ERBB2-Specific TCR Engineering for Stronger Tumor-Reactive T Cells
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Solution Overview
Problem
Existing immunotherapies targeting the ERBB2 receptor, such as monoclonal antibodies and cancer vaccines, have limited efficacy in treating ERBB2-expressing cancers due to weak T-cell responses and immunological self-tolerance, necessitating the development of potent CD8+ T-cells with high functional avidity and tumor reactivity.
Innovation Solution
Development of a purified T cell receptor (TCR) specific for the HER2/Neu (ERBB2) epitope, comprising specific TCR alpha and beta chains, which can be encoded by particular nucleic acid sequences, and administered to generate high-affinity T-cells capable of recognizing and targeting ERBB2-expressing cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies (e.g., trastuzumab) are used to treat ERBB2-overexpressing breast cancer, then tumor targeting is achieved, but efficacy is limited and does not translate well to ovarian cancer
Solution Approach 1:
The patent replaces antibody-based immunotherapy with T cell receptor (TCR)-based cellular immunotherapy. The TCR-transduced T cells directly recognize and kill ERBB2-expressing tumor cells through cell-mediated cytotoxicity, representing a fundamental shift from humoral (antibody) to cellular immunity, thereby achieving more reliable and versatile tumor regression across different cancer types
Solution Approach 2:
The patent changes the immunological mechanism from passive antibody binding to active T cell recognition and destruction. By modifying T cells ex vivo with ERBB2-specific TCRs and expanding them in vitro, the therapy creates a potent cellular response that can adapt to different tumor microenvironments and cancer types, improving both efficacy and versatility
2Reliability
If cancer vaccines are used to induce specific anti-tumor immunity, then T-cell response is generated, but the response is weak and does not induce objective tumor regression
Solution Approach 1:
The patent performs preliminary T cell activation and expansion ex vivo before administration. T cells are stimulated with ERBB2 peptides and co-stimulatory molecules in a controlled laboratory environment, allowing optimal activation and proliferation to occur before the cells are infused into the patient, thereby ensuring potent tumor regression without the weaknesses of in vivo vaccination
Solution Approach 2:
The patent uses TCR-transduced T cells as intermediary effectors between the ERBB2 antigen and the immune system. These engineered T cells serve as potent mediators that directly recognize tumor cells through their TCRs and induce destruction via perforin and granzyme pathways, achieving strong tumor regression that conventional vaccines cannot induce
3Reliability
If T cell receptor gene transfer is used to generate antigen-specific T-cells, then tumor targeting capability is achieved, but immunological self-tolerance limits effectiveness
Solution Approach 1:
The patent extracts and isolates the ERBB2-specific TCR sequence from a donor T cell, removing only the necessary variable regions while using constant regions from human immunoglobulin genes. This extraction approach allows the TCR to recognize ERBB2 without triggering self-tolerance, as the constant regions are derived from self-like immunoglobulin sequences
Solution Approach 2:
The patent creates a functional copy of the ERBB2-specific TCR using human immunoglobulin constant regions instead of murine sequences. By copying the variable regions that confer ERBB2 specificity while using human constant regions, the therapy achieves tumor reactivity without the immunological self-tolerance problems associated with using non-human TCR sequences
Data Source
AI summary
The present invention relates to compositions and methods for treating HER2/Neu (ERBB2) expressing cancer cells. In some embodiments, the invention includes an isolated T cell receptor (TCR) having high affinity for and that specifically binds ERBB2369-377 epitope on a target cell. Other embodiments include a T cell or a population of T cells modified to express ERBB2-specific TCR. Further embodiments include methods of using ERBB2-specific TCR gene transfer for treating ERBB2 expressing cancer cells. Also included are methods and pharmaceutical compositions comprising the modified T cells for adoptive therapy.