IL-36 Secreting CAR-T Cells for Immunosuppressive Tumor Microenvironments

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Solution Overview

Problem

Current cancer therapies, such as adoptive T cell therapies, face challenges due to malignant cells adapting to create an immunosuppressive microenvironment, hindering effective immune recognition and elimination.

Innovation Solution

Engineering immunoresponsive cells, such as T cells, to express an antigen-recognizing receptor (CAR or TCR) and secrete interleukin 36 (IL-36) polypeptides, enhancing their anti-tumor efficacy by modifying the promoter at the endogenous IL-36 gene locus to control gene expression.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Strength

If CAR-engineered T cells are used to target tumor cells, then anti-tumor cytotoxicity is improved, but the tumor microenvironment becomes immunosuppressive, reducing treatment efficacy

Engineering Contradiction:

Improveanti-tumor cytotoxicityVSAvoidimmunosuppressive microenvironment

Core Design Contradiction:

StrengthVSObject-affected harmful factors

Solution Approach 1:

The patent introduces IL-12 as an intermediary substance that mediates between the CAR-T cells and the tumor microenvironment. The IL-12 secreted by engineered T cells acts as a signaling molecule to counteract immunosuppression, recruit additional immune cells, and enhance the overall anti-tumor response without directly targeting the tumor cells themselves

Inventive Principle:

Principle #24Intermediary (Mediator)

Solution Approach 2:

The patent modifies the cytokine secretion profile of T cells by engineering them to constitutively secrete IL-12. This parameter change in cytokine composition transforms the T cell's functional properties, enabling it to simultaneously maintain cytotoxicity while actively counteracting the immunosuppressive microenvironment through IL-12-mediated immune modulation

Inventive Principle:

Principle #35Parameter changes

2Reliability

If IL-12 is secreted by CAR-engineered T cells to counteract immunosuppression, then immune response is enhanced, but IL-2 secretion is suppressed, reducing T and B lymphocyte proliferation

Engineering Contradiction:

Improveimmune response enhancementVSAvoidIL-2 levels

Core Design Contradiction:

ReliabilityVSQuantity of substance

Solution Approach 1:

The patent employs partial action by selectively enhancing IL-12 secretion while accepting that IL-2 levels may be partially suppressed. The design recognizes that IL-12's immune-enhancing effects can compensate for reduced IL-2, achieving sufficient anti-tumor immunity through the IL-12 pathway without requiring high levels of both cytokines simultaneously

Inventive Principle:

Principle #16Partial or excessive action

3Strength

If CAR-T cells are engineered to secrete cytokines, then anti-tumor efficacy is improved, but cell therapy complexity increases

Engineering Contradiction:

Improveanti-tumor efficacyVSAvoidcell therapy complexity

Core Design Contradiction:

StrengthVSDevice complexity

Solution Approach 1:

The patent merges multiple functions into a single cell type by engineering T cells to simultaneously express CAR receptors for tumor targeting and cytokine genes (IL-12) for immune modulation. This consolidation of targeting and immunomodulatory functions into one cell population simplifies the overall therapy architecture compared to using multiple different cell types

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS12544440B2IL-36 secreting immunoresponsive cells and uses thereof

Publication Date: 2026.02.10 MEMORIAL SLOAN KETTERING CANCER CENT

AI summary

The present disclosure provides methods and compositions for enhancing the immune response toward cancers and pathogens. It relates to an immunoresponsive cell comprising an antigen-recognizing receptor (e.g., a chimeric antigen receptor (CAR) or a T cell receptor (TCR)), and expressing increased level of IL-36. In certain embodiments, the engineered immunoresponsive cells are antigen-directed and have enhanced immune-activating properties.