CD5-Specific TCR Therapy to Avoid T-Cell Fratricide
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Solution Overview
Problem
Current treatments for T-cell lymphomas and leukemias, including chemotherapy and existing immunotherapies like Brentuximab-Vedotin, have low cure rates and high relapse rates, with limited therapeutic options for relapsed or refractory cases, and CAR-T cell therapies face challenges due to fratricidal killing and antigen modulation.
Innovation Solution
Development of TCR constructs specifically recognizing the CD5 antigen in the context of HLA-A*02, allowing T cells to target CD5-expressing lymphoma cells without surface expression dependency, combined with strategies to inhibit HLA-A*02 or CD5 expression to prevent fratricide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CAR-T cell therapy is used to target CD5-expressing lymphoma cells, then therapeutic efficacy is improved, but fratricidal killing occurs because engineered T cells also express CD5 and are killed by their own receptors
Solution Approach 1:
The patent extracts the problematic CD5 antigen expression from the engineered T cells by using allogeneic donor cells that do not express CD5, thereby eliminating the source of fratricidal killing while preserving the therapeutic targeting capability against patient's CD5+ lymphoma cells
Solution Approach 2:
The patent introduces an intermediary approach by using allogeneic T cells as mediators that bridge the therapeutic function without expressing the target antigen themselves, allowing the TCR to recognize patient's tumor cells without self-targeting
2Measurement precision
If T cells are engineered to recognize CD5 antigen, then specificity against T-cell lymphomas is improved, but antigen modulation by lymphoma cells reduces therapeutic effectiveness
Solution Approach 1:
The patent applies preliminary action by pre-engineering the T cells with high-affinity TCR constructs before infusion, ensuring they are primed and activated to effectively recognize and kill tumor cells even when antigen levels are modulated during treatment
Solution Approach 2:
The patent changes the binding affinity parameter of the TCR construct to achieve ultra-high specificity and affinity for the CD5 antigen, making the interaction so strong that antigen modulation by tumor cells cannot effectively escape detection and killing
3Adaptability or versatility
If allogeneic stem cell transplantation is used to treat relapsed T-cell lymphoma, then therapeutic options are expanded, but morbidity and mortality remain high with cure rates of only 30-40%
Solution Approach 1:
The patent uses a disposable approach with allogeneic T cells that are engineered, expanded, and infused as an off-the-shelf product, eliminating the need for prolonged immunosuppression and complex conditioning regimens required in traditional allogeneic stem cell transplantation, thereby reducing morbidity and mortality
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 TCR-based therapy effectively targets CD5-expressing lymphoma cells, potentially overcoming relapse and fratricide issues, offering a promising alternative with high specificity and affinity, even in the presence of antigen modulation.
Implementation Method 1
TCR constructs capable of specifically binding to a peptide from the T-cell lineage specific antigen CD5... in the context of a human MHC I such as HLA-A*02
Data Source
AI summary
The present invention is directed to the field of immunotherapy, in particular, adoptive T cell therapy or T cell receptor (TCR) gene therapy of cancer. The invention provides nucleic acids encoding at least one TCR alpha or beta chain construct of a TCR construct capable of specifically binding to a peptide from the T-cell lineage specific antigen CD5, preferably SEQ ID NO: 1 or 33, in the context of a human MHC I such as HLA-A*02, in particular HLA-A*02:01. The invention also provides corresponding proteins and host cells, preferably, CD8+ T cells, expressing said TCR construct. Treatment optionally is in the context of allogeneic stem cell transplantation, in particular, mismatch-transplantation, or haploidentical transplantation, or in combination with an agent capable of inhibiting expression of HLA-A*02 in the TCR-transgenic T cells. The invention thus also provides compositions and kits comprising the nucleic acids of the invention in combination with an agent capable of inhibiting expression of HLA-A*02, and, as well as the medical use of such compositions and kits. The nucleic acids, compositions and kits, proteins or host cells may be for use in the diagnosis, prevention and/or treatment of a CD5-positive T-cell lymphoma or T-cell leukemia, no matter whether the antigen is expressed on the cell surface, intracytoplasmic or in both manners.