A randomized clinical trial of autologous T-cell therapy in multiple sclerosis: subset analysis and implications for trial design

Abstract

Background: Tovaxin is an autologous T-cell immunotherapy under investigation for the treatment of MS. The product consists of in vitro expanded myelin-reactive T-cells manufactured against up to six immunodominant peptides derived from three myelin antigens. Methods: A Phase 2b placebo controlled study (TERMS) was conducted in 150 subjects to gather safety and efficacy data in relapsing-remitting MS and clinically isolated syndrome subjects. Results: Tovaxin had a favorable safety profile. Although no statistically significant clinical or radiological benefit of Tovaxin immunotherapy was identified in the modified intent-to-treat population, a prospective analysis of subjects with more active disease favored Tovaxin in terms of annualized relapse rate (ARR) and disability progression. An analysis also found a possible legacy effect of prior disease-modifying treatment (DMT) which may have contributed to a lowered ARR in the placebo group. DMT-naïve subjects treated with Tovaxin had a lower ARR compared to the placebo group, particularly in those with active baseline disease (ARR≥1, ARR>1). However, clinical benefit was not was accompanied by a treatment-dependent improvement in MRI measures. Conclusions: Previous DMT exposure may reduce effect size and study power. Limiting subject selection to DMTtreatment-naïve individuals may be a reasonable approach to phase 2 or proof-of-concept studies of limited duration.

Immune responses to polyclonal T-cell vaccination in patients with progressive multiple sclerosis

“…From available data (Fox et al 2012;Huang et al 2014), it appears that myelin basic protein (MBP), proteolipid protein (PLP), myelin oligodendrocyte glycoprotein (MOG) and possibly other yet-unidentified molecules can be implicated in MS development. Hence, antigenic specificity of monoclonal or oligoclonal vaccinal T-cells may be distinguished from self-reactive -cells dominating in autoimmune process by antigenic specificity of their TCR.…”

“…It has been previously shown that T-cell vaccination can be effectively used in the treatment of relapsing forms of MS (Fox et al 2012;Huang et al 2014). A progressive MS is usually less sensitive to therapeutic manipulations compared to relapsing MS.…”

The future of multiple sclerosis treatments

“…TCV include an attenuation step to preventing the encephalitogenicity of myelin-reactive T cells and is safe. Two phase II, placebo-controlled clinical trials of TCV in MS were reported [167,168]. Fox et al showed that treatment with myelin-reactive T-cells against up to six peptides of MBP, MOG and PLP was safe in 100 RRMS and CIS patients, of which 44% were previously treated with DMTs [168].…”

“…Two phase II, placebo-controlled clinical trials of TCV in MS were reported [167,168]. Fox et al showed that treatment with myelin-reactive T-cells against up to six peptides of MBP, MOG and PLP was safe in 100 RRMS and CIS patients, of which 44% were previously treated with DMTs [168]. Although no statistically significant clinical or radiological benefits were obtained when compared with the placebo arm, some post-hoc evidence of clinical efficacy in the active arm in the subgroup of patients DTM-naïve was seen [168].…”

Neuroimmunotherapies Targeting T Cells: From Pathophysiology to Therapeutic Applications

“…A randomized, placebo-controlled, phase IIb trial was conducted using myelin-specific T cells restimulated with 6 myelin peptides from MBP, MOG, and PLP proteins [Tcelna and Imilecleucel-T (Opexa Therapeutics, The Woodlands, TX, USA)] in 150 patients with RRMS [133]. After 1 year, analysis revealed no difference in clinical and radiological parameters.…”