Overview of CAR T cell therapy for the treatment of malignant brain tumors in children

Antonio Pérez-Martínez et al.
, from the Center for the Transformation of Pediatric Oncology Research at La Paz University Hospital in Spain, describes the application
of CAR T-cell therapy in high-grade CNS tumors in children such as medulloblastoma, high-grade glioma and ependymoma.

The article was published in the October 2021 issue
of Cells.

——Excerpt from the article chapter

【Ref: Ferreras C, et al.
Cells.
2021 Oct 29; 10(11):2940.
doi: 10.
3390/cells10112940.
】

Research background

Childhood central nervous system (CNS) tumors are solid malignancies, including medulloblastoma (MB), high-grade glioma in children, and ependymoma
.

High mortality from solid malignant brain tumors in children, especially in young children, with a particularly poor prognosis for disseminated tumors, with a 5-year survival rate of 15%-30%; And the cost of treatment can be high, which can have serious side effects on the developing brain, leaving serious sequelae such as neurodevelopmental, endocrine, cognitive and secondary tumors
.

Recently, advances in immunology have reported the success of chimeric antigen receptor T (CAR T) cells in the treatment of
hematologic malignancies.

CAR T-cell immunotherapy opens up new avenues
for targeted treatment of brain tumors.

Antonio Pérez-Martínez et al.
, from the Center for the Transformation of Pediatric Oncology Research at La Paz University Hospital in Spain, describes the application
of CAR T-cell therapy in high-grade CNS tumors in children such as medulloblastoma, high-grade glioma and ependymoma.

The article was published in the October 2021 issue
of Cells.

Research Methods

CAR T cells exert immune system function to treat malignant tumors
.

CAR T cells involve genetic modifications of autologous or donor T cells to recognize specific antigens; Intracellular signals then trigger CAR T cell activation, which in turn secretes perforin/granzyme and inflammatory cytokines to kill tumor cells
.

In addition to identifying tumor-specific antigens, CAR T cells can also target tumor-associated antigens (TAAs) and immunosuppressive cells
within the tumor microenvironment (TME).

Results of the study

The FDA has approved CAR T for the treatment of refractory large cell B lymphoma, acute lymphoblastic leukemia, mantle cell lymphoma, follicular lymphoma, and multiple myeloma; Anti-CD19 CAR T cells have the same effect on recurrent B-cell malignancies in children and adults, with a complete remission rate of 70%-94%.


CAR T cells have several advantages over chemotherapy drugs, including the ability to target a variety of tumor antigens
.

However, due to the lack of specific tumor antigens, CAR T cells are unable to transport to the tumor site, avoiding T cell activation, proliferation, and survival, resulting in the failure
of CAR T cell therapy for solid tumors.

For special cases of brain tumors, the difficulty of drug transmission through BBB and the avoidance of inflammation or the associated toxicity of any other treatment must be considered
.

Abramson et al.
reported that anti-CD19 CAR T cells could target diffuse B-cell large lymphoma cells in the central nervous system, indicating that CAR T cells can bypass BBBs, a feature that supports further research into the use of CAR T cells for the treatment of brain tumors
.

Certain studies have also shown that CAR T cells can be effectively transported
in children's CNS.

The brain of a child patient is developing, and any damage can lead to lifelong side effects
.

At present, most clinical trials have focused on the treatment of adult glioblastoma (GBM), which has shown some efficacy; Demonstrating the feasibility and safety of CAR T cells in the treatment of brain tumors can further expand the treatment research path
for pediatric patients.

Whereas, the research on CAR T cell therapy is mainly aimed at adult GBM patients and hematologic malignancies
.

There are differences in central nervous system tumors in children and adults, and the findings obtained from adults cannot simply be applied to children
.

Therefore, the new strategy must be adapted to the unique characteristics
of children's CNS tumors.

Future CAR T cell therapy strategies need to consider tumor lack of TAA, heterogeneity, BBB spreadability, TME, and clinical trial sample size
.

There is also a need to develop new therapies such as Exo-CAR T and nanotechnology; Its characteristics and advantages are promising treatments
.

CAR T cells have a low success rate in clinical trials of solid brain tumors and are multifactorial influences; Among them, heterogeneity of tumor antigen expression, limited infiltration of T cells in tumors, and immunosuppressive tumor microenvironment (TME) are the main obstacles
.

For childhood brain tumors, there are other challenges, including anatomical location, BBB barrier, specific immune function of the CNS, and avoidance of toxicity
.

For surgical treatment, the site is a key
.

When applying CAR T cell therapy, the heterogeneity of BBB in different childhood brain tumors must be considered, such as the presence of vascular structural abnormalities and BBB disabatement in the WNT-type medulloblastoma, which is conducive to the entry
of antitumor drugs.

Understanding the state of BBB and how controlling it can enhance the efficacy of
CAR T cell therapy.

The composition of TME in the tumor microenvironment is critical
to elucidating the therapeutic response of CAR T cell therapy.

TME is formed
by the close interaction between tumor cells and non-tumor cells.

Different immunosuppressive cells are regulatory T cells (Tregs), tumor-associated macrophages (TAM), and myeloid suppressive cells (MDSCs), whose expression is associated
with immunosuppression, tolerance, and stability of the internal environment.

In addition, tumor cells can express immunosuppressive ligands, inhibit T cell activity, increase T cell depletion, and promote the formation
of harmful TME.

Children's brain tumors exhibit "cold tumor" properties that are closely related
to CAR T cell therapy responses.

The low tumor mutation load in childhood brain tumors makes it almost impossible to produce neoantigens, making it more difficult to find targets for CAR T cell therapy and affecting T cell activation and immunotherapy response
.

Conclusion of the study

In summary, the current research on CAR T cell therapy mainly targets adult GBM patients and hematologic malignancies
.

Given the differences in central nervous system tumors in children and adults, the results obtained from adults may not be suitable for use in children
.

Therefore, the new strategy must be adapted to the unique characteristics
of children's CNS tumors.

Future CAR T cell therapy strategies need to consider the characteristics
of tumor TAA, heterogeneity, BBB spreadability, TME, and number of patients.

Exo-CAR T and nanotechnology could be promising new technologies
.