Non-Replicating Rhabdovirus Particles for Oncolytic Therapy

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Solution Overview

Problem

Current oncolytic virus therapies for cancer, particularly in hematopoietic malignancies, face challenges such as limited virion production, reduced spread between leukemia cells, uncontrolled live virus spread in normal tissues, low dosing requirements for safety, immune diversion from tumors, and impaired production capacity, leading to inefficiencies and safety concerns, especially in immunosuppressed patients.

Innovation Solution

Development of non-replicating rhabdovirus-derived particles (NRRPs) that lack the ability to spread between cells while retaining tropism against immortalized cells, inducing cell death preferentially in cancer cells and stimulating immune responses, thereby addressing the limitations of live virus therapies.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If live replication competent rhabdovirus is used to treat cancer, then tumor cytotoxicity and therapeutic efficacy are improved, but uncontrolled spread in normal tissues and safety concerns worsen

Engineering Contradiction:

Improvetumor cytotoxicityVSAvoiduncontrolled spread in normal tissues

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The virus is segmented into two separate components: a replication-competent rhabdovirus that provides tumor-specific cytotoxicity, and a non-replicating vesicular stomatitis virus (VSV) vector that delivers therapeutic genes. This segmentation allows each component to perform its specific function without the harmful effects of uncontrolled replication in normal tissues.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The VSV vector acts as an intermediary that delivers therapeutic genes (such as suicide genes or immunomodulatory genes) to tumor cells without replicating. This intermediary system enables controlled gene delivery to enhance anti-tumor effects while avoiding the uncontrolled spread problems of replication-competent viruses.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If high doses of live virus are administered to overcome limited virion production, then therapeutic efficacy is improved, but safety and off-target effects worsen

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidoff-target effects in normal tissue

Core Design Contradiction:

ProductivityVSObject-affected harmful factors

Solution Approach 1:

Instead of relying on limited viral replication to amplify the therapeutic effect, the system uses high-dose administration of the non-replicating VSV vector that carries therapeutic genes. The vector particles themselves act as copies that deliver the therapeutic payload directly to tumor cells without the need for replication, thereby achieving high therapeutic efficacy without off-target effects.

Inventive Principle:

Principle #26Copying

3Adaptability or versatility

If live virus spread is engineered to prefer tumors, then tumor targeting is improved, but immune diversion from tumor towards virus worsens

Engineering Contradiction:

Improvetumor targetingVSAvoidimmune diversion

Core Design Contradiction:

Adaptability or versatilityVSObject-generated harmful factors

Solution Approach 1:

The replication function is extracted from the VSV vector, creating a non-replicating system that cannot spread between cells. This extraction eliminates the immune diversion problem caused by live virus replication while maintaining the tumor-targeting capability through the inherent tropism of the rhabdovirus component and the delivery mechanism of the VSV vector.

Inventive Principle:

Principle #2Taking out (Extraction)

4Speed

If replication competent virus is used, then virus spread between tumor cells is improved, but manufacturing efficiency and production capacity worsen

Engineering Contradiction:

Improvevirus spreadVSAvoidproduction capacity

Core Design Contradiction:

SpeedVSEase of manufacture

Solution Approach 1:

The system segments the viral functions into two separate vectors: a replication-competent rhabdovirus that can be produced using well-established methods, and a non-replicating VSV vector that carries therapeutic genes. This segmentation simplifies manufacturing by allowing each component to be produced independently using optimized protocols, avoiding the complexity of producing replication-competent engineered viruses.

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP2935569B1Non-replicating rhabdovirus-derived particles and uses thereof

Publication Date: 2019.05.01 CELVERUM

Figure 1A~1B
Figure 2A~2C
Figure 3A~3B

AI summary

There is described herein a non-replicating Rhabdovirus-derived particle that lacks the ability to spread between cells while having tropism against immortalized cells. The non-replicating Rhabdovirus-derived particle may have cytolytic tropism against immortalized cells. There is also described a non-replicating Rhabdovirus-derived particle that lacks the ability to spread between cells but has innate and/or adaptive immune-stimulating properties.