The world's first cervical cancer patient survived for more than five years after receiving TIL cell therapy. One patient with advanced breast cancer survived for two and a half years without cancer, and one fatal liver cancer and another patient with advanced colon cancer achieved an amazing recovery.

Why TIL cell therapy can save patients with advanced cancer

TIL is a tumor-infiltrating lymphocyte that contains surgically resected tumor tissue, mostly tumor cells, and a small number of lymphocytes.

Scientists can amplify lymphocytes in these tumor tissues by some culture methods. Simply put, the TIL cells are isolated and expanded from the surgically resected tumor tissue. The expanded cells are mainly CD4 and CD8 T cells, and then cultured in vitro for a sufficient number of TIL cells, which are returned to the patient to exert anticancer effects. . Based on these ideas, TIL cell therapy is rapidly evolving, and NCI's big cow Rosenberg is the promoter of this technology.

But it is undeniable that there are not many cancer patients who can benefit from this cell therapy. So why are patients with the same cancer type not getting similar treatments?

One of the important reasons is:

Hundreds of types of T cells in the body, not every one can become a good cancer warrior. The reinfused TIL cells are a mixture of many cells and have not been specifically screened. Some TIL cells are specific to tumors and some are not specific. Scientists always like to ask questions, of course, to improve efficiency.

To explore which specific types of cells in these mixed cells are tumor-specific, Rosenberger has done a lot of clinical exploration:

1. Finding tumor cell-specific muteins by gene sequencing, and then screening specific TIL cells for this mutation to be returned to patients. Although clinically shown to be very effective, this approach is too personal and cumbersome.

2. Through screening, look for specific biomarkers on the surface of tumor-specific TIL cells, but there are not many relevant researches.

New research finds "bystanders" in TIL cells

Nowadays, with the progress of TIL, CAR-T and PD-1/PD-L1 in the field of tumor immunotherapy and research, scientists have concluded that immunotherapy will be the main direction for cancer in the future. But low efficiency is still the pain point of immunotherapy. In order to achieve wider success, scientists have been digging deep into the resistance mechanism behind them in recent years. As an old-fashioned topic in the field, the doctor has repeatedly reported on relevant research progress.

Most studies have focused on the combination of therapeutic regimens (TIL combined with PD-1) and the exploration of predictive biomarkers for response and resistance immunotherapy to further understand the antigen specificity of tumor infiltrating immune cells to improve the effectiveness of immunotherapy.

There is a class of white blood cells called tumor infiltrating lymphocytes (TIL) in tumors that are associated with treatment outcomes for most cancer types. TIL (called CD8+ TIL) expressing the cell surface glycoprotein CD8 can detect and destroy tumor antigens on the surface of cancer cells.

Therefore, many immunotherapeutic strategies aim to stimulate, enhance and maintain the cancer killing ability of CD8+ TIL cells. However, CD8+ TILs are highly heterogeneous cell populations, not only between different patients but also with tumor types. In addition, researchers know very little about the antigens that activate them.

Recently, a study led by A* STAR (Singapore Science and Technology Research Institute) found that a class of "bystander" T cells present in human lung and colorectal tumors is closely related to the patient's response to immunotherapy. It has a major impact on immunotherapy including TIL, CAR-T and PD-1/L1. The relevant research results were published in the internationally renowned journal Nature.

Dr. Evan Newell from the Singapore Immunology Network, a research institute of the Singapore Science and Technology Research Agency (A*STAR), and colleagues used large-scale cytometry to study patients with lung cancer or colorectal cancer. Antigen specificity of CD8 + TIL in tumors.

Consistent with previous reports, they found that only a small fraction of the CD8+ TIL population was able to recognize tumor-associated antigens. But at the same time, the team also found that a large number of CD8 + TIL (bystander cells) are not sensitive to tumors.

Newell said: "It is very surprising to be able to detect tumor-unrelated CD8+ TILs in human tumors. After all, these cells are infected against other common viruses and should not be present in tumors."

CD39 becomes a key molecule in distinguishing tumor-associated TIL

High patient expression benefits from PD-1 treatment

The researchers found that differences in CD39 expression are key molecules in distinguishing tumor-associated or unrelated CD8+ TIL cells.

CD39 is a molecule involved in chronic immune cell stimulation and is usually up-regulated in a variety of malignant solid tumors, the level of expression of which is related to the stage and severity of the disease.

In this study, 9 out of 24 lung cancer patients and 21 of 42 colorectal cancer patients, two types of TIL cells with different sensitivity to cancer were found, one of which is different from tumor-specific CD8 + TIL. They do not express CD39 molecules.

After transcriptome analysis, the researchers found that the level of CD39+CD8+ TIL expression-related genes is associated with cell proliferation and depletion, which is the T cell characteristic of chronic antigen stimulation. In addition, CD39+ CD8+ TIL isolated from lung cancer and colorectal cancer tumor tissues showed phenotypic and functional depletion characteristics.

This indicates that the activity of these tumor invasive T cells is inhibited, but the anticancer ability still exists. Therefore, there is only one difference between immune cells and anticancer to rescue tumor suppression, and immune checkpoint inhibitor (PD-1) /L1) Don't let it happen.

A colorectal cancer patient experienced a rapid immune response after receiving the PD-1 antibody Keytruda (pembrolizumab).

After analyzing its peripheral blood, the researchers found that CD8+ TIL in peripheral blood of patients highly expressed CD39. That is, changes in CD39+ CD8+ TIL cells in peripheral blood can predict whether a patient can benefit from PD-1 antibody immunotherapy.

In addition, as explained by Newell, the cd39 antibody expression level of CD8 + TIL in 50% of EGFR-mutant lung cancer patients is very low and almost impossible to find, which is the same as the low response rate of patients with PD-1 antibody immunotherapy. Closely related.

Therefore, this new finding may be important for the treatment of such tumors, and CD39 may be a predictive biomarker for tumor-specific CD8 + TIL and patient response to CD8 + TIL-directed cancer immunotherapy.

Currently, in addition to testing whether CD39 can be a useful biomarker, Newell and colleagues are also investigating other cancer types and TILs, such as CD4+ T cells, to determine if similar principles apply.

In conclusion, whether CD8+ TIL cells express CD39 or predict the patient's response to PD-1 antibody therapy is of great help in screening TIL and CAR-T cells for screening for more potential anti-cancer T cells. Further expand the population benefiting from immunotherapy.