PRAME-Specific CAR T Cells Targeting AML via IFN-γ Upregulation
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Solution Overview
Problem
Current CAR T cell therapies for acute myeloid leukemia (AML) are limited due to the innate heterogeneity of AML and the lack of AML-specific targets, with existing treatments not effectively targeting PRAME-expressing cancers.
Innovation Solution
Development of chimeric antigen receptors (CAR) that bind specifically to the PRAME antigen, utilizing the Pr20 monoclonal antibody-derived binding domain and co-administering interferon gamma to enhance PRAME expression, allowing CAR T cells to target and eliminate PRAME-expressing AML cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR T cell therapy is applied to treat AML, then therapeutic potential is improved, but treatment efficacy is limited due to lack of AML-specific targets and AML heterogeneity
Solution Approach 1:
The patent changes the target parameter by selecting PRAME, a cancer-testis antigen that is differentially expressed in AML cells compared to normal hematopoietic cells. This parameter change enables specific targeting of AML cells while sparing healthy cells, resolving the contradiction between therapeutic potential and target availability.
Solution Approach 2:
The patent applies local quality by directing CAR T cells to specifically recognize and bind to PRAME antigen on AML cell surfaces. The CAR construct includes a binding domain that locally targets PRAME, enabling precise differentiation between AML cells (which express PRAME) and normal cells (which do not), thus overcoming AML heterogeneity and lack of specific targets.
2Productivity
If PRAME-specific CAR T cells are used, then cytolytic activity against AML cells is increased, but tumor antigen expression may be downregulated to evade therapy
Solution Approach 1:
The patent applies preliminary action by co-administering interferon-gamma (IFN-γ) before or with CAR T cell therapy. IFN-γ pre-treatment upregulates PRAME antigen expression on AML cells, ensuring that sufficient target antigen is available when CAR T cells arrive, thereby preventing antigen downregulation and maintaining reliable cytolytic activity.
Solution Approach 2:
The patent implements feedback by using IFN-γ, which is also produced by activated CAR T cells, to create a positive feedback loop. CAR T cell activation leads to IFN-γ production, which further upregulates PRAME expression, enhancing subsequent CAR T cell recognition and cytolytic activity, thus maintaining reliable antigen expression throughout the therapeutic process.
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
The PRAME-specific CAR T cells demonstrate in vitro and in vivo efficacy against HLA-A2 restricted AML cells, significantly increasing cytolytic activity and cytokine production, thereby providing a novel approach for treating PRAME-expressing cancers such as t(8;21), Inv(16), and KMT2A-r AML.
Implementation Method 1
chimeric antigen receptors (CAR) that bind Preferentially Expressed Antigen in Melanoma (PRAME) ALYVDSLFFL (ALY, SEQ ID NO: 94)/HLA-A*0201 (HLA-A2)
Implementation Method 2
Particular embodiments include co-administering interferon gamma (IFNγ) to increase PRAME expression by cancer cells
Implementation Method 3
PRAME mTCRCAR T cells demonstrate in vitro and in vivo efficacy against HLA-A2 restricted AML cells expressing the PRAME antigen
Data Source
AI summary
Chimeric antigen receptors (CAR) that bind Preferentially Expressed Antigen in Melanoma (PRAME) ALY(SEQ ID NO: 94)/HLA-A2 are disclosed. The CAR can be used to treat PRAME/HLA-A2 expressing cancers such as the t(8;21), Inv(16), and KMT2A-r forms of acute myeloid leukemia (AML).