Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis

Dolphin · Nov 20, 2018

Somebody with ME was excited by this on Twitter

https://insight.jci.org/articles/view/124714

Research Article Clinical trials Neuroscience Free access | 10.1172/jci.insight.124714

Epstein-Barr virus–specific T cell therapy for progressive multiple sclerosis
Michael P. Pender,1,2,3 Peter A. Csurhes,1,4 Corey Smith,3 Nanette L. Douglas,1,2 Michelle A. Neller,3 Katherine K. Matthews,3 Leone Beagley,3 Sweera Rehan,3 Pauline Crooks,3 Tracey J. Hopkins,5 Stefan Blum,1,2 Kerryn A. Green,1,2 Zara A. Ioannides,1,2 Andrew Swayne,1,2 Blake T. Aftab,6 Kaye D. Hooper,1,2 Scott R. Burrows,1,3 Kate M. Thompson,7,8 Alan Coulthard,1,9 and Rajiv Khanna1,3
First published November 15, 2018 - More info

Related video:
Adoptive transfer of EBV-specific T cells in patients with multiple sclerosis
Author's Take

Multiple sclerosis (MS) is a chronic inflammatory disease of the CNS characterized by progressive demyelination and disability. Epstein-Barr (EBV) virus has been implicated in the pathogenesis of MS, as high anti-EBV titers have been reported in patients with MS. In this episode, Michael Pender and Rajiv Khanna discuss the results of an open-label, dose escalation trial designed to evaluate the safety and efficacy of adoptively transferred in vitro-expanded EBV-specific T cells for patients with progressive MS. Clinical improvement was seen 7 of the 10 patients, with the greatest benefit for patients that received T cells with strong EBV reactivity. The results from this initial trial indicate that the EBV-specific adoptive T cell therapy is well tolerated and support further investigation of this approach in efficacy trials.

Abstract

BACKGROUND. Increasing evidence indicates a role for EBV in the pathogenesis of multiple sclerosis (MS). EBV-infected autoreactive B cells might accumulate in the CNS because of defective cytotoxic CD8+ T cell immunity. We sought to determine the feasibility and safety of treating progressive MS patients with autologous EBV-specific T cell therapy.

METHODS. An open-label phase I trial was designed to treat 5 patients with secondary progressive MS and 5 patients with primary progressive MS with 4 escalating doses of in vitro–expanded autologous EBV-specific T cells targeting EBV nuclear antigen 1, latent membrane protein 1 (LMP1), and LMP2A. Following adoptive immunotherapy, we monitored the patients for safety and clinical responses.

RESULTS. Of the 13 recruited participants, 10 received the full course of T cell therapy. There were no serious adverse events. Seven patients showed improvement, with 6 experiencing both symptomatic and objective neurological improvement, together with a reduction in fatigue, improved quality of life, and, in 3 patients, reduced intrathecal IgG production. All 6 patients receiving T cells with strong EBV reactivity showed clinical improvement, whereas only 1 of the 4 patients receiving T cells with weak EBV reactivity showed improvement (P = 0.033, Fisher’s exact test).

CONCLUSION. EBV-specific adoptive T cell therapy was well tolerated. Clinical improvement following treatment was associated with the potency of EBV-specific reactivity of the administered T cells. Further clinical trials are warranted to determine the efficacy of EBV-specific T cell therapy in MS.

TRIAL REGISTRATION. Australian New Zealand Clinical Trials Registry, ACTRN12615000422527.

FUNDING. MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd., and donations from private individuals who wish to remain anonymous.
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Dolphin · Nov 20, 2018

https://globenewswire.com/news-rele...reated-with-ATA190-an-Autologous-Epstein.html

Atara Biotherapeutics Announces Publication of Phase 1 Study Demonstrating Clinical Improvement in Progressive Multiple Sclerosis Patients Treated with ATA190, an Autologous Epstein-Barr Virus (EBV)-Specific T-Cell Immunotherapy
Findings reported in an article online and to be published in the December 2018 issue of the JCI Insight
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November 19, 2018 08:30 ET | Source: Atara Biotherapeutics, Inc.

SOUTH SAN FRANCISCO, Calif., Nov. 19, 2018 (GLOBE NEWSWIRE) -- Atara Biotherapeutics, Inc. (Nasdaq: ATRA), a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases, today announced that results of a Phase 1 clinical study conducted by the Company's collaborating investigators at QIMR Berghofer Medical Research Institute and The University of Queensland were published online in JCI Insight. The article describes clinical findings observed in progressive multiple sclerosis (MS) patients treated with ATA190, Atara’s autologous EBV-specific T-cell immunotherapy.

“We previously presented promising initial ATA190 results in patients with progressive MS, and the published results confirm our earlier observations,” said Professors Michael Pender, The University of Queensland and Rajiv Khanna, Coordinator of QIMR Berghofer Centre for Immunotherapy and Vaccine Development. “Findings from the study support growing evidence that targeting EBV-positive B cells is a potential novel treatment modality for MS and merit additional investigation.”

The Phase 1 open-label, uncontrolled study evaluated escalating doses of ATA190 in ten patients, five with primary and five with secondary progressive MS. Safety and efficacy were monitored for up to 27 weeks and included Expanded Disability Status Scale (EDSS) score, fatigue, cognitive and other neurological assessments as well as analysis of magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) immunoglobulin G (IgG) production. Prior to ATA190 T-cell immunotherapy, patients had experienced progressive neurological deterioration for a mean of 10.1 years.

ATA190 was well-tolerated and no severe adverse events were observed in the study. Adverse events of grade 1 or 2 severity occurred in 2 participants, with only one grade 1 dysgeusia definitely related to treatment. Seven patients in the study showed symptomatic and objective neurological improvement, which commenced two to 14 weeks after the first infusion. Reduction in fatigue, one of the most frequent and disabling symptoms of MS, was a consistent and prominent feature in patients showing neurological improvement.

Reactivity of ATA190 against target EBV antigens (EBV reactivity) as well as other mechanistic markers of T cell function were assessed. Six participants in the study who received ATA190 with strong EBV reactivity experienced clinical improvement, including three with decreased EDSS scores. One of four participants who received ATA190 with weak EBV reactivity showed improvement and no change in EDSS score was observed. One of ten patients had neurological deterioration during the study.

“We are encouraged by the published results for autologous ATA190, the first prospective clinical study of an EBV-specific T-cell immunotherapy in progressive MS,” said Dietmar Berger, M.D., Ph.D., Global Head of Research and Development of Atara Biotherapeutics. “We are also advancing an ongoing Phase 1 off-the-shelf, allogeneic ATA188 study in patients with progressive MS across clinical sites in the U.S. and Australia. We look forward to continued development of both programs, including our plans to initiate a randomized ATA190 MS study.”

The study was funded by MS Queensland, MS Research Australia, Perpetual Trustee Company Ltd and donations from private individuals.

About Progressive Multiple Sclerosis
MS is a chronic neurological autoimmune disease that affects more than two million people around the world. Progressive MS (PMS) is a severe form of the disease with few therapeutic options. PMS comprises two conditions, both characterized by persistent progression and worsening of MS symptoms and physical disability over time. Primary Progressive MS (PPMS) occurs when continuous progressive disease is present at diagnosis and occurs in approximately 15% of newly diagnosed cases. Secondary Progressive MS (SPMS) initially begins as RRMS and develops into a progressive form. Up to 80% of people with RRMS will eventually develop SPMS. There is substantial unmet medical need for new and effective therapies for patients with PPMS and SPMS. Most treatment options that work well in reducing flares in RRMS have not been shown to be effective in slowing or reversing disability in PMS.

About off-the-shelf, allogeneic ATA188 and autologous ATA190
Epstein-Barr Virus (EBV) is associated with a wide range of hematologic malignancies and solid tumors, as well as certain autoimmune conditions such as multiple sclerosis (MS). T cells are a critical component of the body's immune system and can selectively target specific EBV antigens believed to be important for the potential treatment of MS. Off-the-shelf, allogeneic ATA188 and autologous ATA190, using Atara’s complementary T-cell immunotherapy technology pioneered by Professor Rajiv Khanna at QIMR Berghofer, have the potential to precisely recognize and eliminate EBV-infected B cells in the central nervous system that may catalyze autoimmune responses and MS pathophysiology. In 2017 Professor Michael Pender from The University of Queensland presented results from the first autologous ATA190 study, which was funded by MS Research Australia, MS Queensland, Perpetual Trustee Company Ltd and donations from private individuals. Atara is advancing an ongoing Phase 1 off-the-shelf, allogeneic ATA188 study in patients with progressive MS across clinical sites in the U.S. and Australia and plans to initiate a randomized autologous ATA190 study in progressive MS patients.

About Atara Biotherapeutics, Inc.
Atara Biotherapeutics, Inc. (@Atarabio) is a leading off-the-shelf, allogeneic T-cell immunotherapy company developing novel treatments for patients with cancer, autoimmune and viral diseases. Atara’s most advanced T-cell immunotherapy, tab-cel® (tabelecleucel), is in Phase 3 development for patients with Epstein-Barr virus associated post-transplant lymphoproliferative disorder (EBV+ PTLD), as well as other EBV associated hematologic and solid tumors, including nasopharyngeal carcinoma (NPC). Atara is also developing T-cell immunotherapies targeting EBV antigens believed to be important for the potential treatment of multiple sclerosis (MS). Atara's pipeline also includes next generation chimeric antigen receptor T-cell (CAR T) immunotherapies for patients with hematologic and solid tumors, autoimmune and infectious diseases. The company was founded in 2012 and is headquartered in South San Francisco, California.

Forward-Looking Statements
This press release contains or may imply "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. For example, forward-looking statements include statements regarding: the timing, progress and results of the Company’s Phase 1 studies of ATA188 and ATA190 in patients with progressive MS; the potential advantages of ATA188 and ATA190 in the treatment of progressive MS; the Company’s ability to expand its pipeline; and the potential advantages of its other product candidates. Because such statements deal with future events and are based on Atara Biotherapeutics' current expectations, they are subject to various risks and uncertainties and actual results, performance or achievements of Atara Biotherapeutics could differ materially from those described in or implied by the statements in this press release. These forward-looking statements are subject to risks and uncertainties, including those discussed in Atara Biotherapeutics' filings with the Securities and Exchange Commission (SEC), including in the “Risk Factors” and “Management’s Discussion and Analysis of Financial Condition and Results of Operations” sections of the Company’s most recently filed periodic reports on Form 10-K and Form 10-Q and subsequent filings and in the documents incorporated by reference therein. Except as otherwise required by law, Atara Biotherapeutics disclaims any intention or obligation to update or revise any forward-looking statements, which speak only as of the date hereof, whether as a result of new information, future events or circumstances or otherwise.
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Londinium · Nov 23, 2018

New Scientist has a good overview here: https://www.newscientist.com/articl...-treatment-that-attacks-glandular-fever-virus

Some bits I found interesting:

The Epstein-Barr virus has long been suspected as a possible cause of MS, after researchers noticed that people with a past history of glandular fever were more likely to develop the neurodegenerative condition. Multiple studies have now confirmed that almost every MS patient carries the virus and that non-carriers almost never develop the disease.

After most glandular fever episodes, the virus lies dormant in a group of immune cells called B cells without causing any further problems, says Rajiv Khanna at QIMR Berghofer Medical Research Institute in Australia. But growing evidence suggests that problems with some people’s immune systems allow the virus-infected B cells to invade their brain and spine, he says.
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This seemed redolent of the VanElzakker hypothesis regarding the vagus nerve.

Seven of the people reported improvements, including increased energy and the ability to do everyday activities, as well as better concentration, mental clarity, vision, and balance. In four people, levels of an MS-associated protein called immunoglobulin G also went down. None of the people in the study reported serious side-effects.
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For progressive MS patients, seemed to deal with both fatigue and cognitive impairment. Definitely worth noting however that this is a very small trial and would need replication.

Londinium · Nov 24, 2018

To add: the study also cites this paper (that I hadn't seen before) that has the frankly astonishing fact:

Of the 16,976 patients with MS in the overall population, 5305 (31.3%) were newly diagnosed with MS and had three years of continuous healthcare coverage prior to MS diagnosis. Of these patients, 1534 (28.9%) were labeled with chronic fatigue syndrome (ICD9-780.71) or malaise or fatigue (ICD9-780.79) prior to the diagnosis of MS. One-third of these patients were labeled with fatigue one to two years before the diagnosis; 30.8% were diagnosed only with fatigue and had no other MS symptoms prior to their MS diagnosis.
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If almost a third of multiple sclerosis patients are initially misdiagnosed with ME/CFS or general fatigue that raises an even bigger ethical issue with MUS practitioners' recommendation that, once an MUS diagnosis is made, no further medical testing should follow due to it being counterproductive. This means that somebody with MS could be dumped in the 'do not test' MUS bucket and incur significant physical injury should that delay the correct diagnosis.

Dolphin · Nov 24, 2018

Londinium said: ↑

To add: the study also cites this paper (that I hadn't seen before) that has the frankly astonishing fact:

If almost a third of multiple sclerosis patients are initially misdiagnosed with ME/CFS or general fatigue that raises an even bigger ethical issue with MUS practitioners' recommendation that, once an MUS diagnosis is made, no further medical testing should follow due to it being counterproductive. This means that somebody with MS could be dumped in the 'do not test' MUS bucket and incur significant physical injury should that delay the correct diagnosis.
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It would be interesting to note the breakdown between the two categories. I have written to thousands of people who have enquired to an ME/CFS patient organisation, i.e. months or sometimes years after they first enquired. People sometimes get in touch to say they were re-diagnosed with something else. I'm not sure I recall that anyone said they were rediagnosed with Multiple Sclerosis.

ladycatlover · Nov 25, 2018

Dolphin said: ↑

I'm not sure I recall that anyone said they were rediagnosed with Multiple Sclerosis.
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A friend of mine who I met through the local MEA group (back when they had local groups) was re-diagnosed with MS. Was originally dxd with ME by R H T Edwards of Liverpool Uni. After MS dx was able to obtain DLA, had always been refused when had the ME dx, despite physical condition not having changed. Sadly died a few years ago.

rvallee · Nov 25, 2018

Londinium said: ↑

To add: the study also cites this paper (that I hadn't seen before) that has the frankly astonishing fact:

If almost a third of multiple sclerosis patients are initially misdiagnosed with ME/CFS or general fatigue that raises an even bigger ethical issue with MUS practitioners' recommendation that, once an MUS diagnosis is made, no further medical testing should follow due to it being counterproductive. This means that somebody with MS could be dumped in the 'do not test' MUS bucket and incur significant physical injury should that delay the correct diagnosis.
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I'm not at all surprised by this. Bad guidelines that rely on loose criteria are bad for everyone. They create comparable numbers of false positives as false negatives, helping neither group in the end. In addition of course to blocking all access to mental health resources since patients understand the implications to their already sub-par medical care.

It's a stunning regression to pre-science medicine. What I'm surprised is how other disease advocacy organisations are not concerned by this, especially as the attempt to lump MS at least partly into MUS has started. If psychosocial ideologues get their way many MS patients will have delayed diagnosis, leading to serious deterioration. This will hurt their patients just as badly as it will hurt us and especially MS should be concerned considering that their own history is similar to ours.

adambeyoncelowe · Nov 26, 2018

Dolphin said: ↑

It would be interesting to note the breakdown between the two categories. I have written to thousands of people who have enquired to an ME/CFS patient organisation, i.e. months or sometimes years after they first enquired. People sometimes get in touch to say they were re-diagnosed with something else. I'm not sure I recall that anyone said they were rediagnosed with Multiple Sclerosis.
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I know someone who works with one of the major MS charities. She says it's quite common for patients to initially be diagnosed with ME.

Similarly, if you search the forums for the MS charities, you find lots of these reports. There are plenty of people asking if they've got the right diagnosis or explaining how they were misdiagnosed.

It may just be that once their diagnosis changes, they leave ME circles and join MS circles instead, so we don't hear about it as often.

rvallee · Nov 26, 2018

adambeyoncelowe said: ↑

I know someone who works with one of the major MS charities. She says it's quite common for patients to initially be diagnosed with ME.

Similarly, if you search the forums for the MS charities, you find lots of these reports. There are plenty of people asking if they've got the right diagnosis or explaining how they were misdiagnosed.

It may just be that once their diagnosis changes, they leave ME circles and join MS circles instead, so we don't hear about it as often.
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It would be really great if they raised concerns about this. Sounds like something they really should be raising concerns about. The NICE guidelines are very much a huge part of this and the history of MS mirrors our own, just shifted by decades. They know what it leads to and how cruel it is.

I guess they don't have much extra resources but this sounds like a pretty low-effort thing to do when it directly impacts them in ways that can lead to serious permanent complications, especially with the overall MUS (or is it PPS now? or PDF? or FFS?) movement that will inevitably impact most MS patients but especially those with less common forms.

Meanwhile neurologists who will have to deal with the consequences are basically front and center arguing to regress science with the functional BS.

Mithriel · Dec 3, 2018

It was about 1994 so attitudes may have changed now but when my friend first became ill her family hoped she "just" had ME like me and not MS. (She was more understanding and said there was not much to choose between the 2, though sadly, she is dead now so..)

It makes me wonder if ME has been so trivialised as CFS that it is seen as just a step before doctors realise they actually have a serious disease. MS is seen as such a tragedy by society - to the extent that MS charities have to tell people that it is not as serious as people think and can have a mild form - that patients tend to have a feeling of entitlement, maybe that a lot of people with recognised diseases have, we wouldn't know. So saying you have cancer or MS everyone feels you are seriously sick.

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