PD-1 Knockout TILs for Scalable Manufacturing
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Solution Overview
Problem
Current methods for expanding tumor-infiltrating lymphocytes (TILs) for cancer treatment are limited by technical, logistical, and regulatory issues, particularly in achieving scalable and sterile manufacturing processes, and the potential of TILs with enhanced tumor-specific killing capacity has not been fully realized due to challenges in commercialization and regulatory approval.
Innovation Solution
Genetically modifying TILs to reduce the expression of PD-1, a method involving selecting PD-1 positive TILs, expanding them in a controlled environment with IL-2 and OKT-3, and using antigen-presenting cells to enhance their therapeutic potential, followed by cryopreservation for administration.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If TILs are expanded using the rapid expansion process (REP) with irradiated allogeneic PBMCs as feeder cells and high doses of IL-2, then a 1,000-fold expansion of TILs can be achieved, but the process requires a large excess (200-fold) of irradiated allogeneic PBMCs from multiple donors, increasing complexity and cost
Solution Approach 1:
The patent extracts and removes the requirement for irradiated allogeneic PBMCs from the expansion system by using an open container system that allows direct access to air, eliminating the need for complex feeder cell preparation and multiple donor matching while achieving the same expansion results
Solution Approach 2:
The open container system serves multiple functions simultaneously: it provides gas exchange for cell metabolism, eliminates the need for sterile barriers, and simplifies the manufacturing process while maintaining expansion efficiency, making the system universally applicable without donor-specific requirements
2Productivity
If TILs are expanded using the rapid expansion process (REP), then a 1,000-fold expansion can be achieved in 14 days, but sterility concerns and regulatory approval challenges limit commercialization potential
Solution Approach 1:
The patent converts the potential harm of open container exposure to contaminants into a benefit by deliberately using an open system that allows controlled exposure, then applying genetic modification to eliminate PD-1 expression, thereby ensuring product quality while simplifying the manufacturing process and reducing sterility concerns
3Productivity
If PD-1 positive TILs are selected and expanded, then TILs with enhanced anti-tumor activity can be obtained, but the immunosuppressive nature of PD-1 may reduce therapeutic efficacy
Solution Approach 1:
The patent changes the molecular parameter of PD-1 expression level by using genetic modification (CRISPR/Cas9 or other gene editing technologies) to knock out or knock down PD-1 gene expression in the selected PD-1 positive TILs, thereby eliminating the immunosuppressive effect while preserving the enhanced anti-tumor activity
Data Source
AI summary
Provided herein are TILs that are genetically modified to silence or reduce expression of endogenous PD-1. In some embodiments, the subject TILs are produced by genetically manipulating a population of TILs that have been selected for PD-1 expression (i.e., a PD-1 enriched TIL population). Also provided herein are expansion methods for producing such genetically modified TILs and methods of treatment using such TILs.