Epitope-based precision immunotherapy of Type 1 diabetes

Abstract

Antigen-specific immunotherapies (ASITs) address important clinical needs in treating autoimmune diseases. However, Type 1 diabetes is a heterogeneous disease wherein patient characteristics influence responsiveness to ASITs. Targeting not only disease-relevant T cell populations, but also specific groups of patients using precision medicine is a new goal toward achieving effective treatment. HLA-restricted peptides provide advantages over protein as antigens, however, methods for profiling antigen-specific T cells need to improve in sensitivity, depth, and throughput to facilitate epitope selection. Delivery approaches are highly diverse, illustrating the many ways relevant antigen-presenting cell populations and anatomical locations can be targeted for tolerance induction. The role of persistence of antigen presentation in promoting durable antigen-specific tolerance requires further investigation. Based on the outcome of ASIT trials, the field is moving toward using patient-specific variations to improve efficacy, but challenges still lie on the path to delivering more effective and safer treatment to the T1D patient population.

Soluble antigen arrays provide increased efficacy and safety over free peptides for tolerogenic immunotherapy

“…No anaphylaxis was observed in any of the treatment groups following dose tapering. Our results indicate that ( 1 ) these peptides (p79 and 2.5HIP) in free form do not confer any protection (already evident before dose tapering) but efficiently block the disease in SAgA form ( 2 ), hSAgA and cSAgA have a comparable efficacy if anaphylaxis is averted, and ( 3 ) dose tapering does not result in substantial loss of protection, but it efficiently overcame anaphylaxis. Of note, we excluded ao-modified peptides in this study due to their high anaphylactogenic nature.…”

FASTMAP—a flexible and scalable immunopeptidomics pipeline for HLA- and antigen-specific T-cell epitope mapping based on artificial antigen-presenting cells

“…Owing to the high-throughput potential, our system could be used to create the large amount of allele-specific peptide mapping data that are needed to train prediction tools on endogenously processed peptide ligands to improve the algorithms and reduce the rate of false-positive predictions ( 71 ). Many patients with autoimmune disease are suffering from the high unmet medical need for antigen-specific immunotherapies also considering the patient-specific variations in the HLA genotype ( 105 , 106 ). To overcome this need, our FASTMAP pipeline may facilitate the way for antigen-specific immunotherapies in autoimmune diseases with known antigen(s) to contribute to develop epitope-based therapeutics in the future that mitigate autoimmune inflammation, preserve regular immune function, are disease-specific with minimized side effects, and are curative at best.…”

Application of chimeric antigen receptor-natural killer cells for the treatment of type 1 diabetes

“…These diseases are chronic, debilitating, and occasionally fatal, and their development is the result of unknown interactions between environmental triggers and numerous polymorphic genetic elements [3]. B cells and T cells are the primary contributors to the overactive immune response involved in the pathogenesis of autoimmune diseases [4,5].…”