Engineered Cell Therapy With Folate-Targeted Macrophage Reprogramming

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Solution Overview

Problem

Existing cancer treatments, such as CAR-T therapy and chemotherapy, face challenges in effectively targeting and converting tumor-associated macrophages (TAMs) in the tumor microenvironment (TME) from tumor-supportive to tumoricidal, due to immunosuppressive interactions, and lack specificity for cancer cells, leading to systemic toxicity and poor selectivity.

Innovation Solution

A combination therapy using engineered cells (e.g., CAR T-cells, stem cells) with a drug compound comprising a folate receptor binding ligand and a Toll-like receptor (TLR) agonist, specifically targeting M2-type macrophages to reprogram them to M1-type macrophages, enhancing anti-tumor activity.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Productivity

If high-dose chemotherapy is used to treat cancer, then tumor inhibition is improved, but selectivity for cancer cells deteriorates and toxicity to normal cells increases

Engineering Contradiction:

Improvetumor inhibitionVSAvoidtoxicity to normal cells

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

The chemotherapy approach is segmented into two distinct components: (1) a targeting moiety that specifically binds to cancer cells, and (2) a cytotoxic agent that kills the targeted cells. This segmentation allows the toxic effect to be concentrated on cancer cells only, eliminating the non-selective toxicity that plagues conventional high-dose chemotherapy.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The targeting moiety acts as an intermediary that bridges the cytotoxic agent and the cancer cell. It specifically recognizes and binds to cancer cell surface markers, delivering the cytotoxic agent precisely to the target. This intermediary mechanism replaces the non-specific, diffuse toxicity of conventional chemotherapy with targeted, selective cell killing.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If CAR-T therapy is used to treat hematopoietic cancers, then treatment effectiveness is improved, but effectiveness against solid tumors deteriorates due to immunosuppressive tumor microenvironment

Engineering Contradiction:

Improvetreatment effectivenessVSAvoideffectiveness across different cancer types

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent introduces a targeting moiety as an intermediary that enables CAR-T cells to specifically recognize and bind to solid tumor cells. This intermediary component overcomes the immunosuppressive tumor microenvironment by providing direct, specific targeting capability, allowing CAR-T therapy to be effective against solid tumors where it previously failed.

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The invention creates a composite therapeutic system combining three elements: (1) the CAR-T cell with its antigen recognition capability, (2) a targeting moiety for specific cancer cell binding, and (3) a cytotoxic agent for cell killing. This composite approach integrates the strengths of each component to achieve effectiveness against both hematopoietic cancers and solid tumors.

Inventive Principle:

Principle #40Composite materials

3Ease of operation

If conventional chemotherapy is used, then ease of administration is improved, but tumor specificity deteriorates

Engineering Contradiction:

Improveease of administrationVSAvoidlack of tumor specificity

Core Design Contradiction:

Ease of operationVSObject-affected harmful factors

Solution Approach 1:

The chemotherapy agent is segmented into a targeting moiety and a cytotoxic component. The targeting moiety provides tumor-specific recognition while the cytotoxic component delivers the therapeutic effect. This segmentation maintains ease of administration as a single agent while eliminating the lack of specificity that characterizes conventional chemotherapy.

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 combination therapy effectively reprograms M2-type macrophages to M1-type macrophages, activating anti-tumor responses and improving the potency of engineered cells, thereby enhancing cancer treatment specificity and reducing systemic toxicity.

Implementation Method 1

a drug compound or composition comprising a folate receptor binding ligand and a Toll-like receptor (TLR) agonist

Methodology Applied

Scientific EffectLigand-receptor binding:

Implementation Method 2

a drug compound or composition comprising a folate receptor binding ligand and a Toll-like receptor (TLR) agonist, specifically targeting M2-type macrophages to reprogram them to M1-type macrophages

Methodology Applied

Scientific EffectToll-like receptor activation:

Data Source

PatentUS20250269036A1Methods for enhancement of engineered cell therapies in cancer treatment

Publication Date: 2025.08.28 PURDUE RES FOUND

AI summary

Methods are provided for reprogramming M2-like macrophages to M1-like macrophages, which reverses the proinflammatory to anti-inflammatory shift observed during the course of certain cancers, co-administered with one or more types of engineered cells such as, without limitation, CAR T-cells, engineered natural killer cells, engineered stem cells or the like. The compounds comprise an immune modulator that targets a pattern recognition receptor of a cell and are specific to the cells of interest through the incorporation of a targeting moiety (e.g., folate or a functional fragment or analog thereof). Releasable and/or non-releasable linkers can be included and engineered to facilitate the optimal delivery of the immune modulator. The compounds and compositions can be employed in one or more methods of treatment for cancers.