Epigenetic characterization of PVR shows the correlation between promoter DNA methylation and expression. Credit: Leukemia (2024). DOI: 10.1038/s41375-024-02419-z

Multiple myeloma is a type of blood cancer that appears mainly after the age of 60. Its incidence, therefore, increases with the aging of the population. In this pathology, the bone marrow, the porous structure within the bones that produces normal blood cells, is invaded by an overgrowth of the so-called plasma cells. These cells, which in healthy conditions are part of the immune system and help prevent infections, have been transformed and, in addition to destroying the bone marrow, end up escaping and causing lesions in other locations such as the spine, skull, pelvis and ribs.

Current treatments can control the disease, even for quite a long time, but a definitive cure does not yet exist. With the development of new generations of immunotherapy, using either antibodies or whole immune cells engineered to act as drugs, a new window of opportunity arises to treat patients that relapse or are refractory to standard treatment.

An article published in the journal Leukemia shows how an epigenetic test could determine the efficacy of new immunotherapy treatments against multiple myeloma.

The research was directed by Dr. Manel Esteller, ICREA Research Professor at the Josep Carreras Leukaemia Research Institute (IJC) and Chairman of Genetics at School of Medicine of the University of Barcelona, co-led by Dr. Gerardo Ferrer and fist-authored by Laura Martínez-Verbo from the same center.

“We began looking for altered genes in cancer that had to do with the immune system and the way in which antigens are recognized to trigger a response from our defenses,” explains Dr. Esteller, setting the framework of their research. This approach led to the identification of a subgroup of multiple myeloma patients with an epigenetic alteration in the PVR gene, a key regulator of the immune system, resulting in the loss of its activity.

Dr. Esteller remarks that “it was curious to observe that people with this defect experienced a better evolution of their disease, so we thought that the cancer cells from these individuals, who had a good clinical course, could be more easily attacked by the immune system.”

To test their hypothesis, the team used a cellular model for multiple myeloma and eliminated the PVR gene, to see how they responded to different forms of immunotherapy: plain antibodies, T-lymphocytes and natural killer cells activated by genetic engineering (CAR-T cells). In all cases, the immune response was effective against the tumor cells, in vitro.

With this new information, clinicians may know beforehand what patients would best benefit from immunotherapy, helping with their clinical management. And, beyond that, Dr. Esteller states, “Our results demonstrate that in this malignant blood disease, inhibiting the PVR gene decisively increases the probability of success of immunotherapy. Now, then, it would be the turn of the pharmaceutical industry and clinical research to bring these results to the bedside of the patient.”