TCL1-Specific TCRs for B-Cell Malignancy Immunotherapy
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Solution Overview
Problem
Current T cell-based therapies for cancers, such as B-cell malignancies and solid tumors, face challenges with relapse due to loss of CD19 expression on tumor cells, necessitating novel targets for improved clinical outcomes.
Innovation Solution
Development of T cell receptors (TCRs) with antigenic specificity for the TCL1 oncoprotein, specifically targeting the TCL1 peptide SLLPIMWQLY, to selectively bind and recognize TCL1-expressed cancer cells, enabling targeted immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CD19 CAR T-cell therapy is used to treat B-cell malignancies, then response rates are high, but relapse occurs due to loss of CD19 expression on tumor cells
Solution Approach 1:
The patent develops TCRs that can recognize multiple TCL1 peptide epitopes (TCL165-79, TCL170-79, TCL173-82) presented by different HLA molecules (HLA-A2, HLA-A3, HLA-B7). This multi-epitope recognition capability provides universal coverage against TCL1-expressing tumors, preventing escape through single epitope loss and addressing the limitation of CD19 CAR T-cell therapy where tumor cells can lose the single target antigen.
2Reliability
If TCL1-specific TCRs are developed to target multiple epitopes, then tumor recognition capability is enhanced, but TCR design complexity increases
Solution Approach 1:
The patent segments the TCL1 antigen recognition into multiple discrete peptide epitopes (TCL165-79, TCL170-79, TCL173-82), each recognized by specific TCRs. This segmentation allows the immune system to target different portions of the TCL1 oncoprotein independently, enhancing overall tumor recognition while maintaining manageable individual TCR structures that can be separately engineered and combined.
Data Source
AI summary
Provided are T cell receptors (TCR) and TCR variable regions that can selectively bind the T-cell leukemia/lymphoma 1 (TCL1) oncoprotein. The TCR may be utilized in various therapies, such as autologous TCL1-TCR adoptive T cell therapy, to treat a cancer, such as a B-cell malignancy or a solid tumor expressing TCL1. Methods for expanding a population of T cells that target TCL1 are also provided.