Tweet
Promising SPMS treatment has potential at repair, stopping progression
Wow, oh wow. We can dream, right?!? From Prof Gs blog at Bart's MS in London. -D
As you are aware by now I am one of the people in the field of MS who thinks EBV is the cause of MS. My position is essentially based on epidemiological evidence and causal inference. At the moment I honestly don’t know how EBV causes MS, but one hypothesis is that ongoing EBV infection in the CNS or in a peripheral compartment drives MS disease activity. EBV resides in memory B-cells and memory B-cell appears to be the main target of all effective MS disease-modifying therapies.
The question is can we simply treat MS by targeting EBV and not using a sledgehammer; i.e. depleting all B-cells (anti-CD20) or taking out the memory B-cell with non-selective immune reconstitution therapies (IRTs), e.g. AHSCT or alemtuzumab? One way to do this is to use anti-EBV drugs or cellular therapies targeting EBV infected cells.
This is why one of my highlights at this meeting is Atara Bio’s phase-1 MRI data on using anti-EBV HLA-matched cytotoxic T-lymphocytes as a treatment for progressive MS. Study subjects who had sustained improvement in the EDSS showed a significant increase or improvement in their brain MTR (magnetization transfer ratio) at 12 months compared to baseline. MTR is an MRI marker of tissue integrity and is thought to represent tissue repair and remyelination. The important point for me is the MTR is an objective measure done using software and is blinded to the clinical information or treatment allocation. Having an objective measure on MRI that correlates with a relatively subjective clinical measure improves my confidence that what we are seeing may be real.
The other remarkable observation in this study is by how much some of the responders in this study improved. EDSS scores improved by well over one EDSS point with one patient improving by as much 2.5 points, i.e. from an EDSS of 5.5 to 3.0. Two other subjects went from EDSS 6.0 to 4.5; from needing a walking stick to walk 100m to be able to walk between 300m and 499m unassisted and without taking a rest. Outside of relapses, these sorts of EDSS improvements don’t happen in people with established progressive MS. This is almost as impressive as the Lazarus effect we see rarely in patients treated with steroids or plasma exchange for a relapse. The Lazarus effect describes those patients who go from EDSS 7.0+ (bed-bound) to getting up and walking within hours to days of being treated.
READ MORE from MS researcher Gavin Giovannoni
https://multiple-sclerosis-research....azarus-effect/
P638 - Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosisM.P Pender1, S.J Hodgkinson2,3, S. Broadley4, JW. Lindsey5, Z.A Ioannides1, B. Bagert6, L. Gamelin7, E. Liu7, W. Ye7, J. Willmer7, A. Bar-Or8
1The University of Queensland, Brisbane, Australia, 2University of New South Wales, Sydney, Australia, 3Liverpool Hospital, Liverpool, New South Wales, Australia, 4Griffith University, Southport, Australia, 5University of Texas Health Science Center at Houston, Houston, United States, 6Ochsner Health, New Orleans, United States, 7Atara Biotherapeutics, South San Francisco, United States, 8Center for Neuroinflammation and Experimental Therapeutics, and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Introduction: Mounting evidence suggestsEpstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].
Objectives/aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).
Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.
Results: 25 pts received ≥1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.
Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.
As you are aware by now I am one of the people in the field of MS who thinks EBV is the cause of MS. My position is essentially based on epidemiological evidence and causal inference. At the moment I honestly don’t know how EBV causes MS, but one hypothesis is that ongoing EBV infection in the CNS or in a peripheral compartment drives MS disease activity. EBV resides in memory B-cells and memory B-cell appears to be the main target of all effective MS disease-modifying therapies.
The question is can we simply treat MS by targeting EBV and not using a sledgehammer; i.e. depleting all B-cells (anti-CD20) or taking out the memory B-cell with non-selective immune reconstitution therapies (IRTs), e.g. AHSCT or alemtuzumab? One way to do this is to use anti-EBV drugs or cellular therapies targeting EBV infected cells.
This is why one of my highlights at this meeting is Atara Bio’s phase-1 MRI data on using anti-EBV HLA-matched cytotoxic T-lymphocytes as a treatment for progressive MS. Study subjects who had sustained improvement in the EDSS showed a significant increase or improvement in their brain MTR (magnetization transfer ratio) at 12 months compared to baseline. MTR is an MRI marker of tissue integrity and is thought to represent tissue repair and remyelination. The important point for me is the MTR is an objective measure done using software and is blinded to the clinical information or treatment allocation. Having an objective measure on MRI that correlates with a relatively subjective clinical measure improves my confidence that what we are seeing may be real.
The other remarkable observation in this study is by how much some of the responders in this study improved. EDSS scores improved by well over one EDSS point with one patient improving by as much 2.5 points, i.e. from an EDSS of 5.5 to 3.0. Two other subjects went from EDSS 6.0 to 4.5; from needing a walking stick to walk 100m to be able to walk between 300m and 499m unassisted and without taking a rest. Outside of relapses, these sorts of EDSS improvements don’t happen in people with established progressive MS. This is almost as impressive as the Lazarus effect we see rarely in patients treated with steroids or plasma exchange for a relapse. The Lazarus effect describes those patients who go from EDSS 7.0+ (bed-bound) to getting up and walking within hours to days of being treated.
READ MORE from MS researcher Gavin Giovannoni
https://multiple-sclerosis-research....azarus-effect/
P638 - Updated open-label extension clinical data and new magnetization transfer ratio imaging data from a Phase I study of ATA188, an off-the-shelf, allogeneic Epstein-Barr virus-targeted T-cell immunotherapy for progressive multiple sclerosisM.P Pender1, S.J Hodgkinson2,3, S. Broadley4, JW. Lindsey5, Z.A Ioannides1, B. Bagert6, L. Gamelin7, E. Liu7, W. Ye7, J. Willmer7, A. Bar-Or8
1The University of Queensland, Brisbane, Australia, 2University of New South Wales, Sydney, Australia, 3Liverpool Hospital, Liverpool, New South Wales, Australia, 4Griffith University, Southport, Australia, 5University of Texas Health Science Center at Houston, Houston, United States, 6Ochsner Health, New Orleans, United States, 7Atara Biotherapeutics, South San Francisco, United States, 8Center for Neuroinflammation and Experimental Therapeutics, and Department of Neurology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States
Introduction: Mounting evidence suggestsEpstein-Barr virus (EBV) is a necessary risk factor for development of multiple sclerosis (MS) [Abrahamyan et al. JNNP 2020]. Early experience with autologous EBV-specific T-cell therapy proved safe and may offer clinical benefit [Pender MP et al. JCI Insight 2018; Ioannides ZA et al. Front Neurol 2021].
Objectives/aims: Evaluate the safety and potential efficacy of ATA188 in adults with progressive MS in an ongoing open-label extension (OLE) study, including an imaging biomarker: magnetization transfer ratio (MTR).
Methods: In part 1 of this 2-part Phase I/II study, 4 cohorts received escalating doses of ATA188. Patients (pts) were followed for 1 year and could participate in a 4-year OLE. Sustained disability improvement (SDI; including expanded disability status scale [EDSS] and timed 25-foot walk), as well as safety, were measured [Pender MP et al. EAN 2020]. As a biomarker of improvement, change from baseline in MTR, an exploratory endpoint, was assessed.
Results: 25 pts received ≥1 dose of ATA188 and were followed for up to 33 mos (m). No grade >3 adverse events (AE), dose-limiting toxicities, cytokine release syndrome, graft vs host disease, or infusion-related reactions were observed. 2 treatment-emergent serious AEs were previously reported (muscle spasticity [grade 2; not treatment related]; MS relapse [grade 3; possibly treatment related]) and, as of April 2021, 1 was reported in the OLE (fall; grade 2; not treatment related). Efficacy was evaluated in 24 pts in the initial 12m period and, as of April 2021, in 18 pts in the OLE followed for up to 33m. 9 pts met SDI criteria either in the initial 12m period (n=7) or in the OLE (n=2); of these, 7 had sustained EDSS improvement. Of the 8 pts that achieved SDI and entered the OLE, 7 maintained SDI at all subsequent timepoints. Pts with sustained EDSS improvement (vs those without) had greater increases in MTR signal (in unenhancing T2 lesions and normal-appearing brain tissue) at 12m.
Conclusions: Preliminary data indicate ATA188 is well tolerated. Sustained EDSS improvement drove SDI in most pts, and in all but 1 pt, SDI was maintained at all subsequent timepoints. As a biomarker associated with disability, pts with sustained EDSS improvement (vs those without) showed greater increases in MTR signal at 12m, which may be suggestive of remyelination. The Phase 2 portion of this study, EMBOLD (NCT03283826), is ongoing and currently enrolling.
Comment