By most estimates, more than 75 percent of all adults have been exposed to the John Cunningham (JC) virus during childhood, although most never even know they have it. That's because the germ normally resides harmlessly inside the bone marrow, urinary tract, tonsils, or brain, where it is held in check by a healthy immune system.
However, like Cunningham, who had Hodgkin's lymphoma and was the first person diagnosed with the virus best known by his initials in 1971, patients with cancer or other diseases that damage the immune system are susceptible to triggering latent JC virus, which causes progressive multifocal leukoencephalopathy, or PML, a disease for which there is no FDA-approved treatment and an extremely high mortality rate.
“PML is almost universally fatal,” said Katy Rezvani, MD, PhD, Professor of Medicine and Director of Translational Research in the Department of Stem Cell Transplantation and Cellular Therapy at The University of Texas MD Anderson Cancer Center in Houston. “Sadly, there is nothing you can do for these patients. Often, they progress and die within a few months. Or, if they survive, they are left with very severe neurological sequelae.”
But now the results of a phase II proof-of-concept study led by Rezvani show that adoptive T-cell therapy using ex vivo-expanded, partially HLA-matched, third-party produced, cryopreserved, BKPyV (BK) viral-specific immune cells, or T cells, is a safe and effective approach to treating PML in immunosuppressed patients.
The researchers hypothesized that T cells developed to treat the very common BK virus also would be effective against a JC virus infection because the germs are genetically similar and share the same sequence homology in immunogenic proteins.
After receiving their first infusion of the BK viral-specific T cells, all three patients included in a paper on the results from the ongoing clinical trial recently published had a rapid and significant reduction in JC viral load in their cerebrospinal fluid (CSF) (N Engl J Med 2018;379:1443-1451).
“We demonstrated that taking immune cells from a healthy individual and putting in partially mismatched immune cells against a virus in a patient is not only safe, but it's also effective in that we saw that the viral levels in the CSF of the patients were significantly reduced or they disappeared,” Rezvani said. “And clinically, the patients improved and that was very exciting.”
Also exciting for the MD Anderson researchers was discovering that they could use the mismatch between the donor and recipient to track the T cells infused into one recipient all the way to the patient's CSF and beyond, Rezvani said.
“We demonstrated that the cells that we were giving the patient via IV actually make their way to the patient's CSF and track to the site of the disease,” she explained. “So, we grew the immune cells, and then they became differentiated. And that, to us, was the ‘proof of concept.’”
The results of the landmark study also proved to be the best example of cancer research in the past year, according to Oncology Times, which has named Rezvani, et al, the first place winners of the second annual Excellence in Oncology awards.
“This is definitely a team effort: it takes a village to do this kind of work,” Rezvani said soon after learning her team had won the award. “The approach was developed in my research lab, and we translated it in the GMP [good manufacturing procedure] laboratory at MD Anderson Cancer Center with the help of our brilliant postdocs and GMP technicians. But we also have had input from the clinical teams including the Stem Cell Transplant team, the neurooncologists, infectious disease faculty, and the neuroimaging experts who really helped us to understand the MRI changes and what is reversible and what is not reversible brain damage caused by PML.
“There are a lot of people coming together and trying to find a good treatment for these patients.”
Like JC virus, BK virus belongs to the group of polyomaviruses, but instead of PML it causes a very severe type of symptom in the patient called hemorrhagic cystitis, which causes bleeding in the urine and a lot of pain, and also typically requires many weeks of hospitalization, bladder irrigation, and morphine to control the pain, Rezvani said.
“So, because of this, we started thinking, ‘OK, why don't we grow some immune cells—T cells—that can recognize the BK virus?” she noted. “In the research lab, we can grow the immune cells from the blood of healthy individuals. And then, when these T cells are educated to recognize BK virus, we infuse them into our patients. This way, you are passively transferring immunity to immunosuppressed patients who need them. We were delighted when we saw the amazing clinical responses to the therapy.”
Because BK virus and JC virus share 90 percent homology, the researchers were confident in their hypothesis that the immune cells grown to treat germs would treat the other as effectively. So they requested and received FDA approval to amend the clinical trial to allow them to start treating patients with PML.
“We argued that our BKV CTLs should recognize both viruses because the two viruses are structurally so similar, and that was indeed the case,” Rezvani said. “And so really, that is what led us to do this study. It first started as a study of BK hemorrhagic cystitis, and then it was expanded to treat patients with JC virus-related PML.”
Despite the similarity in germ structures shared by the JC and BK viruses, there is one important difference, Rezvani said.
“With BK hemorrhagic cystitis, at least over time, patients recover. It's very painful and uncomfortable, but it really doesn't lead to mortality in our patients,” she explained.” But PML is either fatal or, if you recover, and some of these patients do, you are left with severe neurological complications and deficits. And for those patients, there is really nothing you can do.”
Among the key takeaways from the JC virus study, Rezvani noted the most important is that the new T-cell approach is safe for patients receiving the infusion. Plus, it works.
“In our [NEJM] paper, the case of Patient No. 1 was a young woman who pretty much recovered fully from her neurological symptoms. She was left with very minimal, if any, neurological deficit,” Rezvani said, referring to a 32-year-old woman with PML that was cleared from her CSF following her initial infusion of the BK viral-specific immune cells, and who remained virus-free after 27 months.
Not all patients with PML will recover fully, however, as it depends on the amount of brain damage already inflicted by the disease prior to receiving the newly developed T cells. For example, in the NEJM paper, Patient No. 3 was a young man with HIV who developed PML several years after stopping his antiretroviral drugs due to side effects. He was brought into the cancer center on a stretcher, unable to sit up because of the amount of neurological damage already done by PML.
“And now he is able to walk with a cane,” Rezvani reported. “He is not back to where a normal 30-year-old should be, but that's probably because he had the infection for some time and some of the damage that was already done to his brain was not reversible.
“Indeed, what often happens with patients with PML who recover is that they can have a degree of atrophy in the brain. And, obviously, when you have atrophy you don't get recovery of the function of that part of the brain.”
In the beginning, scientists in Rezvani's lab at MD Anderson were growing T cells using blood from donors of bone marrow for transplants who were asked to give a little extra blood.
Soon after, the center's blood bank began providing the researchers with the white blood cells and byproducts that they typically discarded after separating them from red blood cells and platelets in donated blood in order to remove allergens and other impurities prior to infusion.
The culturing of the immune cells begins in the presence of peptides that are derived from the immunodominant protein of the BK virus, but are also shared by JC virus, Rezvani said. Cytokines are added to the culture and the immune cells are grown for 2 weeks.
At the end of this period, the new BK viral-specific immune cells are fully characterized prior to being frozen. Finally, the HLA type of the donor cells is noted so that as soon as a patient presents with PML or hemorrhagic cystitis a suitable donor can be quickly located and BKV-specific T cells can be infused within 24 hours.
The cancer center now has a growing bank of the cryofrozen immune cells ready for infusion on very short notice, Rezvani said.
“This is a bank of immune cells that can be used as an off-the-shelf product, which means that as soon as you have a patient that presents to you with PML or hemorrhagic cystitis we can look in our donor bank and find a BKV-specific T-cell line that is best HLA-matched to the recipient and infuse it to the patient,” she said.
“We have manufactured BKV CTL from around 30 different donors. From each donor, we can get somewhere in the region of 10-25 doses. So, we have hundreds of vials of these cells sitting in the freezer, ready to infuse,” said Rezvani. “And then when a patient comes in, we only need to match them partially. However, there needs to be some degree of HLA matching for the T cells to be able to recognize the recipient's virus.”
Since the results from the clinical trial were published, several patients have been referred to MD Anderson by physicians, while others have self-referred after learning of the clinical trial while searching online for more information about PML. But while that's actually welcomed, and even encouraged, referring physicians and potential patients need to understand that there are certain limitations with the new treatment approach, Rezvani said.
“We need to have confirmation of the presence of JC virus in the cerebrospinal fluid or the brain,” she emphasized. “We had a couple of patients reach out to us with symptoms suggestive of PML but we didn't have proof of JC virus infection in the brain. Viruses other than JC virus can cause encephalitis. Our approach is very specific to JCV.”
Interested parties also need to remember that a patient's recovery is limited by how long they have had PML, Rezvani reiterated. “Another point that is important to emphasize is that our cells are very good at targeting the virus, but the amount of clinical recovery will depend on how much irreversible brain damage was already done.”
Additional research will address a number of questions raised by the remarkable results from the clinical trial thus far, all of which Rezvani is eager to tackle.
“We need longer follow-up and to treat additional patients. We also need to understand why some patients will respond quickly to therapy while others don't. What are the predictors of response? Can we improve our strategy by maybe infusing more cells or multiple doses? Can we improve the cells by engineering them to home in and traffic to the brain more efficiently?” she began asking rhetorically.
“Are there differences amongst different donors such that some donor BKV CTL lines are more efficient at clearing the virus? Does the degree of HLA matching matter, so that a better HLA-matched donor will induce a better response in the recipient?” she continued. “Also, we need a better understanding of reversible versus irreversible MRI changes? So, there are many questions for us to address.”
Answering those questions will help Rezvani and her team to refine the new adoptive T-cell therapy approach to treating PML.
“If we confirm our results in additional patients with longer follow-up, the clinical implications of our study could be huge,” she said. “Because, again, this is a disease for which there is no treatment.
“What we need to appreciate it is that clinicians don't necessarily think of JC virus when a patient presents with neurological abnormality since this is a very rare disease. You have to specifically test for the virus in order to find it,” she continued. “With a higher index of suspicion, patients may be diagnosed earlier and referred for therapy before irreversible brain damage has occurred.”
Chuck Holt is a contributing writer.
Excellence in Oncology
Oncology Times annouces winners of the 2019 Excellence in Oncology award contest designed to recognize the wonderful research, dedication, and dramatic impact on patients (and their families) that occur every day in oncology. This initiative garnered submissions from all areas of the cancer field, highlighting research and clinical programs in a variety of specialties and cancer centers. In this issue, honorees will be announced and then highlighted in stories throughout the year. Congratulations to the winners!
Minimally Invasive Versus Abdominal Radical Hysterectomy for Cervical Cancer; Survival After Minimally Invasive Radical Hysterectomy for Early-Stage Cervical Cancer
Lead authors: Pedro Ramirez, MD, and Alejandro Rauh-Hain, MD, MPH, MD Anderson Cancer Center
Curing Patients With CNS Neuroblastoma Metastases
Lead author: Kim Kramer, MD, Memorial Sloan Kettering Cancer Center
Combined Nivolumab and Ipilimumab in Melanoma Metastatic to the Brain
Lead researcher: Hussein A. Tawbi, MD, PhD, MD Anderson Cancer Center
Convection-Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: a Single-Centre, Dose-Escalation, Phase 1 Trial
Lead researcher: Mark M. Souweidane, MD, Weill Cornell Medicine and NewYork-Presbyterian
Practice Transformation—Early Impact of OCM on Hospital Admissions
Lead researcher: David M. Waterhouse, MD, MPH, Oncology Hematology Care, Inc.