Codon-Optimized Lentiviral Vector for T Cell Reprogramming
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Solution Overview
Problem
Current methods for generating antigen-specific T cells for cancer immunotherapy are time-consuming, expensive, and not all patients can benefit due to limited availability of their own T cells, especially those with conditions like HIV infections, and there is a need for efficient mass production techniques.
Innovation Solution
The use of codon-optimized lentiviral vectors to transduce peripheral blood stem cells with T cell receptor (TCR) alpha and beta chain polypeptides, specifically targeting the cancer-testis antigen NY ESO-1, to create cytotoxic T cells that can recognize and kill cancer cells, including the inclusion of a PET reporter and suicide gene for safety and tracking.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If patient's own T cells are extracted and reprogrammed for cancer immunotherapy, then antigen-specific T cells can be generated, but the procedure is time-consuming and expensive
Solution Approach 1:
The patent performs T cell reprogramming in advance by transducing patient T cells with lentiviral vectors encoding desired TCRs ex vivo, then freezing and storing the reprogrammed cells. This preliminary action allows the reprogramming to be completed before clinical need arises, eliminating the time-consuming aspect of on-demand reprogramming while maintaining the reliability of generating antigen-specific T cells.
Solution Approach 2:
The patent creates copies of reprogrammed T cells through ex vivo expansion and cryopreservation. Instead of reprogramming T cells at the time of treatment, the process generates multiple copies of pre-programmed T cells that can be stored and administered as needed, significantly reducing procedure time while maintaining the antigen-specific functionality.
2Adaptability or versatility
If patient's own T cells are used for reprogramming, then personalized immunotherapy is achieved, but not all patients can benefit due to limited T cell availability
Solution Approach 1:
The patent introduces an intermediary step of ex vivo T cell manipulation and cryopreservation. Patient T cells are extracted, reprogrammed with desired TCR specificities in the lab, and stored as viable cellular products. This intermediary process decouples T cell availability from treatment timing, allowing patients with limited T cell availability to receive treatment when sufficient reprogrammed cells are available.
Solution Approach 2:
By performing T cell reprogramming and expansion in advance, the patent creates a reservoir of usable T cell products that can be stored and administered to patients regardless of their immediate T cell availability, thus expanding access to personalized immunotherapy.
3Productivity
If viral vectors are used to transduce T cells with TCR genes, then antigen-specific T cells are produced, but the process is expensive
Solution Approach 1:
The patent employs lentiviral vectors that enable stable, long-term expression of TCR genes in transduced T cells. This self-sustaining expression system eliminates the need for continuous external stimulation or repeated transduction procedures, reducing the overall manufacturing complexity and cost while maintaining high productivity of antigen-specific T cells.
Data Source
AI summary
The invention relates to methods and materials that can be used to product cytotoxic T cells that target cancer cells expressing the cancer-testis antigen NY ESO-1. Illustrative embodiments of the invention include peripheral blood stem cells transduced with a lentiviral vector that comprises a codon optimized TCR alpha and beta chain polypeptides specific for NY ESO-1. These gene-modified cells are useful, for example, in a hematopoietic stem cell transplantation setting to treat patients diagnosed with NY ESO-1 positive cancers.