Nature: What challenges for CAR-T therapy when treating solid tumors?

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Nature: What challenges for CAR-T therapy when treating solid tumors?

Nature: What challenges for CAR-T therapy when treating solid tumors?  CAR-T therapy has become one of the most popular areas of immunotherapy.

Up to now, the US FDA has approved 5 CAR-T therapies to be marketed for the treatment of various types of blood cancers. However, relative to the rapid development in hematological tumors, its application in the field of solid tumors has been difficult to break through the existing limitations, which indirectly hinders the progress and development of this therapy in the field of cancer treatment.

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. Simply put, CAR-T is to transform the patient’s immune T cells in vitro through biotechnology to make them recognize antigens on the surface of tumor cells, and then inject these cells back into the patient to achieve the therapeutic effect of identifying and killing cancer cells.

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. For CAR-T therapies, suitable targets are the main reason for their efficacy and safety. If these targets are expressed on healthy tissues, even if CAR-T therapies are combined with the correct targets, they may kill healthy cells. And produce strong side effects.

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. Nature Reviews Drug Discovery’s review article pointed out that CAR-T therapies targeting multiple different targets have had serious side effects in clinical trials.

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. Among them, NY-ESO-1 belongs to the cancer testis antigen (CTA), which is usually only expressed in the testis or ovarian tissue, but in many cancers, this antigen will start to express again. Therefore, it provides a target antigen with strong specificity but weak side effects for T cell therapy.

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. Clinical results, the results showed positive clinical anti-tumor activity, and the treatment was well tolerated, no off-target toxicity, but did not achieve an objective clinical response.

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. By designing a two-step positive feedback circuit, a switch is added to CAR-T cells, which allows them to distinguish targets according to the S-curve antigen density threshold, so as to prevent CAR-T cells from killing normal cells that express low levels of tumor antigens. It also provides a key tool for conquering solid tumors.

Related results were published in Science, details: CAR-T has overcome the qualitative leap of solid tumors, only killing cancer cells, not healthy cells

The design and mechanism of action of smart CAR-T cell therapy (reference [2])

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. These modifications to CAR-T cells will help improve their specificity in the treatment of solid tumors and reduce toxic side effects.

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., as well as overexpression of TGFβ, IL-10, IL-4 and other immunosuppressive cytokines. This environment can easily lead to poor migration and persistence of CAR-T cells, impaired cell function, and cell failure, resulting in poor therapeutic efficacy.

A variety of factors that may affect the efficacy of CAR-T cells in the tumor microenvironment of solid tumors (reference [1])

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. The combination of CAR-T cells and PAK4 inhibitor drugs can make this engineered cell penetrate and attack Tumors, which significantly enhanced the survival rate of mice.

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 . Related content was published in the Journal of Experimental Medicine.

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 also can be used as a screening tool to discover new unknown T cell function regulators.

Conclusion

Overcoming the limitations of solid tumor treatment with CAR-T therapy 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.

But for a long time, compared with hematological tumors, solid tumors lack selective and highly expressed surface antigens, antigen heterogeneity, immunosuppressive microenvironment, and solid tumors’ thick physical barriers, etc., making intravenous injections” CAR-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 focus.

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. . 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.

(source:internet, reference only)

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