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Patients with PML Might Be Helped by T-Cell Therapy, but More Research Is Needed

Article In Brief

New research suggests that T-cell therapy may be an effective treatment for progressive multifocal leukoencephalopathy (PML), a rare but fatal brain infection.

Figure

MRI at the time of progressive multifocal leukoencephalopathy (PML) diagnosis in patient 1, in A-E. and patient 4, in F–L. (A) Patient 1 had a single progressive multifocal leukoencephalopathy (PML) lesion located in the left rolandic white matter, hyperintense on axial FLAIR images. (B) The adjacent cortex shows a characteristic rim of hypointensity on gradient echo (GE) images. (C, D) No diffusion restriction is evident on b1000 sequences, in C, and ADC sequences, in D, and (E) no contrast enhancement was evident on T1 sequences after gadolinium injection. (F) Patient 4 had a large PML lesion in the right parietal white matter that involved the corpus callosum splenium and reached the contralateral hemisphere, evident as hyperintense on FLAIR images. (G) No cortical rim of hypointensity was evident on GE images. (H, I) Linear rims of diffusion restriction were present along the lateral margins of the PML lesion, corresponding to the front of active demyelination. (J) The PML lesion showed marked hypointensity on T1 sequences after gadolinium injection, but no contrast enhancement. FLAIR, Fluid Attenuated Inversion Recovery.

A small study from Italy lends support to the idea that T-cell therapy might be an effective treatment for progressive multifocal leukoencephalopathy (PML), a rare but often fatal brain infection.

The new study involved nine patients, with six responding favorably to treatment with polyomavirus JC (JCPyV)- specific T-cell therapy, according to an article published online on January 18 in the Annals of Neurology.

The study follows another small proof-of-concept study published in the New England Journal of Medicine in 2018 from researchers at the University of Texas MD Anderson Cancer Center that suggested that T-cell therapy using a virus similar to the JC virus also might be effective.

“Among other novel treatments, T-cell therapy is emerging as a viable treatment option in patients with PML, particularly for those not amenable to restoration of specific immunity,” concluded the Italian research team involved in the Annals of Neurology study that included Patrizia Comoli, MD, of the Fondazione IRCCS Policlinico San Matteo in Pavia, Italy.

The study authors explained that PML, which involves deterioration of white matter of the brain, is caused by JCPyV following prolonged immune suppression because of “HIV infection, hematological malignancies, congenital immune deficiencies, solid organ/hematopoietic stem cell transplantation or following a treatment with monoclonal antibodies.”

“To date, effective antiviral agents to treat JCPyV infections are not available, and infection control relies on the restoration of host immune competence that may not always be attained,” the paper said.

The article noted that PML-associated mortality ranges from 20 percent in patients with immune-mediated disorders that develop PML during treatment with monoclonal antibodies and upwards of 90 percent in patients with hematological malignancies.

Other potential treatments for PML, such as immune checkpoint inhibitors and vaccines, have shown limited effectiveness so far, they pointed out.

Study Design, Findings

The study, conducted between January 2014 and April 2019, involved nine patients with a diagnosis of “definite PML” according to a 2013 consensus definition of the AAN. The patients were HIV-negative and in a state of neurological deterioration and moderate to severe disability when referred from centers throughout Italy to the study site for treatment with JCPyV-specific T lymphocytes.

The cell lines were expanded from autologous or allogeneic peripheral blood mononuclear cells using stimulation with JCPyV antigen-derived peptides. The participants were treated with two doses, 15 days apart.

Six of the nine patients “achieved PML control, with five alive and in good clinical conditions at their last follow-up.” Three patients died from PML progression and another from a varicella-zoster virus reactivation related to immune suppression.

The authors reported no adverse events. Among the patients evaluated, “an increase in the frequency of circulating JCPyV-specific lymphocytes was observed, with a decrease or clearance of JCPyV viral load in cerebrospinal fluid.”

On MRI, “transient appearance of punctate areas of contrast enhancement within, or close to, PML lesions was observed, that was interpreted as a sign of immune control and that regressed spontaneously without the need for steroid treatment,” they said.

The researchers said a downside to the approach was that it took several weeks to generate and test the cell lines used for therapy.

“Patients received the first T-cell infusion after a median of 2.6 months from PML diagnosis, and this delay might be fatal in patients with rapidly progressive disease,” they noted.

“Cell line generation is time-consuming especially when lines are generated ad hoc for each patient, and this might cause a crucial delay in treatment administration,” they said. “The establishment of third-party T-cell banks will possibly make this approach more feasible,” and accessible to more patients.

Expert Commentary

Igor J. Koralnik, MD, FAAN, professor of neurology and chief of the division of neuro-infectious diseases and global neurology at Northwestern University Feinberg School of Medicine, commended the researchers in Italy for focusing on PML, noting that “because it is an orphan disease there is not a lot of research [on it].”

The current research is encouraging, Dr. Koralnik said, but because it was not a case-control study it is not possible to say whether the PML patients who seemed to have responded to the T-cell therapy would have improved on their own without the treatment.

“You can have remission in PML for reasons we don't fully understand,” he said. “In some patients, their immune response takes over. The more we tinker with the immune system, the higher the risk for reactivation of latent viruses,” such as JCV.

In the case of the MD Anderson study, researchers are investigating T-cell therapy using the BK virus, which is genetically similar to JVC, as a treatment for PML, said Katy Rezvani, MD, PhD, professor of medicine in the department of stem cell and cellular therapy at the center.

Dr. Rezvani said the T-cell trial, which reported preliminary results in three patients in 2018, continues to accrue patients, and “the clinic results continue to be very encouraging.”

“I am very pleased to see that other groups are also using the approach of cell therapy to treat patients with PML and are reporting clinical response,” Dr. Rezvani said. “This is an area of unmet need and new therapies are urgently required.”

David B. Clifford, MD, FAAN, Melba and Forest Seay Professor of Clinical Neuropharmacology in Neurology at Washington University in St. Louis, said PML is a “brutally aggressive disease if left unchecked,” with the majority of cases still occurring in HIV patients and patients taking natalizumab for multiple sclerosis.

For HIV patients, starting effective HIV therapy results in sufficient and prompt immune reconstitution to control PML in many cases, he said. The general approach for PML in the setting of natalizumab is to take the patient off the drug, often using plasma exchange to speed clearance of the drug and initiate immune reconstitution.

In other situations where PML develops, such as with hematologic malignancies or organ transplantation, immune checkpoint inhibitor drugs, such as pembrolizumab and nivolumab, are sometimes tried in an effort to enhance immune responses to the JC virus and thus treat the PML. But Dr. Clifford said he is not yet convinced of their usefulness, or for which patients they might provide benefit.

Dr. Clifford said that because the deterioration associated with PML can be rapid, the time required to develop a line of cells, whether autologous or from a donor, for T-cell therapy could be problematic. If a library of such cells that would provide sufficient genetic matches to the patients needing therapy could be developed, in theory, the timeline might be significantly reduced, he said.

Dr. Clifford said the approach may be better suited for patients whose deterioration from PML is slower, but pinpointing which patients might have a better or worse course is difficult, he said.

Despite such logistical challenges, Dr. Clifford said he hopes additional research is done to explore T-cell therapy for PML “as it does seem to have a potential place to treat this cruel disease.”

“I think this is an important and nicely done pilot study that suggests there may be value in this approach,” he said.

Joseph Berger, MD, FAAN, professor of neurology and associate chief of the MS division at Perelman School of Medicine at the University of Pennsylvania, agreed. He said it was noteworthy that the Italian team used JCV, the specific cause of PML, as the basis for the therapy rather than the closely related BKV.

“Despite a 70- to 75 percent genetic homology between the polyomaviruses BKV and JCV, PML is caused by JCV and, therefore, an immune response generated by the virus that is responsible for the disease would be anticipated to be more vigorous,” he said.

Dr. Berger said, “that an abundance of evidence indicates that cell-based immunity against JC is more important in controlling PML than the humoral response dependent on antibodies.”

“The presence of antibodies directed against JCV demonstrates that one is at risk for the disease, but, to date, there is little evidence that they are protective,” he said. “On the other hand, the importance of cell-mediated immunity is highlighted by the arrest of the disease in many patients with natalizumab-associated PML in whom the drug has been withdrawn or in the patients with AIDS-associated PML who are started on highly active antiretroviral therapy.”

Dr. Berger said he has seen good results in some of his PML patients who are given immune checkpoint inhibitors such as pembrolizumab, but a well-designed randomized control trial is warranted to convincingly establish their efficacy.

“I have been surprised by the number of people who have responded,” he said.

Disclosures

Dr. Comoli and study coauthors declared no disclosures. Dr. Koralnik has received royalties from UpToDate for chapters on PML. Berger has consulted with and has received honoraria and his institution has received grants from Biogen and Genentech/Roche. He has also received honoraria from Bristol Myers Squibb/Clegen Millennium/Takeda, Novartis (for serving on the scientific advisory board), and Inhibikase (for serving on the scientific advisory board).

Link Up for More Information

• Berzero G, Basso S, Stoppini L, et al. Adoptive transfer of JC virus-specific R lymphocytes or the treatment of progressive multifocal leukoencephalopathy https://onlinelibrary.wiley.com/doi/full/10.1002/ana.26020?af=R. Ann Neurol 2021; Epub 2021 Jan 18.
    • Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK virus-specific T cells for progressive multifocal leukoencephalopathy https://www.nejm.org/doi/full/10.1056/NEJMoa1801540. N Engl J Med 2018; 379(15):1443–1451.