Antigen-Specific T Cell Generation via Allogeneic MHC Co-Transfection
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Solution Overview
Problem
Current adoptive cell therapies for treating solid tumors face challenges such as the slow activation and expansion of specific T cells, risk of graft-versus-host disease, and inefficacy in rapidly progressing tumors due to limitations in generating T cells with high functional avidity that can recognize tumor-specific MHC-peptide ligands without attacking normal tissues.
Innovation Solution
The method involves co-transfecting dendritic cells with RNA encoding allogeneic MHC molecules and tumor-associated antigens to prime peripheral blood lymphocytes, allowing for the selection and expansion of antigen-specific CD4+ and CD8+ T cells with high affinity TCRs, which can be used to treat solid tumors without the risk of graft-versus-host disease.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If unselected lymphocyte populations are transferred in donor lymphocyte infusions, then the elimination of malignant cells can occur, but the activation and expansion of specific T cells takes several months up to a year
Solution Approach 1:
The patent applies preliminary action by pre-activating and expanding tumor-specific T cells ex vivo before transfer to the patient. T cells are stimulated with antigen-presenting cells and cytokines in culture to generate large numbers of activated, tumor-specific effector cells that can immediately attack tumor cells upon infusion, eliminating the months-long in vivo activation period required by conventional DLI approaches.
2Productivity
If unselected lymphocyte populations are transferred to speed up immune response, then T cells can be expanded faster, but the risk of graft-versus-host disease increases
Solution Approach 1:
The patent applies the extraction principle by isolating and selecting only the tumor-specific T cell subset from the total lymphocyte population through antigen-specific stimulation and expansion. This enriches the transferred cell product for cytotoxic T cells with defined tumor reactivity while removing or minimizing regulatory T cells and other lymphocyte subsets that could mediate graft-versus-host disease, thereby achieving rapid antitumor immunity with reduced toxicity.
3Productivity
If T cells with high affinity TCRs are generated to effectively target tumor cells, then tumor eradication is more effective, but the risk of attacking normal tissues increases
Solution Approach 1:
The patent applies local quality by generating T cell populations with heterogeneous TCR affinities rather than uniformly high-affinity clones. The antigen-specific expansion process naturally selects for cells with appropriate affinity ranges, and the polyclonal nature of the product ensures diverse target recognition. This allows effective tumor cell killing while reducing the risk of autoimmunity compared to highly purified single clones with extremely high affinity.
Solution Approach 2:
The patent applies partial action by transferring a polyclonal population of antigen-specific T cells rather than maximizing the frequency of the single most effective clone. This approach achieves sufficient antitumor activity through the combined effect of multiple T cell clones with different specificities and affinities, while maintaining safety through the dilution effect and presence of regulatory cells within the polyclonal mixture.
4Object-affected harmful factors
If stem cell transplantation is performed to establish tolerance before T cell transfer, then graft-versus-host disease is reduced, but the treatment time and complexity increase
Solution Approach 1:
The patent applies the intermediary principle by using antigen-specific T cell expansion as a bridge between bone marrow transplantation and tumor therapy. The method generates tumor-specific effector cells ex vivo that can be transferred after standard bone marrow recovery, serving as an intermediary step that provides targeted antitumor immunity without requiring complex protocols to induce tolerance. The antigen-specific nature of the cells inherently limits their reactivity to host tissues.
Data Source
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AI summary
The present invention is directed to a method of generating antigen specific T cells. Furthermore, the invention is directed to antigen specific T cells, isolated transgenic TCR's, pharmaceutical compositions containing same and their use in adoptive cell therapy. This invention in particular pertains to the use of cells co-expressing allogeneic MHC molecules and antigens to induce peptide-specific T cells from non-selected allogeneic T cell repertoires.