Ribavirin, a drug that has been approved by the Food and Drug Administration (FDA) to treat hepatitis C, as well as some viral respiratory infections and viral hemorrhagic fevers, has shown promising activity against some types of lymphoma. There is a growing movement to repurpose older drugs that might have mechanisms of action that could benefit cancer patients.
Dr. Leandro Cerchietti
Based on preclinical work performed in the laboratory of Dr. Leandro Cerchietti, the Weill Cornell Medicine and NewYork-Presbyterian Lymphoma Program is planning a clinical trial examining the oral antiviral drug ribavirin in patients with two non-Hodgkin lymphoma subtypes, slow growing follicular lymphoma and mantle cell lymphoma. This clinical trial will be led by principal investigator Dr. Sarah Rutherford.
Previously, physicians and scientists in the Weill Cornell Medicine Lymphoma Program have demonstrated that ribavirin may be able to inhibit lymphoma cell growth. Dr. Cerchietti’s laboratory research has shown that the eukaryotic translation initiation factor 4E (eiF4E) is blocked by ribavirin in B-cell lymphoma cell lines, as well as in patient-derived xenograft (PDX) models, which more closely resemble the way cancer behaves in the human body. Blocking eiF4E ultimately leads to decreases in key proteins (MYC, BCL2, and BCL6) which are crucial for lymphoma cells’ survival.
Additionally, Dr. Rutherford conducted a retrospective review of patients with lymphoma who underwent stem cell transplants at NewYork-Presbyterian Hospital/Weill Cornell Medicine. Patients who were treated with ribavirin for viral infections just before or after their stem cell transplant had better lymphoma-related outcomes compared to what was expected based on their disease risk profiles.
This clinical trial, run by Dr. Rutherford and Dr. Cerchietti, will enroll patients with follicular lymphoma and mantle cell lymphoma, and they will receive 3-6 months of oral ribavirin. Using a blood test, Dr. Rutherford and Dr. Cerchietti will monitor for the presence of a marker of lymphoma in the blood to confirm that ribavirin has the intended anti-lymphoma effect.
“We are excited about opening this clinical trial and aim to conduct additional trials in the future that combine ribavirin with other drugs,” said Dr. Rutherford. “Our goal is to ultimately develop a well-tolerated, targeted oral regimen to control lymphomas.”
This preclinical research is supported by a Translational Research Program from the Leukemia and Lymphoma Society (LLS) awarded to Dr. Cerchietti.
Diffuse large B-cell lymphoma (DLBCL), a fast-growing cancer of abnormal B lymphocyte cells that ordinarily help to fight infection and inflammation in the body, is the most common type of lymphoma. Approximately two-thirds of DLBCL patients are cured by six cycles of the chemotherapy drug combination rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) that serves as a standard treatment, but chromosomal changes involving MYC, BCL-2, and BCL-6 have been linked to more aggressive disease that is harder to cure.
Normally, MYC plays a role in cell growth, protein synthesis, metabolism, DNA replication, and blood vessel formation (known as angiogenesis), while BCL-2 regulates the natural death of cells when they are no longer needed in the body (known as apoptosis), and BCL-6 helps regulate genes that suppress tumor growth.
At the OncLive State of the Science Summit on Hematologic Malignancies, Dr. Sarah Rutherford provided an overview of two aggressive variations of B-cell lymphoma involving MYC and BCL-2 or BCL-6 that are characterized by resistance to chemotherapy: double-hit lymphoma and double protein-expressor lymphoma.
Double-hit lymphoma occurs due to alterations in two chromosomes involving MYC, BCL-2, and/or BCL-6, with the majority of cases involving MYC and BCL-2. This variant is fairly uncommon and has an incidence rate estimated at 5-10 percent of DLBCL cases, which can include instances in which patients’ follicular lymphoma transformed into DLBCL. Many double-hit lymphomas also tend to infiltrate sites outside the lymph nodes, such as the bone marrow and central nervous system.
According to Dr. Rutherford, outcomes for double-hit lymphomas are poor, even when intensive therapies like autologous stem cell transplant are added to treatment. Overall survival (OS) for double-hit lymphoma patients ranges between 5-24 months when treated with six cycles of R-CHOP, but dose-adjusted chemotherapy drug combination etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) has become the standard frontline therapy for double-hit cases. DA-EPOCH-R is more intensive than the R-CHOP approach and appears to have improved outcomes, but data is still limited and new strategies are being planned to increase response rates in the double-hit patient population.
Double protein-expressor lymphomas have increased protein expression of MYC and BCL-2 or BCL-6 in the absence of the chromosomal changes seen in double-hit lymphomas. This variant is more common than double-hit lymphoma, with an incidence rate of about 30-40 percent of DLBCL cases, but it is not as difficult to cure. It is, however, more aggressive and has less favorable outcomes than classical DLBCL cases (those without changes in MYC, BCL-2, and BCL-6). The standard treatment for double protein-expressor lymphomas is six cycles of R-CHOP.
Dr. Rutherford said that the Lymphoma Program at Weill Cornell Medicine/NewYork-Presbyterian Hospital – along with other institutions, including Massachusetts General Hospital – is working hard to develop novel strategies that will improve outcomes for these patients. For example, the team currently has a multi-center investigator-initiated clinical trial open to determine the maximum tolerated dose of BCL-2 inhibitor venetoclax combined with DA-EPOCH-R. The goal is to then open a second clinical trial with an objective of evaluating the efficacy of this promising combination in the double-hit and double-expressor lymphoma population.
Watch Dr. Rutherford speak with OncLive about the discrepancy between double-hit and double protein-expressor lymphoma here:
The enemy approaches. Scouts pick up the scent and send signals to the relay team. The troops are rallied and an attack is prepared, strategically aligned to the specific weaknesses of the foe.
So it is with the body’s immune system. The scouts are T-cells, which pick up the antigen ‘scent’ of foreign invaders and notify their B-cell brethren to shift forms into plasma cells and produce weapons – antibodies – to attack.
Most of the B-cells respond by rapidly producing plasma cells, but this first line of defense is often weak. Luckily, a select few form into a special forces unit: the germinal center. Germinal centers are balls of furiously dividing B-cells that are mutating in order to tailor their antibody genes to attack offending antigens. The result is a much more powerful immunological army, with high affinity antibodies that can fully get rid of the antigen.
Once the job is done, the special forces unit is disbanded, the rapid proliferation and mutations end, and the germinal center cells are reprogrammed into normal plasma cells.
Exactly how this shape shifting process happens has been a mystery – until now. A team of researchers at Weill Cornell Medicine, led by Gebroe Family Professor of Hematology and Oncology Ari Melnick, M.D., has uncovered the mechanisms by which B-cells transform, and found that it requires a special cooperation between regulatory protein EZH2 and transcription protein BCL6.
“The transition from a resting mature B-cell to a germinal center B-cell is nothing short of astonishing, as these cells are radically different from each other and this dramatic change requires extensive epigenetic reprogramming, or loading completely different software into the B-cell hardware,” Melnick said.
The discovery is key to understanding how certain blood cancers, such as the fast-growing diffuse large B-cell lymphoma, form and evolve. And it may have an impact on a potential new therapy.
“The basic properties of germinal center B-cells is to proliferate and mutate. Hence, they are prone to becoming lymphomas if something stops them from unloading the germinal center software,” Melnick said.
Scientists have long debated which regulatory system was responsible for B-cell programming.
EZH2 is an enzyme that chemically modifies the regulatory backbone proteins that control our genomes. It drives germinal center formation by suppressing cell-cycle checkpoint genes, repressing genes involved in plasma cell differentiation, and possibly impairing DNA damage responses.
BCL6 is a master regulator protein that attaches to the genome at sites that are crucial for the development of germinal centers.
Both EZH2 and BCL6 are known to repress transcription, the first step of gene expression, in which a particular segment of DNA is copied into RNA (mRNA).
In a study published August 8 in Cancer Cell, Melnick and first author Wendy Beguelin, Ph.D., show that neither alone is responsible – rather, the two form separate but nearby attachment points to the genome to capture a molecular machine called “BCOR complex” which then carries out the actual work of shutting down regions of the genome.
Just as the Air Force requires two officers to simultaneously punch in personal codes and insert and turn individual keys in order to launch dangerous missiles, the immune system seems to require two biochemical keys to shapeshift a friendly B-cell into a freakazoid germinal center B-cell capable of causing lymphomas.
“We show that the ‘missile’ that causes the final effect of controlling B-cell genes is the BCOR complex, which requires the EZH2 and BCL6 key to launch,” Melnick said. Lymphomas occur when these keys get “stuck” due to mutations or other influences.
“Although it may seem a subtle point it is actually quite profound,” Melnick added. “This is the first time it has been shown that such combinatorial repressive mechanisms exist between these kinds of regulatory proteins.”
The Melnick team also discovered the key missing link between EZH2 and BCL6: the CBX8 protein. It acts as a biochemical bridge by attaching to the histone mark placed by EZH2 and the BCOR protein that interacts with BCL6.
“It is the glue that makes the whole thing work,” Melnick said.
To stop out-of-control, lymphoma-generating germinal centers, the Melnick team suggests that disarming the biochemical “keys” could be key.
“If you hit both keys, then the missile silo goes dark and the germinal center B-cells fall apart,” Melnick said. “Either one alone is only partially effective; you have to disable both arms of the PRC1-BCOR tethering mechanism.”
This is possible by combining BCL6 and EZH2 inhibitors. EZH2 inhibitors are in clinical trials for patients with lymphomas at Weill Cornell and elsewhere, and BCL6 drugs have been developed by Dr. Melnick and colleagues and are not yet in human trials. The Melnick team showed that the EZH2-BCL6 drug combination synergistically suppressed human diffuse large B-cell lymphomas in pre-clinical studies.
“Although both EZH2 and BCL6 inhibitors inhibited tumor growth alone, the combination more potently and significantly suppressed lymphoma growth,” Melnick said. “In addition, the combination was not toxic to normal cells.”
The work was supported in part by grants from the National Institutes of Health, the National Cancer Institute, the American Society of Hematology, and the Leukemia and Lymphoma Society.