Initial results from clinical trials show new drug therapies are effective against lymphomas and other cancers connected to the Epstein-Barr virus.
When Dr. Pierluigi Porcu was attending the University of Torino Medical School in Italy in the 1980s, he developed a great interest in viruses and how they interact with cancer.
“I took a special class in medical school in virology in which we discussed all kinds of viruses, from HIV to hepatitis to the Epstein-Barr virus,” said Porcu.
He learned in that class that the Epstein-Barr virus can cause lymphoma.
Porcu, an oncologist who heads the blood cancer and stem cell transplant department at Sidney Kimmel Cancer Center-Jefferson Health in Philadelphia, continued to study the virus-cancer connection throughout his career.
But he could not generate any interest in his research from pharmaceutical companies.
Meanwhile, Ivor Royston, an oncologist and pharmaceutical industry executive, was also busy studying the Epstein-Barr and lymphoma connection at Johns Hopkins University in Maryland and the National Institutes of Health (NIH).
Royston eventually moved on to other disciplines, including immunology and monoclonal antibodies. He eventually became a biotechnology pioneer who founded and co-founded several cancer biotech companies, including Hybritech and Idec Pharmaceuticals.
But he never lost interest in finding a possible treatment for patients who have Epstein-Barr-associated lymphomas.
And when he learned of the so-called “kick and kill” treatment approach work of Dr. Douglas Faller,the former director of Boston University School of Medicine’s Cancer Center, Royston returned to his virology roots.
The “kick,” Royston explains, activates genes in the body that have been epigenetically suppressed by a virus or cancer.
The “kill,” he notes, activates a therapeutic method that selectively and directly kills virus-harboring cells or activates suppressed immune response genes.
Two years ago, Royston and Purco joined forces after Royston co-created a new biotech company, Viracta Therapeutics. The firm’s focus is on developing treatments for viral-based cancers.
Viracta officials asked Porcu if he was interested in working with them on an Epstein-Barr and lymphoma trial.
“Of course I jumped on board,” Porcu told Healthline.
Viracta initiated a clinical trial using the company’s nanatinostat, along with an antiviral drug, that has shown encouraging results in patients with a wide variety of non-Hodgkin’s lymphomas as well as Hodgkin’s lymphoma.
Scientists have known for years that viruses can cause cancer.
The human papillomavirus (HPV), for example, can cause a variety of cancers, including those of the cervix, vagina, vulva, and penis as well as head and neck cancers.
And hepatitis C can lead to liver cancer and non-Hodgkin’s lymphoma.
What isn’t commonly known, however, is that the first association between a virus and cancer discovered by researchers was Epstein-Barr and Burkitt’s lymphoma.
The Epstein-Barr virus, a member of the herpes virus family, is one of the most common human viruses. Approximately 90 percent of the world’s adult population gets infected with Epstein-Barr (EBV).
Most people get infected with EBV at some point in their lives. EBV spreads most commonly through bodily fluids, primarily saliva. EBV can cause infectious mononucleosis, also called mono, and other illnesses.
But the public is virtually unaware of any link between EBV and lymphoma, Royston says, largely because to date no one has successfully developed a treatment for EBV-associated lymphoma.
EBV-associated cancers are known to be difficult to treat. But a clinical trial from Viracta’s novel therapy in EBV-associated lymphomas has produced early encouraging results.
The latest data from the Viracta clinical trial announced at this month’s American Society of Clinical Oncology (ASCO) meeting in Chicago showed that the combination therapy produced an objective response rate of 58 percent, a complete response rate of 33 percent, and a disease stabilization rate of 75 percent.
Viracta’s stage 1b/2 clinical trial with nanatinostat (VRx-3996), a so-called oral histone deacetylase (HDAC) inhibitor, works in combination with an antiviral medication to treat patients with a wide variety of relapsed or refractory EBV-associated lymphomas, both non-Hodgkin’s and Hodgkin’s.
This includes B-cell and T-cell, diffuse large B-cell lymphoma (DLCBL), and NK T-cell lymphoma.
In April, the Food and Drug Administration (FDA) granted orphan drug designations to nanatinostat, in combination with the antiviral valganciclovir, for the treatment of post-transplant lymphoproliferative disorder (PTLD), plasmablastic lymphoma (PBL), and angioimmunoblastic T-cell lymphoma (AITL).
The orphan drug designation includes both T-cell and B-cell lymphomas, which shows this technology’s ability to target EBV-associated cancer cells regardless of tumor type.
Porcu notes that based on their research to date, about 15 to 20 percent of lymphomas are associated with EBV. But this isn’t something most people with cancer or even oncologists yet know.
Arvin Johnson, 64, a military veteran from Slater, Missouri, had never heard of EBV-associated lymphoma when he was diagnosed in October 2017 with angioimmunoblastic T-cell lymphoma, a rare and often aggressive form of peripheral T-cell lymphoma (PTCL).
Johnson endured many rounds of harsh chemotherapy, but his cancer was relentless.
“After I did chemo, I was preparing for a bone marrow transplant, but the chance for me for getting over the cancer from the bone marrow transplant was low, and even if it worked, there was a 70 percent chance that within three years it would come back,” he told Healthline.
A year ago, Johnson’s doctors recommended he join the Viracta study. Johnson says he’s now in remission.
“I’m doing perfect,” he told Healthline. “I had a PET scan last week and the doctors had told me that if this PET scan looks as good as the one before that, then they can declare that I’m in remission.”
Johnson thinks this new treatment could save a lot of lives.
“I think doctors should know about this,” he said. “I’m also a diabetic and they give me a barrage of tests to make sure they know as much about my diabetes as they can. Cancer doctors ought to do the same thing. When I go to the clinic and they pull 9 to 10 bottles of blood out of me, it doesn’t hurt to go ahead and run a check for this Epstein-Barr.”
Porcu says most people who have lymphoma have no idea that their cancer could be caused by EBV.
“But this trial could change that,” he said.
There are two tests lymphoma patients can take to determine if their cancer is associated with EBV.
One is a simple blood test. The other, which is more thorough and conclusive, is a tissue test that can be done as part of the lymph-node biopsy, which most lymphoma patients undergo.
Few oncologists give their patients the option of taking this test. Why? Presumably because there’s no approved treatment for EBV-associated lymphomas.
But Porcu says that even oncologists who know about the EBV-associated lymphomas still believe that only immune-suppressed people with EBV are prone to getting lymphoma.
“Some oncologists are working with information that is five to 10 years old,” said Porcu, whose research now shows that even people who don’t have any discernible suppression of their immune system can still get lymphoma from EBV.
“My prediction is that once people become aware of our data,” Royston added. “Every lymphoma patient in the world should be tested. It’s a simple $200 test. Very simple on your biopsy to see if you are positive.”
Dr. Erin Reid, a professor of medicine and vice chair of the Lymphoma Working Group at the University of California San Diego Moores Cancer Center, has no financial or working connection with the Viracta trial.
But she’s aware of it and describes it as “encouraging.”
“These strategies that are targeting EBV can be a breakthrough for people whose cancers have not responded well to the current standard of care,” Reid told Healthline.
She added that they represent a powerful addition to a lymphoma patient’s toolbox.
“If these trial results continue to have a favorable toxicity profile and continue to be active in the relapsed/refractory setting, this has the potential to be a frontline therapy,” Reid said. “But it will be combined with other agents. It is rare that a single agent is a home run. Generally, a patient will need different agents.”
Reid says combining Viracta’s approach with other strategies such as cellular therapies could lead to an effective new option for patients with EBV-associated lymphomas.
To put it in perspective, Reid notes that while most people have the Ebstein-Barr virus by the time they are in their late teens, most of us don’t get lymphoma.
“The ratio of lymphoma for all who have EBV, of course, is low, but it happens,” she says. “And other than immuno-suppression or HIV, we still don’t understand why some people with EBV are getting cancer.”
Reid, whose clinic treats EBV-associated cancers typically with standard treatment, including chemotherapy and monoclonal antibidoes such as Rituxan, says her clinic regularly checks for EBV in cancer patients and recommends that every cancer clinic do the same.
“It’s just one of many pieces of information we need to give patients the right diagnosis and help confirm what type of lymphoma you have,” she says. “While the test may not be standardly done at all centers, patients should be aware of it. I do believe patients should ask their doctors about it.”
Because there are so many different types and subtypes of lymphoma, Reid says it’s important to know exactly what kind of lymphoma you have.
“To know all the risk factors and optimal therapies, ideally you want you want to be evaluated by someone who specializes in lymphoma, a hematapathologist, not a generalist,” Reid says. “A person who has special training in lymphoma will come up with a nuanced diagnosis.”
Reid adds that if you have lymphoma and your cancer clinic does not have a hematopathologist — a blood cancer pathologist — you can send out your biopsy to a lymphoma expert as a second opinion, which is included in most health insurance plans.
Viracta has partnered with NantKwest, a pharmaceutical immunotherapy company focused on harnessing the power of the innate immune system by using the natural killer cell (NK) in the body.
NantKwest secured an exclusive license to commercialize nanatinostat for use in combination with NantKwest’s natural NK cell therapies.
Dr. Patrick Soon-Shiong, chairman and chief executive officer of NantKwest and a surgeon-turned-biotech entrepreneur, tells Healthline that a new trial likely later this year will use Viracta’s nanatinostat in combination with NantKwest’s clinical-stage NK cell immunotherapy.
Soon-Shiong says that in preclinical studies, nanatinostat has been shown to reactivate silenced transgenes in tumor cells, thereby turning them into preferential targets for NK cell killing.
It also stimulates a patient’s immune system, offering the potential for improved clinical responses in people with cancer.
Soon-Shiong told Healthline his company will soon initiate clinical trials that include nanatinostat in combination with NantKwest’s haNK and t-haNK cell therapy platforms.
He believes this will work synergistically to enhance the efficacy of the company’s NK cell therapies.
“Identifying new treatment options for patients with therapeutic agents such as Viracta’s HDAC inhibitor, VRx-3996, which can be used in combination with NantKwest’s aNK, haNK, and taNK natural killer cell therapies offer the promising opportunity to stimulate the patient’s own immune system by increasing the tumor cell killing ability of NK cell therapy and is highly synergistic with our vision behind Cancer Breakthroughs 2020,” Soon-Shiong said.
“This strategic relationship will enable us to advance multiple combination therapies, including VRx-3996 with our NK cell platform that offers the potential to benefit cancer patients across a broad range of cancer types,” he added.
Royston says that NantKwest has demonstrated the value of NK cells and the partnership will only enhance the mission of both companies.
“We believe that there is an immune component to our therapy, and having NK cells is a way to enhance the immune response by putting immune cells back into the patient,” he told Healthline. “These are off the shelf, and they will be enhanced by our drug. They work better. It makes sense to use the NK cells to fight viral infections.”
In Africa, it’s widely known that Epstein-Barr, coupled with the widespread malaria in the region, are the reasons why Burkitt’s lymphoma is so prevalent in that region.
More than 50 years ago, the virus was discovered in cultured tumor cells derived from a Burkitt’s lymphoma biopsy taken from an African patient.
This finding pushed new research into viruses as a possible cause of human cancers.
But even as far back as 1887, Sir Albert Cook, a missionary doctor in Uganda, had reported seeing children with symptoms and similar features of Burkitt’s lymphoma.
Burkitt’s lymphoma is common in children living in sub-Saharan Africa.
Royston says he has an agreement to bring treatments to Africa for free, but he hopes to receive charitable support from organizations such as the Gates Foundation.
“We will give the drug away in Africa, including Uganda, Tanzania, Ghana, in those regions,” he said.
Royston says his company also recently signed an agreement with Shenzhen Salubris Pharmaceuticals in China.
EBV-associated nasopharyngeal carcinoma is endemic in southern China, Royston notes.
EBV is also highly associated with the incidence and progression of other solid tumors, including gastric carcinoma, as well as NK/T-cell lymphomas found throughout the Asian nation.
“EBV-driven cancers disproportionately impact patients in China,” Kevin Ye, Salubris chief executive officer, said in a statement. “We look forward to partnering with Viracta to develop this new treatment option in China. The approach holds the potential to provide a valuable new treatment option for these patients, who currently still face considerable morbidity and mortality.”
“We are committed to bringing our treatment approach to cancer patients around the world,” added Royston. “We look forward to developing nanatinostat in collaboration with Salubris to address these major healthcare needs in China.”
Royston says if the trial data continues to be positive, it will be the basis for FDA approval.
“We can see this reaching the market by 2022,” he said.