Professor Qu Yan from the expert lecture hall: Prospects and challenges of immunotherapy for glioma

Glioma is the most common primary malignant tumor in the central nervous system, accounting for about 81% of central nervous system malignant tumors
.

Although a comprehensive treatment method based on surgery and assisted by multiple methods such as radiotherapy, chemotherapy, electric field therapy, and targeted therapy has been formed, the clinical prognosis of patients with glioma is still not optimistic

Glioma

In the past decade, immunotherapy has greatly changed the clinical outcome of tumors
.

Immune checkpoint inhibitors are currently one of the most well-researched and widely used immunotherapies, and they have shown significant anticancer effects in most tumors

In the past decade, immunotherapy has greatly changed the clinical outcome of tumors

Including chimeric antigen receptor (CAR) T cell therapy, cytokine therapy, oncolytic virus therapy and tumor vaccines

Although the application of immunotherapy in glioma faces great challenges, there are still a large number of preclinical and clinical trials of immunotherapy for glioma, especially glioblastoma (GBM), have been completed or are in progress, and a number of related studies They have shown great potential in the treatment of gliomas
.

Immune checkpoint blocking therapy is one of them

PD-1/PD-L1 is an important immunosuppressive target for tumor cells to escape from the body's immune killing
.

However, the current phase III clinical trials of PD-1/PD-L1 monoclonal antibody for the treatment of GBM have ended in failure

Therefore, clinical trials of immune checkpoint blocking therapy combined with other targeted therapies are underway and a breakthrough is expected
.

Animal studies have shown that the combined treatment of anti-PD-1, anti-TIM-3 and local radiotherapy can induce a reduction in the volume of mouse gliomas; combined blockade of IDO, CTLA-4 and PD-L1 can make gliomas tumor-bearing The animal survives for a long time

CAR-T cell therapy is another promising immunotherapy.
Its treatment principle is to establish an engineered transgenic T cell that can express the antigen binding domain of tumor-specific protein antibodies.
The signal transduction molecules related to T cell activation are connected, so that T cells can be activated quickly after contacting tumor cells to play a role in cellular immunity
.

At present, 5 CAR-T therapies have been approved by the FDA for marketing, but the approved CAR-T therapies are all targeted at hematological malignancies.

Recently, a study designed a trivalent CAR-T cell targeting three glioma antigens (IL13Rα2, HER2 and EphA2), which can recognize almost 100% of GBM
.

Although CAR-T cell therapy has shown great potential, the adverse effects such as cytokine storm and nervous system toxicity caused by it need to be further studied

Another immunotherapy strategy is to use dendritic cells (DC) to load tumor-specific peptides, tumor cell lysates, tumor-derived mRNA, viral antigens, or tumor stem cells to prepare DC vaccines based on the individual composition of gliomas.

.
Since the main function of DC cells is to present antigens to T cells and B cells, after the DC vaccine is inoculated into the patient's body, it can induce a tumor-specific immune response, thereby killing tumor cells
.
Successful preclinical research has promoted many clinical studies using DC vaccines
.
A phase I/II clinical study (NCT00846456) used DC vaccine loaded with GBM stem cell mRNA to treat patients and found that the progression-free survival of patients in the treatment group was 2.
9 times longer than that of the control group
.
In a phase I clinical study of newly diagnosed GBM patients, the use of DC vaccines specifically targeting epidermal growth factor receptor variant III (EGFR vIII) and hemocyanin also achieved good results.
The average patient population The survival time was extended to 22.
8 months
.
In another study, 18 newly diagnosed GBM patients received DC vaccine treatment, and 16 received only conventional treatment
.
The results showed that compared with the control group (15.
0 months), the overall survival of the DC vaccine group was significantly increased (31.
9 months)
.
However, due to the existence of tumor heterogeneity, the efficacy of single-target glioma DC vaccines is often not ideal.
Therefore, the development of DC vaccines loaded with multiple antigens has very important clinical significance
.

Tumor-associated macrophage (TAM) therapy is also a method of tumor immunotherapy that has been widely studied in recent years
.
Tumor-associated macrophages generally refer to macrophages that accumulate in the microenvironment surrounding tumors to promote tumor progression
.
The infiltrating TAM in glioma is mainly immunosuppressive M2 macrophages, which not only leads to the formation of immunosuppressive tumor microenvironment, but also promotes the progression of glioma
.
Since the differentiation and survival of TAM depend on colony stimulating factor (CSF), CSF-1 inhibitors such as BLZ945 and PLX3397 have become the main drugs for TAM therapy
.
BLZ945 has been used to treat mouse glioblastoma models.
The results show that BLZ945 can reduce the proportion of M2 macrophages in tumors, thereby reducing tumor volume and improving survival
.
PLX3397 has been confirmed to pass through the blood-brain barrier of living animals.
In a mouse model of glioblastoma, it can reduce the number of tumor-associated microglia and inhibit tumor invasion
.
A phase II clinical study evaluated the safety and effectiveness of PLX3397 in the treatment of 37 patients with recurrent glioblastoma.
The results showed that PLX3397 has good safety, but the treatment effect was not statistically significant
.
So far, TAM suppression strategies have only been tested and evaluated in mouse models and small clinical trials, and have not yet been approved by the FDA
.
Therefore, this therapy still needs a lot of in-depth research to prove its efficacy
.

Tumor-associated macrophage (TAM) therapy is also a tumor immunotherapy method that has been widely studied in recent years

In addition, there are virus therapy, cytokine therapy and immunostimulation gene therapy, etc.
These immunotherapy methods have shown certain therapeutic potential in specific glioma populations
.
However, clinical studies on these immunotherapies have not been applied in larger randomized trials, because the characteristics of the patient population with better response to these immunotherapies are not clear
.
Therefore, effective identification of predictors of patients' responsiveness to specific immunotherapy, stratification of patients who meet the treatment conditions and selection of the most suitable immunotherapy, can better show its therapeutic effect
.

At present, various new immunotherapy strategies have obtained good results in preclinical and clinical studies of various gliomas
.
Some therapies have also found significant therapeutic effects in clinical trials
.
With the deepening of research and the accumulation of data, more meaningful progress will be made in immunotherapy for glioma
.
However, whether these programs can ultimately be applied to the clinic, there are still many obstacles and difficulties that need to be overcome, the most important of which is the tumor heterogeneity of gliomas, individualized selection of multiple targets, combined treatment strategies of multiple immunotherapies, or immunity Multi-therapeutic combined treatment strategies such as treatment and targeted therapy may be an important research direction to solve this problem in the future
.
Secondly, the evaluation of the therapeutic response of immunotherapy is another problem.
In the future, a standardized imaging and molecular biology evaluation system needs to be established to reflect and predict the curative effect of patients
.
With the resolution of these problems, immunotherapy is expected to become an important part of the treatment of glioma in the future
.

At present, various new immunotherapy strategies have obtained good results in preclinical and clinical studies of various gliomas
.
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