Amphipathic Peptides for Tumor-Infiltrating T Cell Generation
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Solution Overview
Problem
Current cancer therapies often suffer from poor selectivity, leading to significant side effects in healthy cells due to non-specific cytotoxic activity, and there is a need for more effective methods to harness the immune system's response against tumour cells, particularly in addressing the lack of strong immune responses to tumour-associated antigens.
Innovation Solution
The use of positively charged amphipathic amino acid derivatives, peptides, or peptidomimetics that can lyse tumour cell membranes to release a broader repertoire of tumour-specific antigens, enhancing the clonality and immunogenicity of tumour-infiltrating T cells, which can then be isolated and used for adoptive cell therapy or vaccine development.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional cancer therapies are used to combat tumours, then cytotoxic activity is achieved, but selectivity is poor leading to side effects in healthy cells
Solution Approach 1:
The patent applies local quality by using amphipathic peptides that specifically target and interact with tumour cell membranes through their hydrophobic regions, while the hydrophilic regions interact with the aqueous environment. This creates a localized effect at the tumour site with selective membrane disruption, sparing healthy cells that lack the specific membrane characteristics. The peptides concentrate their cytotoxic action only where tumour cells are present, achieving high local selectivity.
Solution Approach 2:
The patent employs parameter changes by modifying the physical-chemical properties of the peptide molecules to achieve selective tumour targeting. The amphipathic structure with specific hydrophobicity and charge characteristics allows the peptides to selectively interact with tumour cell membranes. By adjusting parameters such as peptide composition, hydrophobic moment, and charge density, the therapy achieves enhanced selectivity for tumour cells over healthy cells.
2Reliability
If the immune system is stimulated to fight tumours, then immune response is enhanced, but the response to tumour-associated antigens remains weak
Solution Approach 1:
The patent applies preliminary action by using amphipathic peptides to pre-disrupt tumour cell membranes and release tumour-associated antigens before immune system engagement. This preliminary release of antigens makes them more accessible to the immune system, creating a primed state where the immune system can more effectively recognize and respond to tumour antigens. The peptides perform the preparatory work of antigen release, enhancing subsequent immune productivity.
Solution Approach 2:
The patent uses amphipathic peptides as intermediaries that mediate between the tumour cells and the immune system. The peptides first interact with and disrupt tumour cell membranes, releasing antigens, and then the released antigens serve as intermediaries that the immune system can recognize. This two-stage intermediary process overcomes the weak direct response to tumour-associated antigens by creating a more immunogenic intermediate state.
3Quantity of substance
If tumour cell membranes are lysed to release antigens, then antigen repertoire is broadened, but cell membrane integrity is compromised
Solution Approach 1:
The patent applies the taking out principle by using amphipathic peptides to extract and release tumour-associated antigens from within the tumour cell membranes. The peptides insert into the membrane, disrupt it, and extract antigens into the extracellular space where they become accessible to the immune system. This selective extraction of antigens while controlling membrane disruption achieves broad antigen release with manageable loss of membrane integrity.
Solution Approach 2:
The patent employs partial action by using low to moderate concentrations of amphipathic peptides that achieve sufficient membrane disruption to release antigens without causing complete cell lysis. The peptide concentration and exposure time are optimized to achieve the desired degree of membrane permeabilization - enough to release antigens but not so much as to cause excessive cell death. This partial action maintains some membrane integrity while achieving the antigen release goal.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
This approach results in a more effective T cell response against tumour neoantigens, increasing the immunogenicity of tumours and enabling the generation of therapeutic T cell populations that can specifically target and eliminate cancer cells with reduced side effects on healthy tissues.
Implementation Method 1
positively charged amphipathic amino acid derivative, peptide or peptidomimetic which is able to lyse tumour cell membranes
Implementation Method 2
amphipathic amino acid derivative, peptide or peptidomimetic - amphipathic molecules have both hydrophilic (charged) and hydrophobic regions that can insert into lipid membranes
Implementation Method 3
able to lyse tumour cell membranes and then collecting a cellular sample
Data Source
AI summary
The present invention provides a method of generating a population of tumour-infiltrating T cells, said method comprising administering to a subject a positively charged amphipathic amino acid derivative, peptide or peptidomimetic which is able to lyse tumour cell membranes and then collecting a cellular sample from a tumour within said subject and separating T cells therefrom. The present invention further provides a method of generating a population of tumour-infiltrating T cells, said method comprising separating T cells from a cellular tumour sample taken from a subject treated with a positively charged amphipathic amino acid derivative, peptide or peptidomimetic which is able to lyse tumour cell membranes and optionally culturing said T cells. The present invention also provides the tumour-infiltrating T cells described above for use in treating tumour cells or preventing or reducing the growth, establishment, spread, or metastasis of a tumour.