Engineered Killer Phagocytic Cells for Cancer Immunotherapy
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Solution Overview
Problem
Current methods for generating macrophages and dendritic cells for therapeutic use, such as in cancer treatment, face issues like short lifespan upon re-infusion, downregulation of chemokine receptors, and the need for lengthy culture periods, leading to suboptimal outcomes due to the reduction of key functional capabilities.
Innovation Solution
A method to generate a population of myeloid cells from a human biological sample that can differentiate into downstream effector cells and retain their precursor functions, allowing them to traffic to sites of cancer, infection, or inflammation, without altering their intrinsic abilities, by isolating and engineering CD14+/CD16− cells to express recombinant proteins or Chimeric Antigen Receptors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monocytes are cultured for more than 5 days to generate macrophages or dendritic cells, then the cells appear to have strong functional capabilities in vitro, but the cells have short life span upon re-infusion into humans
Solution Approach 1:
The patent applies preliminary action by selecting and preparing monocytes with specific surface marker profiles (CD14+, CD16−, CD64+, HLA-DR+) before culture, and by optimizing culture conditions (cytokine combinations, culture duration of 3-7 days) in advance to generate cells that will maintain functionality after infusion. This preliminary preparation ensures the cells have the right characteristics before being introduced to the patient, resolving the contradiction between in vitro functionality and in vivo persistence.
2Reliability
If monocytes are cultured for more than 5 days to generate macrophages or dendritic cells, then the cells appear to have strong functional capabilities in vitro, but the cells show downregulation of critical chemokine receptors needed for trafficking
Solution Approach 1:
The patent applies parameter changes by carefully controlling culture conditions including cytokine combinations (M-CSF, GM-CSF, IL-4 at specific concentrations), culture duration (3-7 days), and temperature to generate cells that maintain high expression of chemokine receptors (CCR2, CCR5, CXCR3) while acquiring desired functional capabilities. This optimization of cultural parameters resolves the contradiction between in vitro functionality and trafficking ability.
3Ease of manufacture
If classical methods are used to generate macrophages and dendritic cells, then the production process is established, but the process requires more than 5 days (usually at least 7 days) to prepare cells for in vivo application
Solution Approach 1:
The patent applies preliminary action by pre-selecting monocytes with optimal surface marker profiles (CD14+, CD16−, CD64+, HLA-DR+) from patient blood before culture initiation. This preliminary selection ensures that only cells with the right characteristics enter the culture process, reducing the required culture time from 7+ days to 3-7 days while maintaining cell quality and functionality.
Solution Approach 2:
The patent applies parameter changes by optimizing culture conditions including cytokine combinations and concentrations, culture duration (reducing to 3-7 days), and temperature to accelerate cell generation while maintaining quality. These parameter optimizations resolve the contradiction between established processes and time efficiency.
4Adaptability or versatility
If monocytes are differentiated into macrophages or dendritic cells through culture, then the cells can be used for tumor vaccine and other purposes, but the process reduces key functions needed to migrate to sites of disease
Solution Approach 1:
The patent applies parameter changes by carefully controlling culture conditions including cytokine combinations (M-CSF for macrophage lineage, GM-CSF+IL-4 for dendritic cell lineage), culture duration (3-7 days), and temperature to generate cells that maintain high expression of chemokine receptors (CCR2, CCR5, CXCR3) and migratory functions while acquiring desired therapeutic capabilities. This optimization resolves the contradiction between therapeutic versatility and migration function.
Data Source
AI summary
The present disclosure provides compositions and methods for making and using engineered killer phagocytic cells for immunotherapy in cancer or infection by expressing a chimeric antigen receptor having an enhanced phagocytic activity, the chimeric receptor is encoded by a recombinant nucleic acid.