transformation from laboratory to hospital bed.

3. R & D institutions

The head agglomeration effect is obvious. In 2018, a total of 655 companies and institutions carried out research and development of tumor immune drugs, an increase of 42% over the same period last year. In the list of the most active companies and institutions, the top 8 are large pharmaceutical companies. At the same time, academic research institutions are also playing an increasingly important role. Among the 15 companies and institutions with more than 10 clinical trials, 4 belong to scientific research institutions, including Shenzhen Institute of immune gene therapy, General Hospital of the Chinese people's Liberation Army, and the first affiliated Hospital of the third military Medical University.

The trial focused on early clinical trials. TOP15 companies and institutions conducted a total of 213 clinical trials, of which 100 were Phase I trials, accounting for 46.9 percent of the total; 87 Phase II trials, accounting for 40.8 percent of the total; and 10 Phase III trials, accounting for 4.7 percent of the total.

4. target distribution

1. Drug development to focus on hot targets

In 2018, there were 417 targets under research worldwide, half of which focused on the top 48 hot targets. Compared with 2017, the research and development projects targeting tumor new antigens increased by 133 in 2018, and the increased targets are expected to lead to more drugs for future tumor immunotherapy.

2. CD19Increasing PD-1/PD-L1 Concern

In 2018, CD19 had 126 projects under research, an increase of 34 over 2017. PD-1 has 108 projects under research, an increase of 16 over 2017. PD-L1 has 88 projects under research, an increase of 17 over 2017, with three targets ranking the top three in terms of the number of projects. It shows that the research work is moving closer to the target with obvious effect, and it also means that the competition will be more concentrated in the future. Notably, drug programs targeting non-specific tumor-associated antigens (TAAs) are declining, indicating that the field of immunotherapy is moving towards greater precision.

Figure 3 Top10 Target Distribution of Global Projects under Research

Source: ClinicalTrials

5. listed drugs

Since 2010, the FDA has approved a series of tumor immunotherapy drugs, opening a new era of tumor immunotherapy. Among them, the most approved are monoclonal antibody immune checkpoint inhibitors, such as CTLA-4 monoclonal antibody and PD-1/PD-L1 monoclonal antibody, while cell therapies such as CAR-T are studied more fiercely. At present, only a small number of these approved therapies are listed in China, and more are in the clinical trial stage. It is expected that the domestic listing peak will be ushered in the next five years.

Table 1 List of cancer immunotherapy drugs approved by FDA since 2010 (part)

Source: FDA

6. Summary

In recent years, the basic research and scientific and technological progress in the field of tumor immunology have provided profound knowledge precipitation and technical reserves for the development of tumor immune drugs, which has promoted the explosive growth of tumor immune drugs and become the fourth tumor treatment method in parallel with surgery, chemotherapy and radiotherapy.

At present, the treatment scope of tumor immunotherapy is limited, and it can only be effective in a small number of patients. Whether the majority of cancer patients can be treated remains to be further improved in theory and technology. Small molecule immune drugs have been paid more attention because of their ability to regulate the immune pathway targets that some macromolecular drugs cannot reach, and have become an effective supplement to biological drugs in tumor immunotherapy. At the same time, the use of immune mechanisms or immune therapy and other anti-cancer drugs, radiation therapy, such as synergy, combination of drugs to enhance the therapeutic effect of increasing attention by researchers.