Nature Reviews Drug Discovery: What are the challenges for CAR-T therapy to overcome solid tumors?

CAR-T therapy has become one of the most popular areas of immunotherapy.

Recently, Nature Reviews Drug Discovery published an in-depth analysis of the challenges and solutions encountered in the treatment of solid tumors with CAR-T therapy.

To put it simply: Choosing suitable targets and chimeric antigen receptors and overcoming the immune suppression of the tumor microenvironment is expected to become a new direction for CAR-T therapy to overcome solid tumors.

Find the right "target"

CAR-T, namely chimeric antigen receptor T cell immunotherapy.

CAR-T cell therapy process

Among them, the biggest clinical dilemma for CAR-T therapy is how the "bullet" chimeric antigen receptor (CAR) hits the "target" specific antigen.

In the treatment of solid tumors, it is very difficult to find a specific target that is only expressed in tumors but not in healthy tissues.

CAR-T therapy has appeared in clinical trials due to the toxic and side effects caused by binding to targets expressed in non-tumor tissues (reference [1])

At present, in the treatment of solid tumors, the "hot" targets targeted by cell therapy under investigation include HER2, EGFR, mesothelin, NY-ESO-1, PSMA and so on.

In addition, in November 2020, a sub-Journal of Science published a research article from a British research team, reporting 12 cases of neuroblastoma children after receiving a CAR-T cell therapy targeting GD2.

Transform the "bullet" that is easy to kill

In addition to finding highly specific targets, another way to improve the specificity of CAR-T therapy is to modify the receptors expressed by CAR-T cells to enhance their ability to recognize tumor cells.

Recently, researchers at the University of California, San Francisco (UCSF) designed a "smart" CAR-T cell.

Relevant results were published on Science, details: CAR-T overcomes the qualitative leap of solid tumors, only killing cancer cells, not healthy cells

In addition to the above research, scientists have also designed a variety of other "molecular switches", their functions include allowing CAR-T cells to recognize a variety of different antigens; inactivation after recognizing antigens expressed by healthy cells; or through The drug regulates the activity of CAR-T cells.

Overcome the immunosuppression of the tumor microenvironment

An important difference between solid tumors and blood cancers is the tumor microenvironment (TME) formed around solid tumors.

The tumor microenvironment contains a variety of immunosuppressive cells, such as regulatory T cells, tumor-associated macrophages, etc.

A variety of factors that may affect the efficacy of CAR-T cells in the tumor microenvironment of solid tumors

In order to overcome the impact of the tumor microenvironment, scientists have discovered that combined immunotherapy with CAR-T cells and immune checkpoint blockade will be the next frontier of immunotherapy, because it provides two elements necessary for a strong immune response:

1) CAR-T cells infiltrating the tumor;

2) PD-1/PD-L1 blockade can ensure the persistence and function of T cells.

In December 2020, the research team of the University of Pennsylvania School of Medicine published a new study online in Nature Cancer.

In March 2021, the research team at the University of North Carolina Reinberg Comprehensive Cancer Center also found that combining CAR-T cell therapy with an interferon gene stimulating protein (STING) activator can enhance the ability of engineered T cells to treat breast cancer in mice .

In addition, scientists also discovered that CRISPR gene editing technology will become a new tool for transforming CAR-T therapy.
Previously, Tmunity used gene editing to knock out the endogenous T cell receptor (TCR) and PD-1 receptor in T cells, and then expressed TCR targeting the NY-ESO-1 antigen.
The TCR cell therapy developed using this technology has shown positive effects in clinical trials.
CRISPR gene editing technology may not only help knock out genes that may affect the function of T cell therapy, but it can also be used as a screening tool to discover new unknown T cell function regulators.

Concluding remarks

CAR-T therapy overcoming the limitations in the treatment of solid tumors can be said to be one of the most urgent challenges facing this field.
In fact, about 90% of cancer cases worldwide are solid tumors, and the unmet clinical needs are still huge.
However, compared with hematological tumors, solid tumors lack selective and highly expressed surface antigens, antigen heterogeneity, immunosuppressive microenvironment, and solid tumors’ thick physical barriers.
-T cells are not only difficult to enter the tumor and combine with the tumor in the number needed to overcome the cancer, but also difficult to survive and effectively function in the unfavorable microenvironment formed by the tumor lesion.

At present, scientists have a variety of tools to adjust the characteristics of CAR-T therapy, and improve their specificity, controllability, safety, and efficacy.
It is expected to support CAR-T therapy to overcome the multiple obstacles to solid tumor treatment.
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We look forward to CAR-T therapy as soon as possible to overcome the challenges faced in the treatment of solid tumors and benefit more patients.

Original source:

Hou, AJ, Chen, LC & Chen, YY Navigating CAR-T cells through the solid-tumour microenvironment.
Nat Rev Drug Discov (2021).
https://doi.
org/10.
1038/s41573-021-00189-2.