Which pancreatic cancer patients respond to immunotherapy?

Which pancreatic cancer patients respond to immunotherapy? New biomarkers are expected to predict.

Pancreatic cancer has the title of king of cancer, and the difficulty of treatment can be imagined.

In recent years, the application of immunotherapy has changed the treatment pattern of many cancers. However, pancreatic cancer has never been able to take off the title of “king of cancer”.

Oncologist Dr. Michael Castro (who has been awarded the “Top Doctors in the United States” for many years) pointed out that due to the special immune microenvironment of pancreatic cancer, the current immunotherapies are difficult to function and the clinical benefits are greatly limited.

However, recently, a new study by the University of Pennsylvania Abramson Cancer Center team showed that the inflammation in the blood can be used as a new biomarker to identify those that do not respond to the immunotherapy drug CD40 agonistic antibody. Of patients with advanced pancreatic cancer. The research was published in “JCI Insight”.

▌”The King of Cancer” Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. It is currently the third leading cause of cancer deaths in the United States. Although it accounts for only 3% of newly diagnosed cancer cases, it accounts for more than 7% of all cancer deaths. The survival rate is only 10%.

According to the latest data from the World Health Organization, the number of new cases of pancreatic cancer in China in 2020 is about 125,000, ranking eighth in the number of new cases of cancer. In 2020, the number of deaths from pancreatic cancer in China is about 122,000, ranking among cancer deaths. The sixth reason.

In recent years, the incidence of pancreatic ductal adenocarcinoma has been on the rise, with insidious onset and lack of specific symptoms in the early stage. Most patients are found to be late and miss the best opportunity for treatment.

Pancreatic cancer can cause systemic inflammation and can be easily detected in the blood. More and more studies have shown that inflammation plays an important role in the occurrence and development of pancreatic cancer, and it is expected to become an important target in the diagnosis and treatment of pancreatic cancer.

The new study found that when a CD40 agonist is used in combination with the chemotherapy drug gemcitabine, the overall survival rate of pancreatic cancer patients with systemic inflammation is worse than that of patients without inflammation.

▌Agitated antibody: the “good brother” of PD-1

In recent years, immune checkpoint suppression drugs represented by PD-1/PD-L1 have become popular therapies. By blocking immune checkpoints, improving immune cell activity and killing tumors, it is like loosening the “brake” of immune cells. ;

The agonistic antibody “steps on the accelerator” for immune cells (such as dendritic cells) by activating antigen presentation, thereby “activating” immune T cells and enhancing the activity of macrophages, thereby killing tumor cells.

According to Dr. Li Fubin, a researcher, doctoral supervisor, and chief scientist of Perpetual Bio, Shanghai Jiaotong University School of Medicine/Shanghai Institute of Immunology, Dr. Li Fubin said that agonistic antibody drugs have a history of more than ten years of clinical research, with antagonistic antibodies, cell therapy, etc. Once a breakthrough is made in the different mechanisms of action of tumor therapy, it will have great potential for single-drug therapy or combination therapy.

Tumor necrosis factor receptor (TNFR) superfamily members are important tumor immunotherapy targets.

The TNFR superfamily is known to have 29 members (including CD40). The agonistic antibody against TNFR is considered to be one of the immunotherapies with the same therapeutic potential as immune checkpoint inhibitors.

However, previous studies have shown that CD40 agonist combination therapy can shrink tumors in only about half of patients.

Now, using systemic inflammation as a predictor of treatment resistance can help guide treatment decisions and future research, and provide researchers with new exploration targets.

▌Systemic inflammation: promising as a biomarker for CD40 agonists

“CD40 is a very potential target, especially in pancreatic cancer, agonistic antibodies show great promise. However, these agonistic antibody drugs face the problem of lower than expected efficacy in some patients.”

Researchers believe that they have not only discovered a potentially powerful biomarker, but also discovered an important role in the immune system that has been neglected in the past, and they may drive resistance mechanisms.

Researchers analyzed the blood samples of 22 PDAC patients to understand the immune mechanism of agonistic immunotherapy + chemotherapy.

The results showed that most patients were depleted of B cells, monocytes and dendritic cells within 8 days, and CD4+ T cells were activated. However, they found that there was no obvious correlation between T cell activation and prognosis. These findings pose challenges for preclinical research.

On the contrary, the overall survival result is related to the systemic inflammatory response in the blood of the patient detected before treatment. The systemic inflammatory response is characterized by neutrophils, inflammatory cytokines (including interleukin-6 and interleukin-8) and increased acute phase reactants in the peripheral blood, which are signs of pancreatic cancer and other cancers one.

In patients with systemic inflammation before treatment with CD40 agonist + gemcitabine, the median overall survival was only 5.8 months, while the median overall survival of patients without inflammation from the start of treatment was 12.3 months.

Studies have shown that gemcitabine chemotherapy can eliminate monocytes and dendritic cells, which is essential to promote T cell immune response.

However, the team’s previous research has shown that CD40 agonists can make PDAC more sensitive to gemcitabine chemotherapy. Therefore, T cells may not always be needed in the successful results of CD40 agonist combined with chemotherapy.

“Inflammation seems to have a suppressive effect on the immune system, thereby hindering the effectiveness of immunotherapy.” Next, the researchers will look for a combination of therapeutic drugs that can help suppress inflammation and help the immune system promote T cell responses.

▌Agitated antibodies can be expected in the future

At present, a total of 6 agonistic antibodies targeting the TNFR superfamily have entered the clinical stage, namely TNFRSF4 (OX40), TNFRSF5 (CD40), TNFRSF7 (CD27), TNFRSF8 (CD30), TNFRSF9 (4-1BB) and TNFRSF18 ( GITR).

Among them, Apexigen’s CD40 agonistic antibody drug has entered clinical phase II and has been granted orphan drug designation by the FDA for the treatment of esophagus and gastroesophageal junction cancer (GEJ) and pancreatic cancer. The FC variant used on the company’s platform is exactly the FC variant validated in an article published by Professor Li Fubin in “Science” 7 years ago.

China’s Perpetual Bio has applied for a global patented technology for the constant region of agonistic antibodies, which is applicable to multiple TNFR superfamily IO targets.

The agonistic antibody with optimized framework region developed by Perpetual Bio has significantly improved activity compared with the natural, unmodified agonistic antibody in the framework region. And because the optimized antibody activity is more dependent on the tumor environment, the antibody can act more on the tumor, thereby reducing the toxicity of the drug.

(source:internet, reference only)

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