Depleting TFH-like Cells to Reduce ICB Toxicity

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Solution Overview

Problem

Current immune checkpoint blockade (ICB) therapies for cancer, particularly those targeting CTLA-4 and PD-1, do not benefit a significant proportion of patients with metastatic cancer and can cause severe immune-related toxicities, highlighting the need for improved anti-tumor activity and reduced immunosuppression.

Innovation Solution

Depletion of T follicular helper-like cells (TFH) and 4PD1hi cells through administration of BCL6 inhibitors, such as 79-6, or EZH2 inhibitors like EPZ-6438, prior to or concurrent with ICB therapy to enhance the effectiveness of CTLA-4 blockade.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If immune checkpoint blockade (ICB) therapy is administered to patients with metastatic cancer, then anti-tumor immune response is promoted, but severe immune-related toxicities occur and treatment efficacy is limited in a significant proportion of patients

Engineering Contradiction:

Improvetreatment efficacyVSAvoidimmune-related toxicities

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts and targets the harmful 4PD1hi TFH-like cells from the immune system. By administering anti-CD4 antibodies or other agents that selectively deplete this specific cell population, the invention removes the source of immunosuppression while preserving the beneficial anti-tumor immune responses mediated by other T cell subsets, thereby reducing toxicities and improving treatment efficacy

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The invention applies local quality by targeting a specific cell subset (4PD1hi TFH-like cells) rather than broadly suppressing the entire immune system. This selective approach allows the treatment to address the specific immunosuppressive mechanism driven by these cells while maintaining the functionality of other immune cells, thus improving the therapeutic index

Inventive Principle:

Principle #3Local quality

2Power

If combination therapy with anti-CTLA-4 and anti-PD-1 is administered, then anti-tumor activity is enhanced, but immune-related toxicities are significantly increased

Engineering Contradiction:

Improveanti-tumor activityVSAvoidimmune-related toxicities

Core Design Contradiction:

PowerVSObject-affected harmful factors

Solution Approach 1:

The patent converts the harmful effect of 4PD1hi cells (which cause immunosuppression and toxicities) into a therapeutic target. By depleting these cells, the invention transforms the source of harm into the mechanism of treatment, allowing combination ICB therapy to proceed with reduced toxicities while maintaining enhanced anti-tumor activity

Inventive Principle:

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

Solution Approach 2:

The invention applies preliminary action by depleting 4PD1hi TFH-like cells before or at the initiation of combination ICB therapy. This pre-treatment approach removes the immunosuppressive barrier that would otherwise limit the effectiveness and increase the toxicity of subsequent checkpoint blockade therapy

Inventive Principle:

Principle #10Preliminary action

Data Source

PatentUS20230390390A1CD4+ TFH-like cells as a therapeutic target

Publication Date: 2023.12.07 MEMORIAL SLOAN KETTERING CANCER CENT

AI summary

CD4+Foxp3−PD-1hi T cells (4PD1hi) that increase in tumor-bearing hosts after immune checkpoint blockade (ICB) constitute an unconventional T-cell inhibitory subset with TFH-like features, which can affect the outcome of cancer immunotherapy. Inhibition of the molecular pathway leading to the development of TFH cells and TFH-like 4PD1hi cells improves response to ICB therapy.