August 11, 2022

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Pancreatic cancer: PD-1+TIGIT+CD40 combination trials are about to start

Pancreatic cancer: PD-1+TIGIT+CD40 combination trials are about to start

 

 

Pancreatic cancer: PD-1+TIGIT+CD40 combination trials are about to start. PD-1+TIGIT+CD40, three-drug combination to eliminate pancreatic cancer, clinical trials are about to start. 


Pancreatic Cancer is a highly malignant gastrointestinal malignant tumor that is difficult to diagnose and treat.

In recent years, the incidence and mortality of pancreatic cancer have increased significantly. The early diagnosis rate of pancreatic cancer is not high, and it is often found at an advanced stage. At this time, cancer cells have spread. Although some chemotherapy drugs are effective, they usually develop drug resistance. Cancer immunotherapy is also difficult to work. The 5-year survival rate of pancreatic cancer is less than 7%, and it is the malignant tumor with the worst prognosis, so it is also called the “king of cancer.”

According to the latest WHO data, pancreatic cancer is the seventh cancer in China in 2020 (an estimated 120,000 new people will be added in 2020), and the sixth cancer in death (an estimated 120,000 deaths in 2020).

But recently MIT researchers have developed a three-drug combination immunotherapy strategy that can eliminate pancreatic tumors in mice and help enhance the body’s immune defense against tumors. It will enter clinical trials later this year. .

On August 5, 2021, MIT researchers published a research paper titled: The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer in Cancer Cell.

A group of researchers developed an immunotherapy strategy-PD-1 inhibitor + TIGIT inhibitor + CD40 agonist, which can eliminate pancreatic tumors in mice. This three-drug combination strategy can enhance the body’s immune defense against tumors and will enter clinical trials later this year.

 

Pancreatic cancer: PD-1+TIGIT+CD40 combination trials are about to start

Pancreatic cancer: PD-1+TIGIT+CD40 combination trials are about to start

 

 

T cells in the human immune system can recognize and destroy tumor cells that express oncoproteins, but most tumors will produce a highly immunosuppressive tumor environment, inactivating these T cells and helping tumors escape and survive.

Currently, the most widely used immunotherapy in clinical practice is immune checkpoint blocking therapy, which relieves the inhibition of tumor cells on T cells and rejuvenates T cells, thereby destroying tumors.

Blocking the interaction between PD-1 and PD-L1 through PD-1/PD-L1 inhibitors has successfully treated a variety of cancers, and many PD-1/PD-L1 inhibitors have been approved for use It is used in the treatment of melanoma, lung cancer and other cancers, and has achieved beneficial effects. However, they have little effect on pancreatic cancer.

Researchers speculate that the failure of immune checkpoint inhibitors against pancreatic cancer may be due to the fact that pancreatic tumors express too few neoantigens, which leads to insufficient targets for T cells. Therefore, even if T cells are stimulated by checkpoint inhibitors, They also cannot recognize and destroy pancreatic tumor cells.

However, some recent studies have shown that many pancreatic tumors actually express cancer-specific neoantigens. At this time, researchers suspect that in addition to the PD-1/PD-L1 system, there are other similar systems that restrict pancreatic cancer. T cell function.

In this Cancer Cell paper, the research team used a mouse model of pancreatic cancer to conduct research and found that PD-L1 was not expressed at high levels in pancreatic cancer. Most pancreatic cancer cells highly express CD155 protein, which can activate the TIGIT receptor on T cells.

When TIGIT is activated, T cells will enter a “T cell exhaustion” state, in which T cells cannot attack pancreatic tumor cells.

The research team further analyzed pancreatic cancer tissue from patients with pancreatic cancer and observed that about 60% of pancreatic cancer patients expressed TIGIT expression and T cell depletion. They also found that the expression of CD155 on the patient’s tumor cells was high.

The research team pointed out that the function of CD155/TIGIT is very similar to PD-L1/PD-1. Tumor cells highly express CD155. When TIGIT-positive T cells encounter any tumor cells that express CD155, they will enter a state of T cell exhaustion. Causes T cells to be turned off.

Next, the research team began to explore whether they could use this discovery to rejuvenate depleted T cells and attack pancreatic tumor cells. The research team tested various combinations of experimental drugs that inhibit PD-1 and TIGIT, as well as CD40 agonistic antibodies. The CD40 agonistic antibody is currently in clinical trials for the treatment of pancreatic cancer. It can activate T cells and drive them into tumors.

In mouse experiments, the research team found that PD-1 inhibitors have almost no effect on pancreatic cancer. The combination of CD40 agonistic antibodies and PD-1 inhibitors or TIGIT inhibitors can partially inhibit tumor growth, but does not significantly shrink tumors. .

However, when the CD40 agonistic antibody is used in combination with PD-1 inhibitors and TIGIT inhibitors, the effect is very significant. About half of the pancreatic tumors in pancreatic cancer mice receiving this treatment have shrunk, and even more so. 25% of mouse pancreatic tumors disappeared completely. In addition, the tumor did not recur after stopping treatment.

 

Pancreatic cancer: PD-1+TIGIT+CD40 combination trials are about to start


It is reported that the MIT team cooperated with the Lustgarten Pancreatic Cancer Research Foundation, which funded this research, and found two pharmaceutical companies, planning to advance the three-drug combination therapy to clinical trials later this year.

At present, we still do not have a good choice to treat pancreatic cancer. It is a devastating disease clinically. If this method can produce a long-lasting response in patients, it will undoubtedly be a huge problem for patients with pancreatic cancer. good news.

 

(source:internet, reference only)


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