Multicistronic Vector Surface Engineering for In Vivo TIL Expansion
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Solution Overview
Problem
Current cancer immunotherapy methods, such as adoptive T cell therapy, are costly, time-consuming, and risky due to the need for ex vivo expansion of immune cells, highlighting the need for alternative means to expand tumor-infiltrating lymphocytes (TILs) in vivo.
Innovation Solution
The development of multicistronic vectors that generate surface-engineered lentiviral particles using peptides capable of ribosome skipping or self-cleavage, allowing for the expression of fusion glycoproteins and non-viral proteins for viral surface display, which can be used to expand TILs in vivo by transducing them directly within the body.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Quantity of substance
If ex vivo expansion of immune cells is used, then TILs can be expanded and used for therapy, but the process becomes costly, time-consuming, and risky
Solution Approach 1:
The lentiviral particles are pre-engineered with surface display proteins (anti-CD3 scFv, CD86, CD137L) and fusion glycoproteins (COCVG) to enable direct in vivo expansion of TILs. This preliminary preparation of the viral vector eliminates the need for time-consuming ex vivo expansion steps, allowing TILs to expand directly within the patient's body after a single administration.
2Quantity of substance
If ex vivo expansion of immune cells is used, then TILs can be expanded and used for therapy, but costs and risks increase
Solution Approach 1:
The surface-engineered lentiviral particles enable TILs to expand autonomously within the patient's body by providing all necessary costimulatory signals (anti-CD3 scFv for T cell receptor engagement, CD86 for costimulation, CD137L for enhanced activation) directly on the viral surface. This self-sufficient in vivo expansion system eliminates the need for complex ex vivo culture conditions and reduces procedural risks.
3Adaptability or versatility
If multicistronic vectors with multiple polypeptides are used, then surface-engineered lentiviral particles can be generated, but vector complexity increases
Solution Approach 1:
The multicistronic vector uses 2A self-cleaving peptides (P2A, T2A, E2A, or F2A) to segment the polynucleotide sequence into multiple separate polypeptide coding regions. These 2A peptides cause ribosome skipping during translation, resulting in cleavage and release of individual proteins (COCVG fusion glycoprotein, anti-CD3 scFv, CD86, CD137L) that are then displayed on the lentiviral surface, thereby managing vector complexity through functional segmentation.
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 enables efficient in vivo expansion of TILs, reducing the costs and risks associated with ex vivo expansion, while effectively treating cancer by administering surface-engineered lentiviral particles that can recognize and kill tumor cells.
Implementation Method 1
the plurality of polypeptides are joined by linkers comprising peptides capable of inducing ribosome skipping or self-cleavage
Implementation Method 2
the plurality of polypeptides are joined by linkers comprising peptides capable of inducing ribosome skipping or self-cleavage
Data Source
AI summary
The disclosure relates generally to nucleic acid vectors and packaging cell lines for in vivo expansion of T-cells. More particularly, the disclosure relates to intravenous or intratumoral injection of a lentiviral particle adapted for transduction and expansion of tumor-infiltrating lymphocytes in vivo.