Using T cells to target malignant brain tumors

Date:
November 15, 2021
Source:
German Cancer Research Center (Deutsches Krebsforschungszentrum,
DKFZ)
Summary:
Doctors and scientists have successfully tested a
neoantigen-specific transgenic immune cell therapy for malignant
brain tumors for the first time using an experimental model in mice.



FULL STORY ========================================================================== Doctors and scientists from the German Cancer Research Center (DKFZ) and
from Heidelberg University's Medical Faculty Mannheim have successfully
tested a neoantigen-specific transgenic immune cell therapy for malignant
brain tumors for the first time using an experimental model in mice.


========================================================================== Cellular immunotherapies that specifically target malignant tumors
are thought to be a promising approach in cancer medicine. However, a
basic requirement for this kind of targeted immunotherapy is to identify
target molecules that are found exclusively on the tumor cells and are recognized by the immune system.

Malignant gliomas are incurable brain tumors that spread in the brain
and cannot be completely removed by surgery. "Gliomas are very difficult
to treat, and the lack of suitable target structures is a considerable challenge for developing immunotherapies," explained Lukas Bunse, an immunologist at the DKFZ and a doctor at University Hospital Mannheim
(UMM).

Using an experimental mouse model, Bunse and his team have now
demonstrated for the first time that transgenic T cells targeting tumor neoepitopes can be used to treat gliomas.

Tumor neoepitopes arise as a result of genetic mutations in cancer cells
that lead to structural changes in the proteins produced. They therefore
occur exclusively in the cancer cells. Using a prediction model, Bunse and
his team identified a segment of the CIC protein (capicua transcriptional repressor) as a promising target structure for T cell attacks; around
two percent of all gliomas show a recurrent mutation in this protein.

Mice vaccinated with the CIC neoepitope developed a population of T helper cells that showed a high level of activation in response to the vaccine peptide. The researchers used particularly active T cells to isolate the
gene for the T cell receptor (TCR) responsible for epitope recognition.

They subsequently transferred the isolated TCR gene to cells and were
thus able to grow large amounts of "transgenic" T cells in a petri dish
that all had an identical, highly active TCR targeting the CIC neoepitope.

In order to study their efficacy, the researchers injected the transgenic
cells directly into the brain ventricles of glioma-bearing mice. In
combination with radiotherapy, the T cell therapy led to glioma rejection
in some of the animals.

"Here we have shown for the first time in an experimental model that a neoantigen-specific TCR-transgenic cell therapy can be effective against gliomas," explained Michael Kilian, first author of the study. "These
kinds of neoepitope-specific TCR-transgenic T cells could be used in
future in cancer patients who cannot be treated using CAR T cells,"
he added.

Chimeric antigen receptor (CAR) T cells, which have already been approved
for treating patients with B cell leukemia, can only attack tumor antigens present on the surface of the cancer cells. However, these proteins are
not usually found exclusively on tumor cells, so CAR T cells could damage healthy tissue too.

In contrast, the TCR-transgenic T cells can also attack mutated proteins
from the cell interior, which must be exposed on the cell surface by
special presentation molecules known as major histocompatibility complex
(MHC) proteins. Most T cells respond solely to antigens presented by
MHC molecules.

To achieve results that can be transferred to humans, Lukas Bunse and
his team therefore needed to work with mice transgenic for human MHC
molecules.

"Our work suggests that TCR-transgenic T cells can also be used to
treat patients with brain tumors," remarked Michael Platten, head of the Clinical Cooperation Unit Neuroimmunology and Brain Tumor Immunology at
the DKFZ and Medical Director of Mannheim University Hospital's Department
of Neurology. In collaboration with Wolfgang Wick, Medical Director of the Medical Faculty of Heidelberg's Department of Neurology, Platten and the
team of neurooncologists hope to use comparable approaches to refine the TCR-transgenic T cell therapy and to study it in early clinical trials.

========================================================================== Story Source: Materials provided by
German_Cancer_Research_Center_(Deutsches
Krebsforschungszentrum,_DKFZ). Note: Content may be edited for style
and length.


========================================================================== Journal Reference:
1. Michael Kilian, Mirco Friedrich, Khwab Sanghvi, Edward Green, Stefan
Pusch, Daisuke Kawauchi, Martin Lo"wer, Jana K. Sonner, Christopher
Kra"mer, Julia Zaman, Stefanie Jung, Michael O. Breckwoldt,
Gerald Willimksy, Stefan B. Eichmu"ller, Andreas von Deimling,
Wolfgang Wick, Felix Sahm, Michael Platten, Lukas Bunse. T
cell receptor therapy targeting mutant capicua transcriptional
repressor in experimental gliomas. Clinical Cancer Research, 2021;
clincanres.1881.2021 DOI: 10.1158/1078-0432.CCR-21-1881 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2021/11/211115123437.htm

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