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T cells have always been at the center of tumor immunotherapy. In recent years, CAR-T therapy has shown its power to treat certain types of cancer, and the FDA has approved two CAR-T therapies for the treatment of lymphoma or leukemia. At the same time, there are currently hundreds of clinical studies using CAR-T therapy in the treatment of other diseases, including solid tumors.

The name of CAR-T therapy is derived from the chimeric antigen receptor (CAR), which can help immune cells recognize specific antigens.

But T cells are just one of the immune cells. By the influence of these therapies, researchers have begun to apply other types of immune cells to tumor immunotherapy, such as NK cells and macrophages.

CAR-NK therapy will likely be safer, faster to make, lower in cost, and potentially applicable to a patient population that is not suitable for general CAR-T therapy. CAR-macrophage therapy also has some advantages.

“Although these therapies are unlikely to replace the status of CAR-T therapy, these therapies may complement CAR-T therapy,” said oncologist Katy Rezvani of the MD Anderson Cancer Research Center.

Rezvani is leading a clinical study of CAR-NK therapy, which was launched in 2017, and she is planning another clinical study in the second half of this year.

CAR-T therapy requires first collecting the patient’s own T cells, and then transforming the T cells to enable them to express chimeric antigen receptors, thereby having the ability to kill specific cancer cells. Currently approved therapies target the antigen CD19.

In clinical trials, the efficacy of CD19 CAR-T therapy is striking, but there are still some problems with this type of therapy. For example, some patients have previously received multiple rounds of radiotherapy and chemotherapy, making it difficult for doctors to collect enough T cells to prepare CAR-T cells. In addition, CAR-T therapy can also produce fatal toxic reactions.

However, the biggest obstacle to CAR-T therapy today is the poor efficacy of solid tumors. CAR-T therapy may not infiltrate the tumor, and immunosuppression of the microenvironment may also inhibit the efficacy of CAR-T cells. Researchers have begun experimenting with multiple strategies to overcome these obstacles.

NK cells have some unique advantages. NK cells are the first line of defense against tumors. For more than 20 years, scientists have tried to use various methods to exploit the ability of NK cells to kill tumor cells to develop corresponding therapies, but the efficacy of these therapies is not satisfactory. Therefore, scientists hope to enhance the ability of such cells to kill tumor cells by NK cell transformation and expression of chimeric antigen receptors.

For example, at the beginning of this year, UCSD stem cell biologist Dan Kaufman and his colleagues reported a study that found that in mouse models, CAR-NK cells have similar tumor killing effects as CAR-T cells, but CRS and Less toxic side effects such as nervous system damage. Moreover, since CAR-NK cells do not rely solely on CAR to recognize tumor cells, CAR-NK cells are less likely to escape antigen than CAR-T cells.

CAR-NK cell-related clinical trials were first conducted in China in 2016, and early results indicate that these therapies are safe. Early clinical studies led by Rezvani will begin with lymphoma and leukemia. A clinical study currently underway in Europe is testing the efficacy of CAR-NK therapy in the treatment of glioblastoma.

However, there are still some unknown factors in the field, such as the source of NK cells.

There are many obvious differences between NK cells and T cells. If non-patient T cells are used for CAR-T therapy, T cells will likely attack healthy tissue cells of patients, leading to severe graft-versus-host disease. However, the use of exogenous NK cells is unlikely to trigger this response.

Although NK cells can also be extracted from donors, this operation is costly and can cause harm to patients. Therefore, two clinical studies at the MD Anderson Cancer Research Center used NK cells isolated from cord blood and were later modified to express CAR. The donated umbilical cord blood supply is relatively sufficient, and it is also possible to extract enough NK cells for culture, so it is a good source.

However, NK cells used in these clinical trials in China and Europe have evolved from cell lines derived from a single lymphoma patient. In addition, Kaufman is also trying to obtain NK cells from other sources, such as NK cells obtained from iPS cells.

All of the above methods can obtain off the shelf CAR-NK cells, thereby avoiding the trouble of taking cells directly from the patient.

The patient’s immune system will eventually clear these exogenous NK cells, but these NK cells will have a certain time window to exert anti-tumor effects before being cleared. The question at hand is whether the survival time of these cells enables them to exert sufficient anti-tumor activity and benefit patients.

Similar to NK cells, macrophages are also able to fight tumor cells. However, it should be noted that some of the macrophages in the tumor microenvironment can exert antitumor activity, but there is also a class of macrophages that can inhibit the anti-tumor immune response. Tumor cells can alter the behavior of macrophages to facilitate the growth of tumor cells.

Saar Gill, an oncologist at the University of Pennsylvania, discovered an operation that allows them to load chimeric antigen receptors into macrophages while inhibiting this functional switch of macrophages. Gill and his graduate student Michael Klichinsky founded Carisma Therapeutics, a company dedicated to research in this area. Although still in the early stages of research, progress in this area is still worth looking forward to.

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