Double Negative T Cells Targeting Chemotherapy-Resistant AML
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Solution Overview
Problem
Current treatments for acute myeloid leukemia (AML) are limited by low long-term survival rates, resistance to chemotherapy, and the lack of effective strategies for targeting chemotherapy-resistant leukemic stem cells, with conventional therapies failing to achieve complete clearance and leading to high relapse rates.
Innovation Solution
The use of double negative T cells (DNTs), which are mature peripheral T lymphocytes that express the CD3-TCR complex but not CD4 or CD8, in combination with chemotherapeutic agents, to target and kill AML cells, including those resistant to chemotherapy, without causing toxicity to normal cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional chemotherapy is used to treat AML, then initial remission is achieved in >70% of patients, but relapse occurs in >70% of patients within 2 years due to chemotherapy-resistant leukemic stem cells
Solution Approach 1:
The patent segments the AML cell population into different subsets and targets them with different therapies. Conventional chemotherapy targets bulk leukemic cells to achieve initial remission, while adoptive T cell therapy specifically targets leukemic stem cells to prevent relapse. This segmentation allows each therapy to address its specific target effectively.
Solution Approach 2:
The patent uses adoptive T cell therapy as an intermediary mechanism to bridge the gap between conventional chemotherapy and complete disease clearance. The T cells act as mediators that specifically recognize and eliminate leukemic stem cells that chemotherapy cannot kill, thereby preventing relapse and extending disease-free survival.
2Reliability
If allogeneic hematopoietic stem cell transplantation is used to treat AML, then disease-free survival is improved, but severe toxicity and tissue damage occur due to donor-derived T cell mediated anti-leukemic effects
Solution Approach 1:
The patent applies local quality by directing T cell activity specifically toward leukemic cells through antigen-specific recognition. The T cells are engineered or selected to recognize specific leukemia-associated antigens, ensuring that the anti-leukemic effect is localized to cancer cells rather than affecting normal tissues broadly, thus reducing toxicity while maintaining disease-free survival.
Solution Approach 2:
The patent uses T cell therapy as a functional copy or surrogate of the more toxic allogeneic stem cell transplantation. Instead of transplanting whole stem cells that cause graft-versus-host disease, the patent uses T cell clones that replicate the anti-leukemic function without the harmful systemic effects, achieving a safer alternative with similar disease control.
3Reliability
If LAA-specific T cells are used to treat AML, then anti-leukemic activity is demonstrated in vitro and in animal models, but isolation and expansion of these cells is difficult
Solution Approach 1:
The patent extracts or isolates T cell clones from peripheral blood mononuclear cells that have been stimulated to express specific T cell receptors against leukemia-associated antigens. By taking out these pre-enriched T cell populations through flow cytometry and magnetic sorting, the patent overcomes the difficulty of isolating rare antigen-specific T cells and enables their expansion for therapy.
Data Source
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AI summary
Methods for the treatment of cancer using double negative (DN) T cells are described. The DNTs may be used for the treatment of chemotherapy- resistant cancers such as recurring or relapsing acute myeloid leukemia (AML). The use of allogenic DNTs, such as those derived from healthy donors, that do not exhibit toxicity towards normal host tissues and the complications associated with graft-versus-host-disease, is also described.