Antigen-Specific T Cell Expansion via Cytokine and Co-Culture
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Solution Overview
Problem
Current methods for adoptive T-cell therapy in cancer treatment face challenges in achieving long-term survival and expansion of antigen-specific T cells post-reinfusion, as existing protocols often require multiple restimulations, which can render cells less active and closer to apoptosis, and do not predict in vivo efficacy based on IFN-y release and tumor cell killing alone.
Innovation Solution
An in vitro method involving co-culturing tumor antigen receptor-expressing T cells with allogenic dendritic cells and sensitized lymphocytes in the presence of anti-CD3 antibodies, supplemented with IL-2, IL-7, IL-15, and IL-21, to enhance proliferation and survival of antigen-specific CD4+ and CD8+ T cells, promoting their activation and resistance to apoptosis.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If multiple restimulations are performed to reach clinically relevant levels of tumor specific cytotoxic T cells, then the quantity of T cells is increased, but the cells become less active and closer to apoptosis
Solution Approach 1:
The patent changes the cytokine environment parameters by adding IL-7 and IL-15 to the culture medium during T cell expansion. These cytokine parameter changes promote T cell survival and maintain cell activity while achieving clinically relevant quantities, avoiding the apoptosis-inducing effect of multiple restimulations
Solution Approach 2:
The patent uses allogeneic dendritic cells and sensitized lymphocytes as intermediary elements in the co-culture system. These intermediaries provide continuous antigen-specific stimulation and costimulatory signals that enable T cell expansion without requiring repeated restimulations, thereby maintaining cell activity and preventing apoptosis
2Manufacturing precision
If IFN-y release and tumor cell killing are used as selection criteria for adoptive transfer, then the functional quality of T cells is improved, but the in vivo efficacy cannot be predicted
Solution Approach 1:
The patent performs preliminary expansion and selection of T cells in vitro using a co-culture system with dendritic cells and sensitized lymphocytes before adoptive transfer. This preliminary action creates a more comprehensive functional phenotype that better predicts in vivo efficacy, going beyond simple IFN-y release and tumor cell killing assays
Solution Approach 2:
The patent uses the co-culture system with dendritic cells and sensitized lymphocytes as a feedback mechanism to select T cells with improved in vivo persistence and expansion capacity. The system provides real-time functional assessment that correlates better with clinical outcomes than traditional assays
3Quantity of substance
If conventional expansion methods are used to obtain large numbers of T cells, then the quantity is increased, but the proliferative capacity and survival are reduced
Solution Approach 1:
The patent changes the cultural parameters by supplementing the medium with IL-7 and IL-15 cytokines during expansion. These parameter changes maintain T cell proliferative capacity and survival while achieving the necessary cell quantities for clinical therapy
Solution Approach 2:
The patent establishes a continuous co-culture system with dendritic cells and sensitized lymphocytes that provides ongoing antigen-specific stimulation and costimulatory signals. This continuous useful action enables sustained T cell proliferation and survival without the need for discontinuous restimulations that deplete cell activity
Data Source
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AI summary
The present invention relates to an in vitro method for priming genetically modified T cells suitable for administration to a patient having a tumor. The invention is also directed to the composition obtained by the method and uses thereof.