Retroviral Particles for Lymphocyte Genetic Modification
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current methods for genetically modifying lymphocytes, such as T cells and NK cells, are complex, time-consuming, and require extensive ex vivo manipulation, leading to safety concerns and inefficiencies, particularly in activating resting cells and achieving controlled proliferation and survival within the tumor microenvironment.
Innovation Solution
The development of simplified methods and compositions that allow for in vivo or ex vivo genetic modification of lymphocytes using replication incompetent retroviral particles (RIPs), which include activation elements and lymphoproliferative elements, enabling rapid and controlled expansion of T cells and NK cells without the need for extensive pre-processing or lymphodepletion.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If extensive ex vivo manipulation and lymphodepletion are used to genetically modify lymphocytes, then genetic modification efficiency is improved, but treatment complexity and time requirements increase
Solution Approach 1:
The patent extracts and removes the lymphodepletion step from the traditional CAR-T protocol. By using RIPs that can transduce resting lymphocytes directly without requiring prior activation or lymphodepletion, the complex ex vivo manipulation steps are eliminated while maintaining genetic modification efficiency
Solution Approach 2:
The patent segments the genetic modification process into a simplified in vivo step using RIPs, separating the transduction event from the expansion phase. This allows genetic modification to occur independently of complex ex vivo manipulation, reducing overall treatment complexity
2Reliability
If extensive ex vivo manipulation is performed to activate resting lymphocytes, then genetic transduction is improved, but treatment time is increased
Solution Approach 1:
The RIPs are pre-engineered with integrated activation elements and lymphoproliferative elements that automatically perform the activation function when they encounter resting lymphocytes in vivo, eliminating the need for time-consuming ex vivo activation steps
Solution Approach 2:
The RIPs autonomously activate resting lymphocytes through their surface activation elements without requiring external stimulation reagents or ex vivo manipulation. The system self-services the activation function that traditionally required complex laboratory procedures
3Reliability
If lymphodepleting chemotherapy is administered to facilitate T cell engraftment, then engraftment efficiency is improved, but patient safety and tolerance are worsened
Solution Approach 1:
The patent converts the previously harmful lymphodepletion step into a beneficial outcome by using RIPs that naturally select for and expand transduced cells in the tumor microenvironment. The harmful chemotherapy is replaced by a mechanism that achieves engraftment efficiency through controlled in vivo proliferation of modified cells
4Quantity of substance
If long ex vivo expansion times are used to produce CAR-T cells, then cell dosage is improved, but cell viability and sterility are worsened
Solution Approach 1:
The patent inverts the traditional approach by administering a low initial dosage of genetically modified cells that then proliferate in vivo within the tumor microenvironment. Instead of expanding cells ex vivo to high doses, the system uses in vivo expansion to achieve therapeutic cell numbers, thereby maintaining cell viability and avoiding contamination risks
Data Source
AI summary
The present disclosure provides methods and compositions for genetically modifying lymphocytes, for example T cells and/or NK cells. In some embodiments, the methods include reaction mixtures, and resulting cell formulations, that are created using whole blood, or a component thereof that is not a PBMC, and additionally comprise T cells and recombinant retroviral particles having polynucleotides that encode a CAR. In some embodiments, modified lymphocytes are reintroduced into a subject subcutaneously. In some embodiments, polynucleotides that provide T cells the ability to regulate cell survival and proliferation in response to binding to a CAR, are provided.