A new study in Nature-Cancer successfully prevented the growth of neuroblastoma in mice by modifying CAR-T cells. This means that CAR-T cells that usually only have a good effect on hematological tumors can also play a role in solid tumors.

This not only means that neuroblastoma may be treated with CAR-T, and if the ideas in the study are , perhaps the confinement of CAR-T in solid tumors will finally be broken.

We need to know that the most basic chimeric antigen receptor is usually formed by the fusion of the extracellular tumor antigen binding domain and the intracellular CD3-ζ chain. The former can help T cells target tumors, and the latter can provide immune initiation signals.

Then there are two ways to enhance the function of CAR-T. One is to increase the extracellular antigen recognition area to enhance the ability to hunt tumors; the other is to enhance internal signals to maintain the growth and metabolism of T cells. Let it exist in the body longer.

The former is easier to understand, because there are usually a variety of antigens on the surface of tumor cells, and CAR-T cells can usually recognize some of these antigens after modification to attack the target. We only need to add external targets that attack different antigens at the same time to improve the anti-cancer ability of CAR-T. This is also the recently emerging dual-targeting CAR-T concept.

Compared with CAR-T cells that recognize only one antigen, these dual-target T cells can track the whereabouts of cancer cells more efficiently and prevent them from evading the immune system.

For internal modification, in the past few generations of CAR technology update iterations, chimeric antigen receptors have basically added some costimulatory molecules, including CD28 and 4-1BB, etc., costimulatory molecules can maintain and enhance CAR-T The function and proliferation ability.

However, past studies using a single costimulatory molecule on dual-target chimeric receptors have found that this cannot control tumor growth for a long time, nor can it solve the problem of solid tumors. Therefore, the research team at the University of North Carolina decided to introduce the signals of two costimulatory molecules at the same time and carry them on different dual-target receptors to further promote the ability of CAR-T cells.

The study used neuroblastoma as the test target, and CAR-T cells also carry the target binding regions of the tumor antigens GD2 and B7-H3, and the two chimeric receptors each carry a costimulatory molecule CD28 Or 4-1BB. This dual target-dual signal CAR-T can completely kill cells in vitro after being co-cultured with neuroblastoma.

In the mouse experiment, the researchers introduced neuroblastoma cells into the mice, and the mice using only a single antigen target would suffer tumor recurrence soon after. However, the previous generations of CAR-T methods cannot prevent the tumor recurrence process. Only dual target-dual signal CAR-T cells can achieve this goal and control tumor growth.

And the mice receiving the new therapy can still achieve the effect of tumor control even if they undergo the tumor re-stimulation process. The test results show that after 2 and 4 weeks of treatment, high levels of dual target-dual signal CAR-T cells can still be detected in the mice. This means that such cells can last forever in the body.

From the test results, this advantage may come from the mutual assistance of the two signals in the cell. For example, the chimeric receptor of CD28 and 4-1BB can improve the signal effect of CD3-ζ and enhance the metabolism and proliferation of T cells.

In general, the study provides a new idea of using CAR-T to solve solid tumors. However, the specific costimulatory molecules to be used need to be determined according to different tumor environments.