LSD1 Inhibitor Modulation of Tumor Microenvironment for Immunotherapy
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Solution Overview
Problem
Current cancer treatments, particularly immunotherapies targeting PD-1 and PD-L1, face challenges in efficacy due to mechanisms like dysfunctional T cells and lack of T cell infiltration, limiting their effectiveness in many patients.
Innovation Solution
Administering a lysine-specific demethylase 1A (LSD1) inhibitor in combination with PD-1 and/or PD-L1 inhibitors to modulate the tumor microenvironment, enhancing anti-tumor immunity and making checkpoint blockade therapies more effective.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If immunotherapy targeting PD-1 and PD-L1 is administered, then anti-tumor immunity is enhanced, but efficacy is limited due to dysfunctional T cells and lack of T cell infiltration
Solution Approach 1:
The patent applies preliminary action by using LSD1 inhibitors to pre-condition the tumor microenvironment before administering immunotherapy. The LSD1 inhibition creates dsRNA stress that activates cGAS-STING pathway and promotes T cell infiltration in advance, preparing the tumor site to receive and respond to subsequent PD-1/PD-L1 blockade therapy more effectively.
Solution Approach 2:
The patent introduces dsRNA stress as an intermediary mechanism between LSD1 inhibition and immune activation. The accumulated dsRNA acts as a mediator that triggers cGAS-STING pathway activation, leading to type I interferon production and subsequent T cell recruitment, thereby bridging the gap between epigenetic modification and immune response.
2Reliability
If LSD1 inhibitor is administered alone, then dsRNA stress is increased and anti-tumor adaptive immunity is activated, but tumor burden relief is insufficient without combination therapy
Solution Approach 1:
The patent merges two distinct therapeutic mechanisms: LSD1 inhibition (which increases dsRNA stress and activates innate immunity via cGAS-STING) and PD-1/PD-L1 blockade (which enhances adaptive T cell response). The combination therapy integrates epigenetic modification with immune checkpoint inhibition to achieve synergistic anti-tumor effects that neither agent achieves alone.
Solution Approach 2:
The patent establishes continuity of useful action by creating a sequential immune activation process: LSD1 inhibition continuously generates dsRNA stress that sustains cGAS-STING pathway activation and type I interferon production, while concurrent PD-1 blockade continuously enhances T cell function, maintaining persistent anti-tumor immunity throughout treatment.
Data Source
AI summary
Provided herein are methods of treating cancer using LSD1 inhibitors in combination with immunotherapy.