Genetically Modified Dendritic Cells for Stable Tolerogenic Immunotherapy

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Solution Overview

Problem

Current immunotherapy approaches for autoimmune diseases and organ transplantation face challenges in maintaining stability and efficacy of dendritic cells (DC) and inducing long-term tolerance, with existing methods having limitations in specificity, safety, and side effects.

Innovation Solution

Genetically modified dendritic cells or their precursors expressing a chimeric protein consisting of a human invariant chain fused with an antigenic peptide and an immuno-modulatory molecule, using lentiviral vectors to ensure stable and durable expression, and incorporating miRNA target sequences for post-transcriptional regulation to control antigen presentation.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If dendritic cells are used for tolerogenic immunotherapy, then antigen-specific tolerance is induced, but stability and maintenance of tolerogenic properties remain problematic

Engineering Contradiction:

Improvestability of dendritic cellsVSAvoidmaintenance of tolerogenic properties

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent applies preliminary action by genetically modifying dendritic cells before administration to express tolerogenic molecules (CTLA-4, PD-L1, IDO) and regulatory cytokines (IL-10, TGF-β). This pre-engineering ensures the cells are primed with tolerogenic properties that they will maintain during their in vivo function, addressing the stability and duration issue by preparing the cells in advance with their functional program already in place.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The patent employs parameter changes by modifying the molecular and genetic parameters of dendritic cells through lentiviral transduction. The cells are engineered to overexpress specific proteins (CTLA-4, PD-L1, IDO) and cytokines (IL-10, TGF-β), fundamentally changing their phenotypic parameters from standard immunogenic DCs to stable tolerogenic DCs that maintain their regulatory function over time.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If conventional immunosuppressive therapies are used, then graft rejection is prevented, but side effects and long-term toxicity increase

Engineering Contradiction:

Improveprevention of graft rejectionVSAvoidside effects and toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent converts the potentially harmful effect of dendritic cell activation into a benefit by engineering DCs to constitutively express tolerogenic molecules and regulatory cytokines. Instead of relying on activation-induced tolerance (which can be unstable), the modified DCs continuously present tolerogenic signals, transforming the activation state from a source of immunogenicity into a source of sustained tolerance, thereby preventing rejection without conventional immunosuppressive drugs.

Inventive Principle:

Principle #22Blessing in disguise (Convert harm into benefit)

Solution Approach 2:

The patent introduces dendritic cells as intermediary agents that mediate tolerance between the graft and the host immune system. These genetically modified DCs act as specialized messengers that deliver tolerogenic signals (through CTLA-4, PD-L1, IDO, IL-10, and TGF-β) to T cells, replacing the need for direct pharmacological immunosuppression and thereby reducing drug-related side effects and toxicity.

Inventive Principle:

Principle #24Intermediary (Mediator)

3Reliability

If dendritic cells are genetically modified for enhanced tolerogenicity, then immunotherapy efficacy is improved, but complexity of cell manipulation increases

Engineering Contradiction:

Improveefficacy of tolerogenic responseVSAvoidcomplexity of genetic modification

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent applies universality by using a single lentiviral vector system that simultaneously delivers multiple transgenes (CTLA-4, PD-L1, IDO, IL-10, TGF-β) into dendritic cells. This multi-functional approach consolidates what would otherwise require multiple separate manipulation steps into one unified transduction process, improving efficacy through combined tolerogenic mechanisms while managing complexity through vector-based co-delivery.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The approach induces a tolerogenic response, promotes the generation of antigen-specific Tregs, and maintains long-term tolerance with reduced risk of immune activation and side effects, offering a safer and more effective immunotherapy for autoimmune diseases and transplantation.

Implementation Method 1

Lentiviral vectors (LVs) transduce human DC precursors (16) and induce strong and durable anti-tumor T cell responses (17)

Methodology Applied

Scientific EffectLentiviral transduction:

Implementation Method 2

incorporating miRNA target sequences for post-transcriptional regulation to control antigen presentation

Methodology Applied

Scientific EffectmiRNA-mediated post-transcriptional regulation:

Implementation Method 3

Tolerogenic DC (tolDC) present Ag and prime Ag-specific T cells

Methodology Applied

Scientific EffectAntigen presentation:

Data Source

PatentUS20210277354A1Production of engineered dendritic cells and uses thereof

Publication Date: 2021.09.09 FOND AZIONE TELETHON

AI summary

The present disclosure relates to a genetically modified dendritic cell or precursor thereof expressing at least one anti-gen-derived peptide and at least one immuno-modulatory molecule, its medical use and method of preparation. The invention also relates to an in vitro method to produce IL-10-producing CD49b+LAG-3+ Tr1 cells or antigen-specific FOXP3+ T cells and relative medical uses and pharmaceutical compositions.