Background: Infection with Epstein-Barr virus (EBV) is a necessary risk factor for the development of multiple sclerosis (MS) [Abrahamyan S et al. JNNP 2020; Pakpoor J et al. Mult Scler 2012]. ATA188 ? an off-the-shelf, allogeneic EBV-targeted T-cell immunotherapy ? is being evaluated in a two-part Phase I/II, multicenter study in adults with progressive forms of MS (PMS; NCT03283826). Part 1 of the study (Phase I, open-label, single-arm sequential dose escalation) indicated ATA188 is well tolerated, with a greater proportion of patients (pts) appearing to experience sustained disability improvement (SDI) at higher doses [Pender MP et al. EAN 2020]. These data need to be confirmed in a randomized, double-blind, placebo (PBO)-controlled study (DBPCS). Objectives: Part 2 is a Phase II DBPCS designed to evaluate the effect of ATA188 on clinical disability, characterize ATA188 safety/tolerability, and evaluate the impact of treatment on biological markers in PMS. Methods: In this DBPCS, initially 80 pts will be randomized to receive ATA188 or PBO; randomization of up to 120 additional pts will be determined based on an interim analysis. Results: Based on part 1 results, the first 18 pts in part 2 will be randomized to receive ATA188 Cohort 3 dose (2.0×107 cells) or PBO; subsequent pts will be randomized to receive ATA188 Cohort 4 dose (4.0×107 cells) or PBO. During Part 2 and the open-label extension (OLE), the dose may be decreased. In year 1, pts will receive two treatment cycles, ATA188 or PBO. In year 2, pts in the PBO arm will cross over to receive two cycles of ATA188; pts in the ATA188 arm will receive one cycle of ATA188 followed by one cycle of PBO. Pts completing year 2 will be eligible for a 3-year OLE, receiving ATA188 once a year. Eligible pts are those with a current diagnosis of PMS (primary or secondary), EBV seropositivity, age 18<61 years, and an expanded disability status scale (EDSS) score of 3.0-6.5 at screening. Key exclusion criteria include evidence of clinical relapse or radiologic activity within the 2 years prior to screening. Pts in part 1 are not eligible for part 2. The primary endpoint is the proportion of pts with sustained EDSS improvement at 12 months. Secondary endpoints include improvement in clinical disability (proportion of pts with sustained EDSS improvement at 15 months and SDI at 12 and 15 months) and change from baseline in cerebrospinal fluid immunoglobulin (IgG) index, including IgG production. The safety endpoint is the incidence of adverse events. Key tertiary and exploratory endpoints include magnetic resonance imaging measures (cervical spinal cord volume, whole brain volume, and number of gadolinium-enhancing and new or enlarging T2 lesions), measures of product kinetics, and additional clinical outcome measures (eg, ambulatory activity monitoring). Conclusions: Part 2, the randomized, PBO-controlled Phase II portion of this study, is now enrolling pts to evaluate the efficacy and safety of ATA188 in pts with PMS.