Autologous CTLs Expressing EBV-Binding TCRs for Progressive MS
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Solution Overview
Problem
Current treatments for autoimmune diseases like multiple sclerosis (MS), particularly secondary and primary progressive forms, do not effectively target the role of Epstein Barr Virus (EBV) in disease progression, leading to inadequate therapeutic responses.
Innovation Solution
Development of autologous cytotoxic T cells (CTLs) expressing a T cell receptor that specifically binds to EBV peptides presented on MHC, induced through incubation with antigen-presenting cells and selected for high expression of CD107a, IFNγ, TNFa, and IL-2, for administration to patients.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for MS are used, then general immune suppression is achieved, but specificity against EBV-infected cells is lost
Solution Approach 1:
The patent extracts and isolates the specific T cell population that recognizes EBV peptides from the patient's own T cell repertoire. By enriching for EBV-specific T cells through in vitro stimulation with EBV peptides and selecting for cells expressing activation markers (CD107a, IFNγ, TNFα, IL-2), the treatment delivers a focused immunotherapy that targets only EBV-infected cells while sparing other immune functions.
Solution Approach 2:
The patent applies local quality by creating a heterogeneous T cell product with distinct functional zones. The T cell population includes effector cells (expressing CD107a, IFNγ, TNFα) for immediate cytotoxic activity and memory precursors for long-term surveillance. This functional heterogeneity within the product allows simultaneous immediate anti-EBV activity and sustained immune memory against EBV-infected B cells.
2Reliability
If autologous T cells are expanded in vitro, then therapeutic efficacy is improved, but manufacturing complexity increases
Solution Approach 1:
The patent performs preliminary action by pre-stimulating patient T cells with EBV peptides in vitro before administration. This pre-activation step ensures that the infused T cells are already primed and ready to recognize and kill EBV-infected cells immediately upon infusion, eliminating the need for complex in vivo conditioning or multiple sequential infusions.
Solution Approach 2:
The patent implements feedback control by monitoring T cell activation markers (CD107a, IFNγ, TNFα, IL-2) during in vitro expansion to determine when optimal efficacy has been achieved. This quality control approach allows the manufacturing process to be stopped at the precise moment when therapeutic potency is maximized, avoiding unnecessary complexity from extended culture protocols or multiple expansion cycles.
3Power
If T cells are selected for high cytokine expression, then immune response strength is enhanced, but risk of cytokine storm increases
Solution Approach 1:
The patent applies partial action by selecting T cells that express cytokines at moderate-to-high levels (based on flow cytometry gating strategies) rather than attempting to capture every cell with maximum cytokine expression. This selective enrichment achieves sufficient immune power to control EBV infection while avoiding the extreme activation states that would trigger cytokine storm. The approach balances potency with safety by not over-selecting for activated cells.
Data Source
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Figure 2(B)~3
AI summary
Provided herein are methods comprising autologous cytotoxic T cells expressing a T cell receptor that specifically binds to an Epstein Barr virus (EBV) or expressing CD107a, TNF, IFN-gamma or IL-2 for the treatment of multiple sclerosis in a subject or selecting a subject for adoptive immunotherapy.