Dual-Specific T-Cell Engineering for Solid Tumor Immunotherapy
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Solution Overview
Problem
Current adoptive cell transfer therapies for cancer, particularly for solid tumors, face challenges such as inadequate T cell responses, reduced migration of T cells to tumors, and immunosuppressive tumor microenvironments, limiting their effectiveness in achieving durable and complete tumor regression.
Innovation Solution
The development of dual-specific lymphocytes, which are genetically engineered to recognize both tumor-associated antigens and a strong antigen, are transfused back into patients along with the strong antigen being injected directly into the tumor, enhancing T cell recruitment and activation at the tumor site.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive cell transfer of genetically engineered T cells is used to treat solid tumors, then tumor-specific immune response is induced, but T cell migration to tumor and durability of response are reduced
Solution Approach 1:
The patent segments the T cell population into dual-specific T cells (targeting both tumor antigen and pathogen antigen) and mono-specific T cells (targeting only tumor antigen). This segmentation allows different T cell subsets to perform specialized functions: dual-specific cells provide robust proliferation and cytokine production in response to pathogen, while mono-specific cells maintain tumor-specific cytotoxicity, thereby resolving the contradiction between inducing immune response and ensuring its durability.
Solution Approach 2:
The patent introduces a pathogen (or pathogen-derived antigen) as an intermediary to bridge T cell activation and tumor targeting. The pathogen serves as a mediator that stimulates dual-specific T cells to proliferate and produce cytokines, which in turn enhances the activity and durability of tumor-specific immune responses without directly targeting the tumor itself.
2Reliability
If single TAA-targeted immunotherapy is used, then specific T cell response is generated, but coverage of heterogeneous tumor cells is inadequate
Solution Approach 1:
The patent creates dual-specific T cells that possess universal functionality by equipping them with two T cell receptors: one specific for tumor-associated antigens and another for pathogen antigens. This multi-functionality allows a single T cell population to respond to both tumor cells and pathogen, thereby achieving broad coverage of heterogeneous tumor cells while maintaining response specificity.
3Reliability
If T cells are engineered to recognize tumor antigens, then tumor-specific killing is achieved, but T cell migration to tumor site is reduced
Solution Approach 1:
The patent employs periodic action by administering the pathogen in multiple doses or at specific time intervals after T cell transfer. This periodic pathogen administration creates waves of dual-specific T cell activation and cytokine release, which periodically enhance T cell migration to tumor sites, thereby overcoming the initial migration deficit while preserving tumor-specific killing ability.
Data Source
AI summary
The present invention relates to autologous dual-specific lymphocytes, methods of making and uses for the treatment of tumors. In particular, the invention relates to methods producing autologous dual-specific lymphocytes comprising an endogenous receptor for at least one tumor associated antigen and an exogenous receptor for a strong antigen