Adoptive T-Cell Therapy with CARs and Immunogenic Cell Death

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Solution Overview

Problem

Existing adoptive cell therapies for cancer, such as those using chimeric antigen receptors (CARs), face limitations in cell expansion, activation, and targeting to tumor sites due to the tumor microenvironment's immunosuppressive mechanisms, necessitating improved strategies.

Innovation Solution

Combining genetically modified T cells with chimeric antigen receptors (CARs) and agents that induce immunogenic cell death (ICD), optionally with agents that inhibit immune suppression components, to enhance therapeutic efficacy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If patient-derived T cells are infused with chimeric antigen receptors (CARs) to target tumor antigens, then the ability to target any cell surface antigen is improved, but the number of transferred cells that expand, activate, and home to cancer sites is limited

Engineering Contradiction:

Improveability to target any cell surface antigenVSAvoidnumber of transferred cells that expand and home to cancer site

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent segments the CAR structure into modular components (antigen-binding domain, transmembrane domain, costimulatory domains, and signaling domains) that can be independently optimized and combined. This modular approach allows systematic improvement of cell expansion and homing capabilities while maintaining antigen targeting versatility.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs composite CAR structures combining multiple costimulatory domains (e.g., CD28 and 4-1BB) and signaling components within a single receptor construct. This composite design enhances T cell activation, proliferation, and persistence in the tumor microenvironment, directly addressing the limitation on cell expansion and homing.

Inventive Principle:

Principle #40Composite materials

2Reliability

If T cells are transferred to target tumor antigens, then tumor targeting capability is improved, but the tumor microenvironment elicits tolerance or immunosuppression mechanisms that reduce T cell activity

Engineering Contradiction:

Improvetumor targeting capabilityVSAvoidimmunosuppression mechanisms in tumor microenvironment

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the immunosuppressive tumor microenvironment from a harmful factor into a beneficial context by engineering CAR T cells with enhanced resistance mechanisms. The composite CAR structures include domains that specifically counteract suppressive signals, transforming the challenging microenvironment into a setting where engineered T cells can thrive and maintain activity.

Inventive Principle:

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

Solution Approach 2:

The patent applies preliminary anti-action by pre-equipping CAR T cells with protective elements (such as cytokine resistance modifications and enhanced costimulatory signaling) before infusion. This preemptive engineering allows T cells to resist immunosuppression mechanisms before they are encountered in the tumor microenvironment, preserving their targeting capability and activity.

Inventive Principle:

Principle #9Preliminary anti-action

3Power

If CAR T cells are infused to treat malignancies, then therapeutic potency is improved, but cell persistence and activity within the tumor microenvironment are reduced

Engineering Contradiction:

Improvetherapeutic potencyVSAvoidcell persistence and activity within tumor microenvironment

Core Design Contradiction:

PowerVSDuration of action of moving object

Solution Approach 1:

The patent ensures continuity of useful action by designing CAR T cells with sustained activation capabilities through composite costimulatory domains. The engineered receptors maintain continuous signaling that promotes long-term T cell survival, proliferation, and functional activity within the tumor microenvironment, extending the duration of therapeutic action while maintaining high potency.

Inventive Principle:

Principle #20Continuity of useful action

Solution Approach 2:

The patent introduces dynamics by creating CAR T cells that can adapt their response to the tumor microenvironment. The composite signaling domains enable T cells to dynamically adjust their activation state, proliferation rate, and persistence based on local conditions, maintaining therapeutic potency over extended periods through flexible response mechanisms.

Inventive Principle:

Principle #15Dynamics

Data Source

PatentUS12350312B2Methods for improving adoptive cell therapy

Publication Date: 2025.07.08 FRED HUTCHINSON CANCER CENT

AI summary

The present disclosure provides reagents and methods for treating disease using modified immune cells (e.g., T cell comprising CAR or TCR) in combination with an agent associated with induction of immunogenic cell death (ICD) and optionally further in combination with an agent that specifically binds to and/or inhibits an immune suppression component and/or an agonist of an immune stimulatory molecule.