FasL-Binding Receptor for CAR-T Cell Persistence

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

CAR-T cell therapies face challenges in persisting within the tumor microenvironment due to immunosuppressive mechanisms, including upregulation of FasL, which induces apoptosis in CAR-T cells, leading to activation-induced cell death and reduced efficacy.

Innovation Solution

Engineering cells to express a FasL-binding receptor that competitively binds to FasL, inhibiting the Fas-FasL pathway by fusing the Fas ectodomain with a TNFR endodomain or using a membrane-bound decoy receptor 3 (DcR3) to neutralize FasL-induced apoptosis.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR-T cells are activated and transduced with CAR construct, then cytotoxic activity against tumor cells is improved, but FasL expression is upregulated triggering activation-induced cell death and reducing persistence in TME

Engineering Contradiction:

Improvecytotoxic activityVSAvoidpersistence in TME

Core Design Contradiction:

ReliabilityVSDuration of action of stationary object

Solution Approach 1:

The patent introduces a FasL-binding receptor as an intermediary molecule that binds to FasL with high affinity, preventing FasL from interacting with the Fas death receptor on CAR-T cells. This intermediary receptor acts as a decoy that sequesters FasL, thereby blocking the apoptotic signaling pathway while preserving CAR-T cell cytotoxic function and persistence in the tumor microenvironment.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent converts the harmful effect of FasL upregulation (which triggers AICD) into a beneficial outcome by engineering CAR-T cells to express a FasL-binding receptor. The same FasL that would normally cause cell death is now bound by the engineered receptor, transforming the harmful apoptotic signal into a protective mechanism that enhances CAR-T cell survival and persistence while maintaining anti-tumor activity.

Inventive Principle:

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

2Reliability

If FasL is blocked with antibody, then Fas-induced apoptosis is reduced, but killing effects of CAR T cell are hindered since FasL is an important weapon for T cells to exert killing

Engineering Contradiction:

Improveresistance to apoptosisVSAvoidkilling effect

Core Design Contradiction:

ReliabilityVSProductivity

Solution Approach 1:

The patent applies local quality by making the FasL-binding capability specific to the CAR-T cell surface through membrane-bound receptor expression. The FasL-binding receptor is localized to the cell membrane of CAR-T cells, creating a localized protective effect at the cell surface without systemically blocking FasL activity. This localized approach allows CAR-T cells to maintain their killing function while being protected from apoptosis by FasL bound at their own surface.

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent segments the FasL interaction into two distinct functions: (1) FasL binding for protective purposes mediated by the engineered FasL-binding receptor on CAR-T cells, and (2) FasL-mediated killing function preserved through endogenous Fas receptors on target tumor cells. This segmentation allows differential regulation where protection is achieved without compromising the cytotoxic killing capability of CAR-T cells.

Inventive Principle:

Principle #1Segmentation

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 FasL-binding receptor enhances the resistance of CAR-T cells to apoptosis, improving their persistence and infiltration into the tumor vasculature, thereby enhancing the effectiveness of CAR-T cell therapy.

Implementation Method 1

a receptor which competitively binds to FasL and neutralises the Fas-FasL pathway

Methodology Applied

Scientific EffectCompetitive binding: Adsorption

Implementation Method 2

blocking its capacity to trigger trimerization and recruit a protein called Fas-associated death domain (FADD) via homotypic interactions of their respective death domains

Methodology Applied

Scientific EffectNeutralization: Absorption (physical)

Implementation Method 3

membrane-bound decoy receptor 3 (DcR3) which binds to FasL

Methodology Applied

Scientific EffectDecoy receptor binding: Adsorption

Data Source

PatentUS20230113183A1cell

Publication Date: 2023.04.13 AUTOLUS LIMIED

AI summary

The present invention relates to a cell which comprises; (a) a chimeric antigen receptor (CAR) or a transgenic T-cell receptor (TCR); and (b) a FasL-binding receptor (FLBR) comprising; (i) a Fas ectodomain and a TNFR endodomain, wherein the TNFR endodomain comprises the signalling portion of the decoy receptor 2 (DcR2), GITR, CD30, XEDAR, CD40, CD27, BCMA or Fn14 endodomain, or (ii) a membrane-bound decoy receptor 3 (DcR3).