ΔNPM1 Peptide Immunotherapy for Low-Neoantigen AML
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Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) have low efficacy and high toxicity, particularly in patients over 65 years old, and existing immunotherapies targeting low mutational load tumors like AML are ineffective due to limited neoantigens.
Innovation Solution
Identification of HLA-restricted peptides derived from the ΔNPM1 protein, specifically CLAVEEVSL, AVEEVSLRK, CLAVEEVSLRK, and AVEEVSLR, which can be used as therapeutic agents or targets for T cells with specific T cell receptors (TCRs) to treat AML, and TCR gene transfer approaches using these peptides to enhance immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If standard chemotherapy and alloSCT are used to treat AML, then survival rates improve for some patients, but toxicity increases and relapse occurs within 3 years in most patients
Solution Approach 1:
The invention segments the treatment approach by identifying and targeting specific neoantigens (CLAVEEVSL, AVEEVSLRK, CLAVEEVSLRK, AVEEVSLR) derived from the ΔNPM1 mutation, rather than using non-specific chemotherapy. This allows for targeted immunotherapy that spares healthy tissues from toxic effects while maintaining anti-tumor efficacy.
Solution Approach 2:
The invention uses HLA-restricted peptides as intermediaries to bridge the immune system and tumor cells. These peptides present tumor-specific antigens to T cells through HLA molecules, enabling the immune system to specifically recognize and attack ΔNPM1-positive leukemia cells without the broad toxicity of chemotherapy.
2Reliability
If checkpoint inhibitors and TIL therapy are used to target neoantigens, then immune response against tumors is enhanced, but effectiveness is limited in tumors with low mutational load like AML
Solution Approach 1:
The invention extracts and utilizes the limited neoantigens that do exist in AML by identifying specific peptides (CLAVEEVSL, AVEEVSLRK, CLAVEEVSLRK, AVEEVSLR) derived from the recurrent ΔNPM1 mutation. Rather than requiring high overall mutational load, the approach focuses on capturing and targeting these specific tumor-derived peptides that are present in ΔNPM1-positive AML cells.
Solution Approach 2:
The invention changes the parameter of neoantigen selection by focusing on peptides derived from recurrent driver gene mutations (ΔNPM1) rather than relying on the overall mutational burden. This shifts the approach from quantity-based neoantigen availability to quality-based specific neoantigen targeting, enabling effective immunotherapy in low-mutational-load tumors.
3Measurement precision
If T cells with specific TCRs are used to target ΔNPM1 peptides, then specific recognition of tumor cells is achieved, but the intracellular localization of ΔNPM1 protein limits antigen accessibility
Solution Approach 1:
The invention performs preliminary processing by synthesizing peptides that mimic the ΔNPM1 mutation and presenting them on HLA molecules. This pre-presentation makes the otherwise intracellular antigen accessible to T cells, allowing specific recognition without requiring direct access to the intracellular ΔNPM1 protein.
Solution Approach 2:
The invention uses HLA-peptide complexes as intermediaries to bridge the intracellular ΔNPM1 protein and the extracellular T cell receptor. The HLA molecules present processed peptides derived from ΔNPM1 on the cell surface, enabling T cells to recognize tumor cells specifically without direct contact with the intracellular mutation.
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
Provides an effective immunotherapy for HLA-A*02:01, HLA-A*03:01, HLA-A*11:01, and HLA-A*01:01 positive patients with AML by targeting ΔNPM1-positive cells, offering a novel treatment modality with reduced toxicity.
Implementation Method 1
TCRs specific for a peptide selected from CLAVEEVSL (SEQ ID NO:1), AVEEVSLRK (SEQ ID NO:26), CLAVEEVSLRK (SEQ ID NO: 27), VEEVSLRK (SEQ ID NO:28) and AVEEVSLR (SEQ ID NO:29)
Data Source
AI summary
Novel nucleic acid sequences, vectors, modified cells, peptides and pharmaceutical compositions are provided that are useful in the treatment of human subjects having a ΔNPM1 positive haematological malignancy. Corresponding methods and uses are also provided.