HLA Haplotype Expression in Tumor Cells for TCR-T Therapy

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Solution Overview

Problem

Current TCR-T therapy is limited by the requirement for a matching HLA haplotype between tumor cells and T cells, restricting its applicability and effectiveness due to the need for both tumor-associated antigens and specific HLA expression, and downregulation of HLA in tumor cells.

Innovation Solution

Genetic modification of tumor cells to express a different HLA haplotype, allowing them to be recognized by TCR-engineered T cells, thereby increasing their sensitivity to TCR-T therapy and overcoming HLA mismatch and downregulation issues.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If TCR-T therapy is applied to tumors, then tumor cell susceptibility to TCR-engineered T cells increases, but the therapy is limited by the requirement for matching HLA haplotype between tumor cells and T cells

Engineering Contradiction:

Improvetumor cell susceptibility to TCR-T therapyVSAvoidapplicability of TCR-T therapy

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

Instead of requiring the T cell to match the tumor's HLA haplotype, the invention inverts the approach by genetically modifying the tumor cells to express a different HLA haplotype that matches the TCR-engineered T cells. This allows the tumor to be adapted to the therapy rather than the therapy being constrained by the tumor's characteristics.

Inventive Principle:

Principle #13The other way round (Inversion)

Solution Approach 2:

The invention changes the HLA haplotype parameter of the tumor cells through genetic modification. By introducing new HLA alleles into the tumor cells, the system alters the molecular recognition interface to enable TCR-T therapy effectiveness regardless of the patient's original HLA background.

Inventive Principle:

Principle #35Parameter changes

2Reliability

If tumor cells express HLA haplotype for TCR recognition, then T cell recognition and killing efficiency improves, but tumor cells downregulate HLA expression to escape immune detection

Engineering Contradiction:

ImproveT cell recognition efficiencyVSAvoidHLA expression stability in tumor cells

Core Design Contradiction:

ReliabilityVSStability of the object's composition

Solution Approach 1:

The invention performs preliminary genetic modification of tumor cells to express multiple HLA haplotypes or specific HLA alleles before TCR-T therapy is administered. This pre-engineering ensures that when T cells recognize and kill HLA-matched tumor cells, alternative HLA-expressing tumor cells remain as targets, preventing escape through HLA downregulation.

Inventive Principle:

Principle #10Preliminary action

Solution Approach 2:

The genetically modified tumor cells express multiple HLA haplotypes simultaneously, making them universally recognizable by different TCR-engineered T cell populations. This multi-functionality in HLA expression prevents the tumor from escaping immune detection through downregulation of a single HLA type.

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS20240156869A1Methods of enhancing diversity of HLA haplotype expression in tumors to broaden tumor cell susceptibility to TCR-t therapy

Publication Date: 2024.05.16 T CURE BIOSCIENCE INC

AI summary

The present invention provides methods for increasing the sensitivity of tumor cells to a TCR-engineered T cells (TCR-T) therapy comprising genetically modifying the tumor cells to express an haplotype, for example an HLA haplotype, different from the haplotype endogenous to the tumor cells.