Modified Lymphocytes Enhancing Persistence via BCL2L11 Reduction

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Solution Overview

Problem

Current immunotherapy approaches face challenges with lymphocyte exhaustion and reduced efficacy over time due to impaired effector function and survival issues in CD8 T cells, particularly in chronic infections and cancer treatments.

Innovation Solution

Modifying lymphocytes to exhibit reduced BCL2L11 levels and increased BATF3 levels, either by genetic modification or using exogenous inhibitors/activators, to enhance their persistence, metabolism, and memory development, thereby improving their therapeutic effectiveness.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If lymphocytes are used in immunotherapy, then anti-tumor activity is improved, but lymphocyte exhaustion occurs and efficacy decreases over time

Engineering Contradiction:

Improvetherapeutic efficacyVSAvoidlymphocyte persistence

Core Design Contradiction:

ReliabilityVSDuration of action of moving object

Solution Approach 1:

The patent modifies lymphocyte parameters by altering BCL2L11 expression levels and AP-1 transcription factor activity, transforming the cell state from exhausted to persistent. This parameter change enables lymphocytes to maintain therapeutic efficacy over extended periods by fundamentally changing their survival and metabolic characteristics.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates dynamically adaptable lymphocytes that can adjust their metabolic state and survival properties in response to chronic antigen exposure. By modulating BCL2L11 and AP-1 pathways, the lymphocytes transition from a static exhausted state to a dynamic persistent state, maintaining functionality throughout the therapeutic period.

Inventive Principle:

Principle #15Dynamics

2Productivity

If lymphocytes undergo massive expansion to eliminate infected cells, then effector to target ratio is improved, but memory cell quality deteriorates

Engineering Contradiction:

Improveeffector cell expansionVSAvoidmemory cell quality

Core Design Contradiction:

ProductivityVSReliability

Solution Approach 1:

The patent applies preliminary action by pre-modifying lymphocytes with altered BCL2L11 expression and AP-1 transcription factor activity before expansion. This pre-conditioning ensures that during subsequent massive proliferation, the cells maintain their memory potential and do not differentiate exclusively into short-lived effectors, thus preserving memory cell quality while achieving necessary expansion.

Inventive Principle:

Principle #10Preliminary action

3Duration of action of moving object

If BCL2L11 levels are reduced to enhance survival, then lymphocyte persistence is improved, but cell death regulation may be compromised

Engineering Contradiction:

Improvelymphocyte survivalVSAvoiduncontrolled cell death

Core Design Contradiction:

Duration of action of moving objectVSObject-affected harmful factors

Solution Approach 1:

The patent carefully modulates BCL2L11 expression to optimal levels rather than complete elimination, changing the parameter from normal to reduced but controlled. This precise parameter adjustment enhances survival while maintaining sufficient cell death regulation capacity, avoiding the harmful effects of uncontrolled proliferation or inability to eliminate dysfunctional cells.

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20230303975A1Modified lymphocytes

Publication Date: 2023.09.28 JULIUS MAXIMILIANS UNIV WURZBURG

AI summary

The present invention relates to a lymphocyte, modified to exhibit a reduced BCL2L11 level and/or an increased BATF3 level. The invention also relates to a method for producing such lymphocytes and a pharmaceutical composition comprising such lymphocytes. The lymphocytes and the pharmaceutical composition of the present invention may be used in methods for treating a disease in a patient.