Glioma subtype may hold the secret to the success of immunotherapies


Date:
September 29, 2021
Source:
Michigan Medicine - University of Michigan
Summary:
A common mutation in gliomas sensitizes them to immunotherapy,
a finding which researchers believe could have broader therapeutic
implications for all glioma patients.



FULL STORY ==========================================================================
A common mutation in gliomas sensitizes them to immunotherapy, a finding
which researchers believe could have broader therapeutic implications
for all glioma patients.


==========================================================================
A single common genetic mutation, or error, may hold the key to making immunotherapy more effective against gliomas, according to new mouse
model findings from the University of Michigan Health Rogel Cancer Center.

The flip of a single amino acid from arginine to histidine in a subset
of these brain and nervous system tumors sets off a series of changes
that, it turns out, sensitizes them to treatment with immune-stimulating therapy, to which they would otherwise be largely resistant.

Having discovered this sensitivity and mapped the underlying mechanisms,
the research team identified a blood growth factor secreted by tumors
harboring the mutation -- one already used by doctors to stimulate
the production of white blood cells and reduce the risk of infection
in patients receiving chemotherapy -- that holds promise for making
treatments against gliomas more effective. The findings appear in
Science Advances.

"It's been known for about a decade that patients with low-grade gliomas
that have this IDH1 mutation have a much longer median survival,"
said the study's co-senior author Maria Castro, Ph.D., a professor of neurosurgery and cell and developmental biology at U-M. "We set out to try
to understand why, and to see if there were any differences that could be harnessed to improve outcomes more broadly." In a mouse model of glioma without the IDH1mutation, administering G-CSF, the blood growth factor
produced by their mutant cousins, more than doubled median survival
times. When immunotherapy was also added in, the effect was even more
profound, the study found.



==========================================================================
Even low-grade gliomas are uniformly fatal, eventually coming back after treatment with some combination of chemotherapy, radiation and surgery.

"It's an inescapable destiny, so we really need new therapies," Castro
said.

First, they needed a mouse model When the team started, there weren't
any mouse models for this low-grade glioma subtype, one with the
IDH1mutation and two other mutations that are always found with it. So,
they developed one.

Doing so allowed them to better study the biological impact of the
mutation as well as the effects of an immune system-stimulating gene
therapy on mice with and without the mutation.



==========================================================================
The treatment, called TK+Flt3L, for herpes simplex type-I thymidine
kinase plus Fms-like tyrosine kinase ligand-mediated immune stimulatory
gene therapy, is the same one that was developed by the group and
then deployed in a Phase 1 clinical trial against glioblastoma at U-M (NCT01811992) led by study co-senior author Pedro Lowenstein, M.D.,
Ph.D., a professor of neurosurgery and of cell and developmental biology.

"For the non-mutant tumors, when we treated the animals with the
immunotherapy, it improved survival and there were a significant number,
more than 20%, that were tumor-free at the end of the experiment,"
Lowenstein said. "But in the mice with the IDH1mutation, we saw a really profound effect -- 90% survived long-term and remained tumor free."
The big question then was why.

Using a number of sophisticated techniques including single-cell RNA sequencing, the researchers discovered that in the non-mutant tumors, immunotherapy was less effective due to a previously unknown population
of immune-suppressing cells in the tumor microenvironment.

In the tumors with mutated IDH1, however, these same cells were present,
but they functioned differently and had lost their immune-suppressive properties, explained first author Mahmoud Alghamri, Ph.D., a postdoctoral research fellow in the Castro-Lowenstein lab.

The single amino acid difference in IDH1was enough to change the enzyme's function and cause it to produce a new metabolite -- 2-hydroxyglutarate,
or 2HG.

"What this metabolite does is elicit a very profound epigenetic
remodeling - - that is, it changes the gene expression within the tumor
cells," Castro added. "And what we found was that this leads to the
production and release of a blood growth factor called granulocyte colony-stimulating factor, or G-CSF." And it is G-CSF that causes
changes to the immune-suppressive cells in the tumor microenvironment,
causing them to stop being immune-suppressive, the team painstakingly
pieced together.

Bench-to-bedside Armed with this knowledge, further experiments showed
that giving G-CSF, which is already used clinically as an immune system
booster in cancer patients to mice with non-mutant IDH1also increased
their survival. And giving it in combination with the immune-stimulating
gene therapy had an even bigger impact.

The team also confirmed that patients who have gliomas with mutated
IDH1also have higher levels of G-CSF circulating in their blood --
a clue that the findings will be applicable beyond the mouse models.

The next step, says Lowenstein, will be to work on moving these findings
into a clinical trial, building on the current, ongoing trial using the immunotherapy/ gene therapy combination.

"Our study shows two main things: Patients with the IDH1mutation
may benefit from immunotherapy due to the G-CSF their tumors
are producing," he said. "And patients without the mutation may
benefit from combining treatment with G-CSF and immunotherapy." ========================================================================== Story Source: Materials provided by
Michigan_Medicine_-_University_of_Michigan. Original written by Ian
Demsky. Note: Content may be edited for style and length.


========================================================================== Journal Reference:
1. 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.

Nu'n~ez, Mari'a Bele'n 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 Nu'n~ez, 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.abh3243 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/09/210929154202.htm

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