Scientists at the University of California San Diego School of Medicine and Ionis Pharmaceuticals are taking a new, targeted approach to the treatment of myeloma: silencing IRF4, a gene that allows myeloma stem cells and tumor cells to proliferate and survive. Past studies have shown that high IRF4 levels are associated with lower overall survival rates for patients with the disease.
In a study “Selective antisense oligonucleotide inhibition of human IRF4 prevents malignant myeloma regeneration via cell cycle disruption” published in Cell Stem Cell, the team reports on their work which involved inhibiting IRF4 with an antisense oligonucleotide, an engineered piece of DNA specifically designed to bind the genetic material coding for IRF4, causing it to degrade. The oligonucleotide, an investigational antisense medicine developed by Ionis and known as ION251, lowered disease burden, reduced myeloma stem cell abundance, and increased survival of mice bearing human myeloma, according to preclinical study data.
Authors say the results support a Phase I clinical trial recently launched to assess the safety and efficacy of ION251 to treat humans with myeloma.
“In multiple myeloma, inflammatory and anti-viral pathways promote disease progression and cancer stem cell generation. Using diverse pre-clinical models, we investigated the role of interferon regulatory factor 4 (IRF4) in myeloma progenitor regeneration,” write the investigators.
“In a patient-derived xenograft model that recapitulates IRF4 pathway activation in human myeloma, we test the effects of IRF4 antisense oligonucleotides (ASOs) and identify a lead agent for clinical development (ION251). IRF4 overexpression expands myeloma progenitors, while IRF4 ASOs impair myeloma cell survival and reduce IRF4 and c-MYC expression. IRF4 ASO monotherapy impedes tumor formation and myeloma dissemination in xenograft models, improving animal survival.
“Moreover, IRF4 ASOs eradicate myeloma progenitors and malignant plasma cells while sparing normal human hematopoietic stem cell development. Mechanistically, IRF4 inhibition disrupts cell cycle progression, downregulates stem cell and cell adhesion transcript expression, and promotes sensitivity to myeloma drugs. These findings will enable rapid clinical development of selective IRF4 inhibitors to prevent myeloma progenitor-driven relapse.”
“As scientists, we don’t usually have direct contact with patients, as a daily reminder of what our research could do, or why it’s important,” said co-senior author Leslie Crews, PhD, assistant professor in the division of regenerative medicine at the UC San Diego School of Medicine. “But I’ve been working with a local support group for patients with multiple myeloma. They inspire me. They ask the most insightful questions, and it really makes it personal. I hope this work will eventually give them new potential treatments to prevent relapse, and ultimately get better.”
The school and Ionis Pharmaceuticals have a long history of collaborating on the development of investigational antisense medicines. Several Ionis antisense drugs have been commercially approved, including the FDA-approved SPINRAZA, a therapy for spinal muscular atrophy. In addition, several other therapies are currently in clinical trials.
One challenge myeloma researchers face is that myeloma cells don’t grow well in laboratory dishes. To study the disease and test new treatments, the best method, Crews said, is to transplant human myeloma cells into mice that lack an immune system and thus won’t reject the human cells.
The team tested ION251 on these myeloma mouse avatars. Compared to untreated mice, the treated mice had significantly fewer myeloma cells after two to six weeks of treatment. What’s more, 70 to 100% of the treated mice survived, whereas none of the untreated control mice did. There were 10 mice in each treatment or control group, and they received daily doses of ION251 or a control for one week, followed by three doses per week.
In separate experiments using human cells isolated from myeloma or healthy donor samples, doses of ION251 used were enough to eradicate the myeloma stem cells while sparing healthy blood cells.
“The results of these preclinical studies were so striking that half the microscopy images we took to compare bone marrow samples between treated and untreated mice kept coming back blank. In the treated mice, we couldn’t find any myeloma cells left for us to study,” said Crews, who is also associate member of the Moores Cancer Center and member of the Altman Clinical and Translational Research Institute at UC San Diego. “It makes the science more difficult, but it gives me hope for patients.”
In addition to working on its own, the treatment improved myeloma tumor cell sensitivity to standard-of-care cancer therapeutics. The researchers also drilled down to the mechanisms at play and described the molecular effects of IRF4 inhibition to obtain information that both clarifies how myeloma forms in the first place, and how the treatment works.
“These proof-of-principle studies will enable rapid clinical development of anti-sense oligonucleotide-mediated IRF4 inhibition to prevent myeloma relapse driven by drug-resistant cancer stem cells,” said co-senior author Catriona Jamieson, MD, PhD, Koman Family Presidential Endowed Chair in Cancer Research, deputy director of Moores Cancer Center, director of the Sanford Stem Cell Clinical Center and director of the CIRM Alpha Stem Cell Clinic at UC San Diego Health.
The Phase I clinical trial to assess the safety of ION251, sponsored by Ionis Pharmaceuticals, is now recruiting participants at Moores Cancer Center at UC San Diego Health and elsewhere.
According to the National Cancer Institute, multiple myeloma is the second most common blood cancer in the US, with more than 32,000 new cases predicted in 2020 and a five-year survival of only 53.9%.