A promising approach against certain blood cancers

(UCLouvain press release [FR])

In 2020, Sophie Lucas and her research group at the de Duve Institute succeeded in neutralizing a molecule responsible for blocking immune defenses in cancer. A clinical trial has been launched to test this new immunotherapy by combining it with another, already used but not always effective in melanoma and lung or bladder cancers. Today, the same team, and in particular Sara Lecomte and Julien Devreux, discovered that their immunotherapy is also effective against certain blood cancers, this time without having to combine it with another. Their discovery is promising because these blood cancers are difficult to treat. It is published in Blood, a high-impact journal in the field of hematology and immunology.

Years of research

This result is part of a long history of research conducted by the president of the de Duve Institute and WELBIO investigator.

2004 : Sophie Lucas tries to understand the functioning of so-called regulatory T-lymphocytes (T-REGs), which block immune responses in the event of cancer.
2009 : she discovers the GARP molecule on the surface of T-REGs.
2018 : the group succeeds in understanding the role of GARP: sending signals in order to block immune defenses. Sophie Lucas and her team develop a tool, anti-GARP antibodies, to block the sending of these signals. This discovery is published in the journal Science.
2020 : the results of the first tests combining this new immunotherapy with another, already widely used, are promising. They are published in Nature Communications and mark the launch of a first phase of tests, currently underway, with an industrial partner.

An immunotherapy to combat solid and liquid cancers

Today, Sophie Lucas' group has succeeded in demonstrating that the anti-GARP antibodies developed in the laboratory are very effective against some blood cancers, often called "liquid cancers", whereas they had been developed and are being tested for "solid" cancers (bladder, lung, intestine, etc.). Moreover, the new treatment works alone in these blood cancers, without having to combine it with another immunotherapy.

For the scientists, this was an unexpected discovery. They had known for long that GARP, the molecule targeted with the antibodies, is expressed on immunosuppressive T-REG cells, but also on platelets and megakaryocytes (cells in the bone marrow that produce platelets), which are abnormally abundant in certain blood cancers.

Effective... for an unexpected reason

« We studied these blood cancers in particular because they are accompanied by an abnormal proliferation of megakaryocytes and platelets. We thought it would be interesting to target these cancer cells with our anti-GARP antibodies », explains the president of the de Duve Institute. The results were conclusive... but there was a surprise! « Indeed, platelets and cancerous megakaryocytes do express GARP, but it is not because our antibodies target these cells that they are effective, it is because they target the T-REGs. We didn't expect that at all! » The focus - blood cancers, megakaryocytes, platelets... - actually explains why Sophie Lucas' team worked with hematologists (including Julien Devreux) and why the study is published in a hematology journal, Blood.

The UCLouvain scientists are thus opening up a promising new avenue for fighting certain blood cancers.

Anti-GARP antibodies developed by the laboratory of Sophie Lucas are currently tested in a phase I trial to treat patients suffering from so-called “solid” cancers (cancers of the bladder, or lung, or colon … ). Recent work from the lab now shows that these antibodies could also serve to treat blood or bone marrow cancers called myeloproliferative neoplasms. Although these “liquid” cancers are usually quite difficult to treat, the anti-GARP antibodies exerted therapeutic activity in mice even when used alone (as a “monotherapy”), by acting on immune-suppressive cells called Tregs.
This is the first demonstration that anti-GARP antibodies can serve as an immunotherapeutic approach for blood cancers.

mAb: monoclonal antibody
Treg: regulatory T cell
BM: bone marrow
GARP: molecule present on Tregs and megakaryocytes
TGF-ß1: immunosuppressive cytokine produced by Tregs thanks to GARP

Article describing this research

Therapeutic activity of GARP:TGF-β1 blockade in murine primary myelofibrosis.
Lecomte S*, Devreux J*, de Streel G, van Baren N, Havelange V, Schröder D, Vaherto N, Vanhaver C, Vanderaa C, Dupuis N, Pecquet C, Coulie PG, Constantinescu S, Lucas S.
Blood (2022) 141(5): 490-502

In the press

LeSoir.be - Cancer: des chercheurs de l’UCLouvain découvrent une immunothérapie prometteuse - 29/12/2022

WELRI.org - GARP dans le cancer : l'histoire continue... - 9/01/2023

EngineeringNet.be - Une immunothérapie se révèle efficace contre certains cancers du sang - 12/01/2023

RTFlash.fr- Une immunothérapie se révèle efficace contre certains cancers du sang - 14/02/2023

Aussi sur MSN.com

Funding

This work was supported by grants from the Fondation contre le Cancer, from the European Research Council (ERC), from the Actions de Recherche Concertées, from the FNRS, from the Région Wallonne and from WELBIO.