Immune Checkpoint Therapy with ATM Inhibition and cGAS/STING Activation

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Solution Overview

Problem

Current immune checkpoint blockade (ICB) therapy benefits only a minority of cancer patients and is associated with undesirable side effects, necessitating new approaches to enhance its effectiveness on a wider range of cancers and subjects.

Innovation Solution

Activating the cGAS/STING pathway by inhibiting the kinase activity of Ataxia Telangiectasia Mutated (ATM) protein using ATM inhibitors in conjunction with immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1 therapies, to enhance cancer immune checkpoint therapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immune checkpoint blockade therapy is administered to cancer patients, then cancer treatment is provided, but only a minority of patients benefit and undesirable side effects occur

Engineering Contradiction:

Improvetherapy effectivenessVSAvoidpatient applicability range

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent modifies the therapeutic parameters by combining ICB with ATM inhibitors, changing the biochemical state of the tumor microenvironment through cGAS/STING pathway activation. This parameter change enables the therapy to work effectively across a broader range of patient types and cancer stages, resolving the contradiction between reliability and adaptability.

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The ATM inhibitor acts as an intermediary agent that bridges the gap between standard ICB therapy and enhanced efficacy. By activating cGAS/STING pathway as an intermediate mechanism, it amplifies the immune response without directly replacing the ICB therapy, thus maintaining broad patient applicability while improving effectiveness.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Productivity

If ATM inhibitor is administered to activate cGAS/STING pathway, then lymphocyte infiltration and immune response are enhanced, but cancer cell growth is inhibited

Engineering Contradiction:

Improveimmune cell infiltrationVSAvoidcancer cell growth

Core Design Contradiction:

ProductivityVSObject-generated harmful factors

Solution Approach 1:

The patent converts the harmful effect of ATM protein activity (which normally promotes cancer cell survival) into a beneficial effect. By inhibiting ATM, the pathway that would normally support tumor growth is instead activated to promote immune cell infiltration and anti-tumor immunity, thus turning a harmful factor into a therapeutic benefit.

Inventive Principle:

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

Solution Approach 2:

The therapy is segmented into two functional components: ATM inhibition to activate cGAS/STING pathway and ICB to block immune checkpoints. This segmentation allows the immune activation and cancer growth inhibition functions to be performed by separate mechanisms working synergistically, improving overall therapeutic efficacy.

Inventive Principle:

Principle #1Segmentation

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

Enhances lymphocyte infiltration into the tumor microenvironment, stimulates CD8+ and CD4+ T cell infiltration, and activates innate interferon responses, thereby improving the efficacy of ICB therapy and inhibiting cancer cell growth.

Implementation Method 1

activation of the cGAS/STING pathway comprises inhibiting the kinase activity of Ataxia Telangiectasia Mutated (ATM) protein

Methodology Applied

Scientific EffectKinase inhibition:

Implementation Method 2

the at least one ATM inhibitor stimulates mitochondrial DNA release in a subject

Methodology Applied

Scientific EffectMitochondrial DNA release:

Implementation Method 3

the at least one ATM inhibitor activates an innate interferon response in a subject

Methodology Applied

Scientific EffectInterferon response activation:

Data Source

PatentUS12558351B2Compositions and methods for enhancing cancer immune checkpoint therapy

Publication Date: 2026.02.24 LI CHUAN YUAN

AI summary

The present disclosure provides, in part, compositions and methods for enhancing the efficacy of immune checkpoint blockade therapy in a subject. Methods for identifying subjects that are appropriate for immune checkpoint blockade therapy are also provided.