CSF1R-Specific CAR T Cells for Targeted AML Therapy
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Solution Overview
Problem
Current therapies for acute myeloid leukemia (AML) lack specific targeting and are associated with toxicity due to the expression of target antigens on both cancer cells and healthy hematopoietic cells, limiting their effectiveness and causing severe side effects.
Innovation Solution
Development of lymphocytes genetically engineered to express a chimeric antigen receptor (CAR) specific for colony stimulating factor 1 receptor (CSF1R), which is broadly expressed on AML cells but minimally expressed on healthy cells, allowing for targeted therapy with reduced toxicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current therapies target antigens on cancer cells, then therapeutic efficacy is improved, but toxicity increases due to expression on healthy hematopoietic cells
Solution Approach 1:
The patent applies local quality by engineering T cells to express CAR receptors with highly specific binding affinity for CSF1R. This specificity ensures that the therapeutic effect is localized to AML cells expressing CSF1R, while sparing healthy hematopoietic cells that do not express or minimally express this receptor, thereby resolving the contradiction between efficacy and toxicity
2Adaptability or versatility
If target antigen is broadly expressed on cancer cells, then therapeutic coverage is improved, but selectivity against healthy cells deteriorates
Solution Approach 1:
The patent introduces CSF1R as an intermediary target that is broadly expressed on AML cells but minimally expressed on healthy cells. The CAR-T cells are engineered to specifically recognize this intermediary marker, achieving broad therapeutic coverage across different AML subtypes while maintaining high selectivity against healthy hematopoietic cells
Data Source
AI summary
The present invention relates to the recognition of CSF1R as a marker of hematological cancer and thus relates to CSF1R targeting agents for the treatment of such cancers, in particular, AML. The invention also relates to a lymphocyte recombinantly expressing a chimeric antigen T cell receptor (CAR) specific for CSF1R, in particular, for use in the treatment of cancer characterized by the expression of colony stimulating factor 1 receptor (CSF1R). The present invention further relates to a CAR comprising an extracellular domain that specifically binds CSF1R, a transmembrane domain, and an intracellular T cell activating domain; as well as polynucleotides, vectors and host cells used in the production of the CAR. Further, methods for the production of such lymphocytes and a pharmaceutical composition comprising such lymphocytes are provided. The cells of the invention are preferably human lymphocytes and more preferably primary human lymphocytes such as CD3+ T cells, CD8+ T cells, CD4+ T cells, γδ T cells, invariant T cells or NK T cells.