Immunotherapy to deal with glioma, cell typing is the key!

The results of a new mouse model study by the University of Michigan Health Rogel Cancer Center show that a single common gene mutation or error may be the key to making immunotherapy more effective against glioma

In a subset of these brain and nervous system tumors, the conversion of a single amino acid from arginine to histidine triggers a series of changes.

After discovering this sensitivity and mapping out the underlying mechanism, the research team discovered a blood growth factor secreted by tumors containing this mutation.

The co-author of the study, Dr.

In a mouse model of glioma without IDH1 mutations, given G-CSF (a blood growth factor produced by their mutated cousin), the median survival time more than doubled

Even low-grade gliomas are fatal and eventually recur after a combination of chemotherapy, radiotherapy, and surgery

"This is an inevitable fate, so we really need new therapies," Castro said

First, they need a mouse model

When the research team started the study, there were no mouse models of this low-grade glioma subtype.

In this way, they can better study the biological effects of mutations and the effects of gene therapy that stimulates the immune system on mice with or without mutations

The treatment method is called TK+Flt3L, which is used for the immunostimulatory gene therapy mediated by herpes simplex virus type I thymidine kinase plus Fms-like tyrosine kinase ligand, which is the same as the treatment method developed by the research team.

Lowenstein said: "For non-mutated tumors, when we treated animals with immunotherapy, it improved survival, and at the end of the experiment, a considerable number of tumors were tumor-free, more than 20%

The biggest question at the time was: Why is this happening?

By using many complex technologies including single-cell RNA sequencing, researchers have found that in non-mutated tumors, because of the unknown immunosuppressive cell population in the tumor microenvironment, the effect of immunotherapy is poor

However, the first author, Dr.

The single amino acid difference in IDH1 is enough to change the function of the enzyme, causing it to produce a new metabolite-2-hydroxyglutaric acid, or 2HG

Castro added: "The role of this metabolite is to trigger a very profound epigenetic remodeling-that is, it changes the expression of genes in tumor cells

The research team gradually pieced together the pictures, and it was G-CSF that changed the immunosuppressive cells in the tumor microenvironment, causing them to no longer have an immunosuppressive effect

Basic research to clinical application

With this knowledge, further experiments have shown that giving G-CSF (an immune system enhancer that has been clinically used in cancer patients) to mice with non-mutant IDH1 can also increase their survival rate
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Using it in combination with immunostimulatory gene therapy has had a greater impact
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The research team also confirmed that patients with mutant IDH1 gliomas also have higher levels of G-CSF in the blood—a clue that suggests that the findings will be applicable outside of mouse models
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Lowenstein said that the next step will be to transfer these findings to clinical trials based on the currently ongoing immunotherapy/gene therapy combination trials
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"Our research shows two main things: Due to the generation of G-CSF tumors, patients with IDH1 mutations may benefit from immunotherapy," he said
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"Patients without mutations may benefit from a combination of G-CSF and immunotherapy
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Mahmoud S.
Alghamri, Brandon L.
McClellan, Ruthvik P.
Avvari, Rohit Thalla, Stephen Carney, Margaret S.
Hartlage, Santiago Haase, Maria Ventosa, Ayman Taher, Neha Kamran, Li Zhang, Syed Mohd Faisal, Felipe J.
Nú ñez, María Belén Garcia-Fabiani, Wajd N.
Al-Holou, Daniel Orringer, Shawn Hervey-Jumper, Jason Heth, Parag G.
Patil, Karen Eddy, Sofia D.
Merajver, Peter J.
Ulintz, Joshua Welch, Chao Gao, Jialin Liu, Gabriel Núñez, Dolores Hambardzumyan, Pedro R.
Lowenstein, Maria G.
Castro.
G-CSF secreted by mutant IDH1 glioma stem cells abolishes myeloid cell immunosuppression and enhances the efficacy of immunotherapy .
Science Advances , 2021; 7 (40) DOI: 10.
1126/sciadv.
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