CYP2B6* Stem Cell Engineering for Tumor-Localized Cyclophosphamide Activation

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Solution Overview

Problem

Current treatments for hepatocellular carcinoma, particularly those in advanced stages, have limited efficacy and are associated with significant adverse events, leading to suboptimal outcomes and poor patient compliance.

Innovation Solution

Development of a genetically modified human stem cell, such as mesenchymal or induced pluripotent stem cells, engineered to express a mutant human cytochrome P450 2B6 protein and NADPH-cytochrome P450 reductase protein, integrated into chromosome 17, capable of metabolizing cyclophosphamide and inducing immunological tumor cell death.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If standard treatments (Sorafenib, Regorafenib, Nivolumab) are used for advanced hepatocellular carcinoma, then cancer treatment is provided, but efficacy is limited and adverse events occur leading to poor patient compliance

Engineering Contradiction:

Improvetreatment efficacyVSAvoidadverse events

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the harmful cyclophosphamide into a beneficial therapeutic agent by using CYP2B6* to activate it into toxic metabolites that selectively kill tumor cells. The prodrug approach transforms a potentially harmful chemotherapy into a targeted therapy with reduced systemic toxicity, converting the harm of the parent compound into benefit through controlled metabolic activation.

Inventive Principle:

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

Solution Approach 2:

The CYP2B6* enzyme acts as an intermediary between the administered cyclophosphamide and the toxic metabolites that kill tumor cells. This intermediary enzyme is engineered into the stem cell, allowing controlled conversion of the prodrug into active cytotoxic forms only at the tumor site, thereby mediating the therapeutic effect while reducing systemic harm.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Reliability

If genetically modified stem cells expressing CYP2B6* are used, then complete tumor eradication and protection against recurrence are achieved, but cell engineering complexity increases

Engineering Contradiction:

Improvetumor eradication completenessVSAvoidcell engineering complexity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent merges multiple functions into a single engineered stem cell: tumor cell killing through CYP2B6*-mediated cyclophosphamide activation, immunostimulation through IFN-gamma secretion, and long-term persistence through hematopoietic stem cell properties. This consolidation achieves complete tumor eradication while managing complexity through functional integration rather than separate therapies.

Inventive Principle:

Principle #5Merging (Combining)

Solution Approach 2:

The engineered stem cell performs multiple therapeutic functions simultaneously: direct tumor cytotoxicity via CYP2B6*, immunomodulation through IFN-gamma release, and long-term surveillance through self-renewal capabilities. This multi-functionality approach addresses the complexity by combining several therapeutic mechanisms into one universal cell product that can handle various tumor types and stages.

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 genetically modified stem cells provide complete eradication of solid tumors, offer protection against recurrence and metastases, and improve patient quality of life by reducing treatment-related side effects.

Implementation Method 1

a mutant human cytochrome P450 2B6 protein (CYP2B6*)... capable of metabolizing cyclophosphamide

Methodology Applied

Scientific EffectCytochrome P450 enzymatic metabolism: Enzyme

Implementation Method 2

a NADPH-cytochrome P450 reductase protein... integrated into chromosome 17

Methodology Applied

Scientific EffectNADPH-cytochrome P450 reductase electron transfer: Enzyme

Data Source

PatentUS20250320461A1Genetically modified human stem cell expressing a mutant human cytochrome p450 2b6 protein and its use thereof in the treatment of cancer

Publication Date: 2025.10.16 ASSISTANCE PUBLIQUE HOPITAUX DE PARIS (APHP)

AI summary

The present invention relates to a genetically modified human stem cell, wherein said human stem cell comprises an exogenous nucleic acid comprising a region encoding a fusion protein comprising a mutant human cytochrome P450 2B6 protein (CYP2B6*) of SEQ ID No. 1, or a variant or fragment thereof and a NADPH-cytochrome P450 reductase protein of SEQ ID No. 2 or a variant or fragment thereof, operably linked to a promoter, said exogenous nucleic acid having been inserted into chromosome 17 of said human stem cell. The invention also relates to the use of said cell in the prevention and/or treatment of cancer and/or associated metastases, notably solid tumours, in particular hepatocellular carcinomas, and/or recurrent cancer and/or associated metastases.