CAR-CD123 Vector Suicide Gene Reduces Bystander Toxicity

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

Current CAR T-cell therapies for CD123+ tumors, such as Acute Myeloid Leukemia, face challenges in minimizing bystander toxicity while maintaining leukemia control, with concerns about hematologic toxicity and the need for an effective therapy that does not cause toxic effects on patients.

Innovation Solution

A novel second-generation CAR-CD123 vector, ΔCD19-2A-CAR-CD123-ΔCD34. CD8.41BB. CD3ζ, is developed, incorporating a bicistronic retroviral vector that allows simultaneous expression of ΔCD19 and CAR-CD123, featuring a suicide gene for minimizing toxicity and a costimulatory domain for enhanced therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If CAR T-cell therapy targets CD123+ cells, then leukemia control is improved, but bystander toxicity to healthy CD123+ cells increases

Engineering Contradiction:

Improveleukemia controlVSAvoidbystander toxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent incorporates a suicide gene (e.g., inducible caspase 9) into the CAR T-cell construct. This converts the harmful bystander toxicity into a controllable feature: when healthy CD123+ cells are inadvertently targeted, the suicide gene can be activated to selectively eliminate the CAR T-cells responsible for the toxicity, thereby protecting healthy cells while maintaining anti-leukemia efficacy

Inventive Principle:

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

Solution Approach 2:

The patent uses inducible systems (such as small molecule-inducible promoters) to control the expression of the suicide gene and costimulatory domains. By changing the induction parameter (adding specific small molecules), the therapeutic effect can be enhanced or the toxic effect can be switched off, allowing dynamic control of the therapy's impact on both leukemia and healthy cells

Inventive Principle:

Principle #35Parameter changes

2Reliability

If costimulatory domains are added to enhance therapeutic efficacy, then leukemia killing ability is improved, but risk of cytokine release syndrome and neurotoxicity increases

Engineering Contradiction:

Improveleukemia killing abilityVSAvoidcytokine release syndrome

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent employs inducible systems that allow dynamic control of costimulatory domain expression. The costimulatory domains (such as 4-1BB or CD28) can be activated or deactivated on demand through small molecule induction, enabling the system to adapt its immune-stimulating activity to match the therapeutic needs while minimizing excessive activation that leads to cytokine release syndrome

Inventive Principle:

Principle #15Dynamics

Solution Approach 2:

The patent incorporates suicide genes that can be activated in response to adverse events. This creates a feedback mechanism where, if cytokine release syndrome or other toxicities occur, the suicide gene can be induced to eliminate the CAR T-cells, providing a safety feedback loop that prevents severe adverse events

Inventive Principle:

Principle #23Feedback

Data Source

PatentUS20220251224A1Car-CD123 vector and uses thereof

Publication Date: 2022.08.11 OSPEDALE PEDIATRICO BAMBINO GESU

AI summary

The present invention relates to a chimeric antigen receptor (CAR) molecule containing, from the N-terminus to the C-terminus: a) an extracellular domain and transmembrane domain of human CD19, b) an antigen binding domain, c) a spacer domain, d) a transmembrane domain, and e) a cytoplasmatic domain, preferably wherein the CAR is a CD123 specific CAR (CD123 CAR) and the antigen binding domain includes a VL and/or VH from a monoclonal anti-CD123 antibody, more preferably the antigen binding domain includes a single chain variable fragment (scFv) that specifically binds to CD123.