Immuno-oncology: Institut Curie and Mnemo Therapeutics highlight a new approach to identify unknown therapeutic targets
The human genome is commonly divided into two broad categories. 4% of the genome codes for proteins and the remaining 96% is made up of non-coding or very little known elements: this is called the "dark genome". The "grey genome", also known as the part of the dark genome that is annotated, transcribed and sometimes translated, represents about 45% of the total human genome. These genomic regions have been neglected because they are poorly understood. However, a growing body of evidence indicates that probing the gray genome could expand the potential universe of previously unknown targets by identifying features that code for specific cancer targets that are both tumor-specific and shared by significant proportions of patients.
Two studies published in the journal Science Immunology on February 3, from work conducted by Institut Curie researchers, reveal that transposon-exon splice junctions, present in the gray genome, are a source of novel recurrent, cancer-specific targets, which could contribute to the development of more effective and less toxic immunotherapies. This work, conducted in collaboration with Mnemo Therapeutics, a biotech company spun off from Institut Curie, confirms that the "grey genome" can be exploited to find significant cancer targets and offer a diagnostic approach to identify tumor-specific antigens.
In the first study*, directed by Sebastian Amigorena, CNRS Research Director and head of the Immune responses and cancer team (Institut Curie/Inserm) and scientific co-founder of Mnemo Therapeutics, and Marianne Burbage, Inserm researcher on the team, researchers identified a new family of antigens derived from non-canonical splicing junctions in mouse tumor cell lines. These antigens prompt an immune response in tumor-bearing mice and successfully delayed tumor growth when these peptides were administered as prophylactic[1] or therapeutic vaccines. Additionally, inactivation of Setdb1, a histone methyltransferase, resulted in increased expression of this family of antigens and tumor cell immunogenicity (the ability to trigger an immune response that stops tumor growth).
The second study**, led by Sebastian Amigorena and Joshua Waterfall, head of the Integrative functional genomics of cancer team (Institut Curie/Inserm), specifically examined this family of antigens in non-small cell lung cancer (NSCLC) patient and healthy tissue samples. The team identified tumor-specific non-canonical splicing junctions that generated immunogenic peptides in NSCLC patients, thus describing a new source of recurrent, tumor-specific antigens in NSCLC cancer patients.
Identifying targets that are unique to cancer cells and absent from healthy tissue has been a major barrier to developing more successful immunotherapies.The collective findings advance our knowledge of tumor-specific antigens, unlocking new possibilities for the treatment of cancer not only in the cell therapy space, but across multiple approaches and modalities.
said Sebastian Amigorena.
Current cancer targets originate from a very small percentage of the human genome, leaving regions with potential oncology targets largely overlooked. By mining the grey genome, the authors have uncovered an entirely new class of cancer antigens that are highly tumor-specific and recurrent in cancer patients. We are eager to not only better understand how these new tumor antigens synergize with our current pipeline, but also the ways they might be further leveraged as part of strategic partnerships to advance the broader immuno-oncology field.
said Robert LaCaze, CEO of Mnemo Therapeutics.
[1] A prophylactic vaccine consists in the immunization of a peptide by subcutaneous route in the presence of an adjuvant before exposure to a tumor line.
