Allogeneic Immune Cells with Inactivated CD38 for CAR Therapy

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Solution Overview

Problem

Current adoptive immunotherapy using autologous cells for cancer and infections is hindered by technical and logistical challenges, including high costs, the need for dedicated facilities, and variability in efficacy and safety, while allogeneic cells face rejection and graft-versus-host disease issues due to the expression of CD38 on both therapeutic and host cells.

Innovation Solution

Genetically engineer immune cells to inactivate the CD38 antigen marker and express a chimeric antigen receptor (CAR) targeting CD38, using RNA-guided endonucleases like CRISPR/Cas9, to create non-alloreactive, CAR-expressing cells that can selectively target CD38-expressing pathological cells without harming the immune cells themselves.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Ease of manufacture

If allogeneic immune cells are used for immunotherapy, then standardization and affordability are improved, but host rejection and graft-versus-host disease occur due to CD38 expression on both therapeutic and host cells

Engineering Contradiction:

Improvestandardization and affordabilityVSAvoidhost rejection and graft-versus-host disease

Core Design Contradiction:

Ease of manufactureVSReliability

Solution Approach 1:

The patent extracts and removes the problematic CD38 antigen marker from the surface of allogeneic immune cells through genetic inactivation. By specifically targeting and eliminating CD38 expression on therapeutic cells while preserving it on host cells, the invention resolves the recognition conflict that causes host rejection and graft-versus-host disease, enabling standardized allogeneic cell therapy production.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent applies local quality by creating asymmetric CD38 expression patterns: therapeutic immune cells have CD38 inactivated (absent), while host cells retain normal CD38 expression. This localized differentiation allows the immune system to distinguish between self and non-self, preventing rejection responses while maintaining the therapeutic function of the engineered cells.

Inventive Principle:

Principle #3Local quality

2Reliability

If CD38-targeting CAR is expressed on immune cells, then ability to target CD38-expressing pathological cells is improved, but auto-stimulation and aggregation of immune cells occur due to CD38 expression on immune cells themselves

Engineering Contradiction:

Improvetargeting abilityVSAvoidauto-stimulation and aggregation

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent removes the self-recognizable CD38 antigen from the surface of immune cells expressing anti-CD38 CARs. This extraction eliminates the source of auto-stimulation and aggregation, allowing the CAR-expressing cells to target pathological cells without mistakenly attacking or clumping with themselves.

Inventive Principle:

Principle #2Taking out (Extraction)

3Adaptability or versatility

If autologous cells are used for adoptive immunotherapy, then patient-specific treatment is achieved, but high costs and variability in efficacy and safety result from individual fabrication requirements

Engineering Contradiction:

Improvepatient-specific treatmentVSAvoidhigh costs and variability

Core Design Contradiction:

Adaptability or versatilityVSEase of manufacture

Solution Approach 1:

The patent creates universal allogeneic immune cells with inactivated CD38 that can be manufactured once and used for multiple patients. By removing the patient-specific requirement through allogeneic sourcing and standardizing the CD38 inactivation process, the invention maintains broad applicability while eliminating the costs and variability associated with individual autologous cell fabrication.

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

This approach enables the development of standardized, affordable immunotherapy products that can effectively treat cancer and infections with reduced risk of auto-stimulation and improved safety by eliminating CD38 expression on immune cells, allowing for the use of allogeneic cells without host rejection or graft-versus-host disease.

Implementation Method 1

This inactivation is typically performed by using transgenes encoding RNA-guided endonucleases (ex: Cas9/CRISPR), meganucleases, Zinc-finger nucleases or TAL nucleases

Methodology Applied

Scientific EffectCRISPR/Cas9 gene editing:

Data Source

PatentEP3334442B1Cells for immunotherapy engineered for targeting CD38 antigen and for CD38 gene inactivation

Publication Date: 2024.12.18 CELLECTIS SA

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AI summary

Methods of developing genetically engineered immune cells for immunotherapy, which can be endowed with Chimeric Antigen Receptors targeting an antigen marker that is common to both the pathological cells and said CD38 immune by the fact that the genes encoding said markers are inactivated in said immune cells by a rare cutting endonuclease such as TALEN, Cas9 or argonaute.