Chimeric PD-1 4-1BB Receptor for TCR T Cell Persistence

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Solution Overview

Problem

Current immunotherapies targeting PRAME in cancer treatment face challenges due to the immunosuppressive tumor microenvironment, which inhibits the efficacy and persistence of TCR-modified T cells, particularly in solid tumors, where the PD-1/PD-L1 axis reduces T cell infiltration and leads to exhaustion.

Innovation Solution

A combination of a high avidity T cell receptor (TCR) specific for the PRAME peptide SLLQHLIGL and a chimeric co-stimulatory receptor with an extracellular PD-1 domain and an intracellular 4-1BB domain is used to enhance T cell functionality, overcoming the immunosuppressive tumor microenvironment by improving cytokine release, proliferation, and cytotoxicity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TCR-modified T cells are used to target PRAME in solid tumors, then tumor-specific cytotoxicity is improved, but the immunosuppressive tumor microenvironment causes T cell exhaustion and reduced persistence

Engineering Contradiction:

ImproveT cell persistenceVSAvoidimmunosuppressive tumor microenvironment

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent applies the 'Blessing in disguise' principle by targeting the harmful PD-1/PD-L1 axis in the tumor microenvironment. The chimeric receptor binds to PD-L1 on tumor cells, converting the inhibitory signal into a stimulatory one through the 4-1BB intracellular domain, thereby transforming the immunosuppressive environment into a pro-inflammatory one that enhances T cell persistence and anti-tumor activity

Inventive Principle:

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

Solution Approach 2:

The patent uses a composite receptor structure combining PD-1 extracellular domain with 4-1BB intracellular domain. This chimeric construct integrates the binding capability of PD-1 for PD-L1 with the co-stimulatory signaling of 4-1BB, creating a multi-functional receptor that simultaneously engages tumor cells and delivers potent activation signals to enhance T cell durability in the tumor microenvironment

Inventive Principle:

Principle #40Composite materials

2Measurement precision

If high avidity TCR is used for PRAME targeting, then tumor cell recognition specificity is improved, but T cell infiltration into solid tumors is reduced due to PD-1/PD-L1 axis

Engineering Contradiction:

Improveantigen specificityVSAvoidT cell infiltration

Core Design Contradiction:

Measurement precisionVSProductivity

Solution Approach 1:

The patent converts the harmful PD-1/PD-L1 interaction into a beneficial mechanism by designing a chimeric receptor that binds PD-L1 and triggers 4-1BB signaling. This transforms the inhibitory checkpoint into a gateway for T cell entry and activation, thereby enhancing T cell infiltration into solid tumors while maintaining high PRAME-specificity through the TCR component

Inventive Principle:

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

3Reliability

If T cells are engineered with enhanced effector functions, then cytokine release and cytotoxicity are improved, but T cell fitness and proliferation are reduced in the immunosuppressive environment

Engineering Contradiction:

Improveeffector functionVSAvoidT cell proliferation

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent transforms the immunosuppressive PD-1/PD-L1 axis into a pro-proliferative signal by coupling PD-L1 binding to 4-1BB intracellular domain. This generates potent co-stimulatory signaling that simultaneously enhances effector functions and drives T cell proliferation, thereby improving both cytotoxicity and fitness in the tumor microenvironment

Inventive Principle:

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

Solution Approach 2:

The chimeric receptor combines PD-1 binding capability with 4-1BB co-stimulatory signaling in a single molecular construct. This composite structure enables simultaneous engagement of tumor cells and activation of T cell proliferation pathways, resolving the contradiction between effector function enhancement and T cell fitness maintenance

Inventive Principle:

Principle #40Composite materials

Data Source

PatentUS20240277762A1Combination of prame specific t cell receptors and chimeric co-stimulatory receptors

Publication Date: 2024.08.22 MEDIGENE IMMUNOTHERAPIES GMBH

AI summary

The present invention relates to the combination of a T cell receptor (TCR) specific for the FRAME peptide SLLQH-LIGL and a chimeric co-stimulatory receptor comprising an extracellular domain derived from PD-1(CD279) and an intracellular domain derived from 4-1BB (CD137). In particular, the invention refers to a cell comprising said TCR and chimeric co-stimulatory protein. Further the invention refers to a nucleic acid encoding the TCR and the co-stimulatory receptor, a corresponding vector and a corresponding nucleic acid composition. Moreover, the invention relates to the according pharmaceutical composition. Accordingly the invention also relates to the cell and the nucleic acid constructs for use as a medicament, in particular to the TCR for use in the treatment of cancer.