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Tumor immunotherapy can treat cancer by activating the body’s own immune system. However, tumor immunotherapy is a large class of treatments, including many research directions, such as checkpoint inhibitors, tumor vaccines, oncolytic viruses, and adoptive cell transfer (ACT).

 

In general, adoptive cell therapy refers to T cell-related therapies, but other types of cells such as NK cells are sometimes used.

 

ACT therapy has many advantages over directly activating T cells in patients. For example, ACT therapy can easily amplify T cells in vitro, thereby overcoming the inhibition of immune cells by the tumor microenvironment, and can artificially select those T cells with potentially high antitumor activity.

 

In the 1960s, people’s perception of T cells was almost blank. At the time, researchers found that immune cells could mediate immune rejection in experimental animal models, but because of the lack of effective means of culturing T cells in vitro, researchers were unable to obtain sufficient amounts of immune cells for tumor therapy.

 

However, it was also found that after the radiotherapy or chemotherapy, the mice were largely cleared of immune cells, and even a small amount of immune cells were input into the mice to observe a relatively obvious anti-tumor effect.

In 1976, after the discovery of the T cell growth factor IL-2, researchers had a way to expand T cells in vitro. In 1985, researchers found that the use of IL-2 can cause long-term remission in some patients with metastatic melanoma. This has prompted researchers to begin researching related T cells and antigens that mediate this anti-tumor effect.

 

At the same time, researchers have also found that the use of IL-2-amplified tumor infiltrating lymphocytes (TIL) can also cause some solid tumor patients to be relieved.

Adoptive cell therapy with TIL

 

These studies have laid the foundation for subsequent research. In 1988, researchers first demonstrated that ACT therapy using their own TIL can produce an objective response in patients with metastatic melanoma. At that time, TIL cells mainly contained CD8+ and CD4+ T cells.

 

This is the first direct evidence that T cells can mediate a strong anti-tumor immune response: T cells play a crucial role in the body’s anti-tumor immunity.

 

However, the duration of this anti-tumor effect is generally short-lived, and the reinfused T cells disappear in the patient’s body after a few days.

A very critical advance in this field stems from a discovery in 2002 when studies have shown that the use of certain chemotherapy regimens to remove immune cells from patients before TIL cell reinfusion can increase the anti-tumor effect of TIL and prolong these cells. The survival time in the body.

 

However, researchers have long discovered that this therapy is generally only effective for melanoma. In order to expand the range of applications of ACT therapy, some people in the 1990s began to use genetic engineering to transform T cells to express specific receptors. These studies have also spawned the maturity of TCR-T and CAR-T therapy.

Last year, the FDA approved the launch of two CAR-T therapy-related products, and also ignited the enthusiasm of the pharmaceutical industry and investors for cell therapy. But the field still faces a lot of obstacles.

Cassian Yee is a professor of melanoma oncology medicine and immunotherapy at the MD Anderson Cancer Center and one of the pioneers of ACT therapy. Cassian Yee is the leading leader in MD Anderson’s ACT technology platform.

Currently, Cassian Yee is mainly engaged in three potential research directions for ACT therapy. One is the well-known CAR-T therapy and the other is TIL therapy. In addition, his team is still studying endogenous T cell therapy. ETC).

Unlike the first two therapies, ETC therapy does not require the acquisition of immune cells from tumors, nor does it require genetic modification of T cells. Instead, it relies on T cells with antitumor activity present in peripheral blood of patients to treat cancer.  Generally, such cells are extremely low in peripheral blood and are difficult to separate and expand.

Cassian Yee’s laboratory has isolated a variety of T cells that target antigens that are widely distributed across multiple types of tumors. The Cassine Yee team has now used ETC therapy to treat multiple advanced cancer patients who have failed traditional treatments, and some patients have a sustained, complete response after treatment. Moreover, they found that the same benefits may be benefited in patients who fail to checkpoint inhibitor treatment.

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