CD4+ TCR-Engineered TIL Therapy for Neoantigen Tumor Recognition
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Solution Overview
Problem
Existing immunotherapies for cancer, particularly adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL), have response rates ranging from 28-55% and lack substantial improvement, highlighting the need for more effective CD4+ T cell-based therapies.
Innovation Solution
Engineering CD4+ T cells with novel T cell receptors (TCR) comprising specific CDR3 regions, such as those encoded by SEQ ID NOs, to enhance their recognition and response to tumor antigens, particularly through MHC Class II presentation, and administering these cells in adoptive cell therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL) is used, then treatment can be administered to cancer patients, but response rates are limited to 28-55% and substantial improvement is lacking
Solution Approach 1:
The patent changes the key parameter of T cell receptor specificity by engineering CD4+ T cells with novel TCRs that recognize neoantigens presented by MHC Class II molecules. This parameter change transforms the limited response rate of conventional ACT into enhanced therapeutic effectiveness by targeting tumor-specific neoantigens with high specificity.
Solution Approach 2:
The patent introduces MHC Class II molecules as intermediaries in the immune response mechanism. By engineering CD4+ T cells to recognize neoantigens presented on MHC Class II, the invention creates a new mediation pathway that overcomes the limitations of conventional CD8+ T cell-based approaches and achieves improved response rates.
2Adaptability or versatility
If CD4+ T cell-based immunotherapies are developed, then new treatment options can be provided, but engineering novel T cell receptors increases device complexity
Solution Approach 1:
The patent segments the T cell engineering process into distinct components: isolating CD4+ T cells, introducing novel TCR genes encoding specific CDR3 regions, and selecting for functional expression. This segmentation of the complex engineering process into manageable steps reduces overall complexity while achieving therapeutic effectiveness.
Solution Approach 2:
The patent uses gene copying by introducing TCR alpha and beta chain genes with specific CDR3 sequences into CD4+ T cells. This molecular copying approach allows precise replication of antigen-specific recognition capabilities without requiring de novo design of entire receptor structures, thereby reducing engineering complexity.
Data Source
AI summary
Disclosed are novel adoptive cell therapies comprising engineered CD4+ T cells comprising novel T cell receptors and methods of their use in the treatment of cancer. Further, wherein an engineered CD4+ T cell comprising a T cell receptor (TCR) alpha (TCRa) chain comprising a complimentary determining region (CDR) 3 (CDR3) is disclosed.