Most of you know by now that I am one of the main proponents supporting EBV as the primary cause of MS. I think EBV is actively driving MS disease activity. The corollary to this statement is that we may be able to treat MS with anti-EBV drugs. We have suggested that all MS DMTs work by affecting memory B-cell biology and that this is the cell that host the EB virus. At Barts-MS, we have an active research programme to test anti-EBV drugs in MS.
One way of targeting EBV is via immunotherapy and Michael Pender, from Brisbane, has been promoting this strategy for over a decade. His data on using autologous ant-EBV CTLs (cytotoxic T-lymphocytes) is impressive. Almost too good to be true! Most of the MS community has dismissed his data as being biased due to being unblinded and from one centre. However, if you drill down into his data you will see that most of the MSers he has treated have had quite advanced disease with high EDSS scores and the improvements in disability have been so profound that it would be difficult to ascribe this to biased EDSS-rating. I am convinced that Michael Pender is onto something big and something very important.
This is why the ATARA Bio early phase 1b data is my one of my #ECTRIMS2019 highlights. Instead, of autologous cells, ATARA Bio is using MHC-matched allogenic CTLs. The good news from their poster presentation is that these cells seem safe as a treatment and at the high doses they are reproducing Pender’s single-centre results.
I agree it is too early to be jumping up and down and that we need to wait for the results of a randomised double-blind controlled study, but imagine a world in which we treat MS with anti-EBV CTLs and our MSers notice profound improvements in disability? This would be a true paradigm shift, a black swan event! Overnight MS would be classified as an infectious disease. Could you imagine what would happen to the MS DMT market? I sincerely hope for the MS community that this remarkable story pans out to be true.
Prof G’s ECTRIMS Highlight #2
Pender et al. Preliminary safety and efficacy of ATA188, a pre-manufactured, unrelated donor (off-the-shelf, allogeneic) Epstein-Barr virus-targeted T-cell immunotherapy for patients with progressive forms of multiple sclerosis. ECTRIMS 2019 Abstract: P1657.
Introduction: Evidence suggests Epstein-Barr virus (EBV) infection is associated with multiple sclerosis pathogenesis. In patients (pt) with progressive forms of MS (pMS), autologous EBV-specific T cells may prevent progression and improve symptoms (Pender, et al. JCI Insight. 2018).
Objectives: To evaluate ATA188, an off-the-shelf, allogeneic, EBV-targeted T cell immunotherapy comprised of HLA-matched, in vitro-expanded, cytotoxic T lymphocytes in a first-in-human, multicenter, 2-part study in adults with pMS (NCT03283826). Preliminary data are reported.
Methods: Eligible pt (age 18‒< 66) are EBV-seropositive with pMS and an Expanded Disability Status Scale (EDSS) score of 3‒7. Cohorts (cht) 1‒4 (6‒9 pt/cht) receive escalating doses of ATA188. 1° endpoints: safety and identification of the recommended phase 2 dose (RP2D) of ATA188. Efficacy criteria: EDSS, MS Impact Scale-29, Fatigue Severity Scale, and 12-Item MS Walking Scale scores; timed 25-foot walk; 9-hole Peg Test; and visual acuity. A responder (R) has sustained ≥ minimal clinically significant (MCS) improvement from BL in 2 consecutive evaluations on ≥2 efficacy criteria; a partial responder (PR) has ≥ MCS improvement from baseline (BL) in any 1 evaluation on ≥2 efficacy criteria; and a non-responder (NR) has ≥ MCS decline from BL in any 1 evaluation on ≥2 efficacy criteria (if both criteria are met, pt is NR). Plasma inflammatory biomarkers (IL-2, IL-1β, TNF-α, IL-6) are monitored throughout treatment.
Results: As of 27 May 2019, 19 pt (53% male; median age, 56 years) have enrolled (6 in each of cht 1‒3; 1 in cht 4) and received ≥1 dose of ATA188. Treatment-emergent AEs (TEAE) occurred in 63% (12/19) pt and treatment-related AEs (TRAE) in 37% (7/19) pt; 1 pt (cht 2) had a grade ≥ 3 TEAE, and 1 (cht 4) had a serious TRAE. No dose-limiting toxicities or fatal TEAE have been reported. Efficacy data are available for cht 1 and 2: cht 1, 1 R, 1 PR, and 4 NR at 6 months and 1 R, 0 PR, and 1 NR at 12 months; cht 2, 2 R, 4 PR, and 0 NR at 6 months. On measures of disability, 3/6 showed improvement and 3/6 showed decline in cht 1; 4/6 showed improvement and 1/6 showed decline in cht 2. Inflammatory cytokines remained at or near baseline.
Conclusion: Preliminary data indicate ATA188 is well tolerated and improves efficacy measures in adults with pMS, even at lower doses. These results support continuing part 1 to identify RP2D for part 2, (randomized, double-blind, placebo-controlled portion).
Pender et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018 Nov 15;3(22). pii: 124714. doi: 10.1172/jci.insight.124714.
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.