Lentiviral Vector for In Vivo T Cell Transduction
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Solution Overview
Problem
Current methodologies for in vivo transduction of immune cells to treat cancer and B-cell malignancies face technical, logistical, consistency, and cost challenges, primarily due to the difficulty in activating T cells and controlling the expansion of engineered cells.
Innovation Solution
A viral particle comprising a vector genome with a polynucleotide sequence encoding an anti-CD19 chimeric antigen receptor is used for in vivo transduction of T cells, which includes a multipartite cell-surface receptor and immune cell-activating proteins, allowing for the administration of the viral particle without pre-activation of immune cells and enabling targeted therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If ex vivo transduction methodology is used, then T cells can be genetically modified with anti-CD19 CAR, but the process requires complex logistics including leukapheresis, cGMP facility manufacturing, and coordinated timing of lymphodepleting chemotherapy
Solution Approach 1:
The invention extracts the T cell activation and CAR expression steps from the complex ex vivo manufacturing process and relocates them to occur in vivo within the patient's body. The viral vector delivers the CAR construct directly to T cells in the patient, eliminating the need for leukapheresis, cGMP facility manufacturing, and complex coordination of chemotherapy timing.
Solution Approach 2:
The patient's own immune system serves as the manufacturing facility. T cells are activated and engineered in vivo within the patient's body, using the patient's physiological environment rather than requiring external cGMP facilities. The viral vector autonomously delivers the CAR construct to T cells that naturally encounter it in the patient's circulation.
2Device complexity
If in vivo transduction is used, then logistical complexities are reduced, but T cells require activation and expansion control in the body
Solution Approach 1:
The viral vector is engineered with pre-built-in T cell activation capabilities through its envelope proteins that bind to CD3/CD28 on T cells. The vector also includes regulatory elements that control CAR expression levels and duration in advance, eliminating the need for external activation signals and expansion control measures during in vivo treatment.
Solution Approach 2:
The viral vector performs multiple functions simultaneously: it delivers the CAR construct, activates T cells through envelope protein interactions, controls CAR expression levels, and regulates expansion. This multi-functional design simplifies the overall process by consolidating multiple complex steps into a single administered vector.
3Manufacturing precision
If ex vivo manufacturing process is used, then consistent CAR expression can be achieved, but manufacturing costs and time delays increase
Solution Approach 1:
The invention extracts the CAR expression process from the time-consuming ex vivo manufacturing timeline and executes it directly in the patient's body. The viral vector transduces T cells in vivo, allowing CAR expression to begin immediately after administration without waiting for weeks of external manufacturing processing.
Solution Approach 2:
The viral vector is pre-engineered with optimal promoter elements and regulatory sequences that ensure consistent and robust CAR expression upon delivery. These pre-built-in regulatory mechanisms guarantee reliable expression without requiring the extensive quality control and optimization processes needed in ex vivo manufacturing.
4Ease of operation
If in vivo transduction is used, then treatment can be administered directly to patient, but control of engineered cell expansion becomes challenging
Solution Approach 1:
The viral vector includes built-in feedback mechanisms through regulatory elements that monitor and adjust CAR expression levels based on physiological conditions. The system responds to tissue-specific signals and cellular states, automatically modulating expansion and activity to maintain appropriate therapeutic levels without external intervention.
Solution Approach 2:
The vector design incorporates dynamic regulatory elements that allow CAR expression and T cell activation to be modulated in response to changing physiological conditions. The system adapts its behavior based on tissue environment, cellular state, and therapeutic response, providing flexible control without requiring external manipulation.
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
The approach effectively transduces immune cells in vivo, activates T cells, and achieves significant depletion of CD19+ B cells, with sustained B cell depletion and enhanced proliferation in response to rapamycin, demonstrating improved efficacy and reduced logistical complexities.
Implementation Method 1
a viral particle comprising a vector genome comprising a polynucleotide sequence encoding an anti-CD19 chimeric antigen receptor, wherein the viral particle transduces immune cells in vivo
Implementation Method 2
The viral particle comprises a polypeptide comprising a single-chain variable fragment that specifically binds CD3 (anti-CD3 scFv) exposed on the surface and/or conjugated to the surface of the viral envelope
Data Source
AI summary
Provided are compositions and methods for transducing immune cells in vivo where a viral particle comprising a polynucleotide encoding a chimeric antigen receptor and a multipartite cell-surface receptor is administered to a subject.