CAR-T Cell Composition With CD4/CD8 Selection for Engraftment
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Solution Overview
Problem
Existing methods for treating acute lymphoblastic leukemia (ALL) relapse following allogeneic hematopoietic stem cell transplantation (HSCT) are ineffective, and the survival and proliferation of T-cells with chimeric antigen receptors after transfer to patients are suboptimal, necessitating improved cellular therapies.
Innovation Solution
The method involves selecting and enriching CD4+ and/or CD8+ T-cells from a mixed population, activating them, genetically modifying them with a chimeric antigen receptor, and propagating them in cytokine-enriched cultures to enhance survival, engraftment, and retention of cell surface receptors like CD62L and CD28.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If T-cells are generated using conventional methods, then the treatment process is simpler, but the survival and proliferation rates of T-cells after transfer are suboptimal
Solution Approach 1:
The patent segments the T-cell generation process into distinct stages: (1) selecting and enriching CD4+ and/or CD8+ T-cells from a mixed population, (2) activating the selected T-cells, (3) genetically modifying them with chimeric antigen receptors, and (4) propagating them in cytokine-enriched cultures. This segmentation allows optimization of each stage independently to improve overall survival and proliferation rates.
Solution Approach 2:
The patent applies preliminary action by selecting and enriching specific T-cell populations before genetic modification, and by providing cytokines during the propagation phase to support survival and proliferation. These preliminary steps ensure that the T-cells are in the optimal state before receiving the chimeric antigen receptor, thereby improving their subsequent performance.
2Manufacturing precision
If T-cells are propagated in conventional cultures, then the manufacturing process is simpler, but the retention of cell surface receptors is reduced
Solution Approach 1:
The patent changes the cultural parameters by propagating T-cells in cytokine-enriched cultures rather than conventional media. Specific cytokines are provided to support survival, engraftment, and proliferation, while also maintaining retention of critical cell surface receptors such as CD62L, CD28, and CD27. This parameter change optimizes the manufacturing precision of the final T-cell product.
3Reliability
If existing treatment methods are used for ALL relapse, then the treatment approach is more established, but the treatment effectiveness is insufficient
Solution Approach 1:
The patent generates T-cells with chimeric antigen receptors that can target multiple cancer types and stages. The methodology is adaptable to different patient scenarios, including recurrent and chemotherapy-refractory cases, by modifying the T-cell activation and propagation conditions. This universal approach enables effective treatment across diverse patient populations.
Data Source
AI summary
Aspects of the invention described herein, concern approaches to make genetically modified T-cells comprising a chimeric antigen receptor for human therapy. In some alternatives, the methods utilize a selection and/or isolation of CD4+ and/or CD8+ T-cells from a mixed T-cell population, such as, peripheral blood or apheresis derived mononuclear cells. Once selected/isolated, the CD4+ and/or CD8+ T-cells are then activated, genetically modified, and propagated, preferably, in separate or isolated cultures in the presence of one or more cytokines, which support survival, engraftment and/or proliferation of the cells, as well as, preferably promoting or inducing the retention of cell surface receptors, such as CD62L, CD28, and/or CD27. Included herein are also methods of treatment, inhibition, amelioration, or elimination of a cancer by administering to a subject in need thereof, one or more types of the genetically engineered T-cells or compositions that comprise the genetically engineered T-cell prepared as described herein.