CRISPR-Cpf1 T-Cell Editing for Solid-Tumor Persistence
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Solution Overview
Problem
Existing adoptive transfer of genetically engineered T cells for cancer treatment, particularly in solid tumors, faces limitations in T cell proliferation, survival, and function, leading to suboptimal therapeutic efficacy.
Innovation Solution
Utilizing CRISPR/Cpf1 system-mediated gene editing to knockout or alter specific T-cell expressed genes such as FAS, BID, CTLA4, PDCD1, CBLB, PTPN6, B2M, TRAC, and TRBC, to enhance T cell proliferation, survival, and function, thereby improving cancer immunotherapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If adoptive transfer of genetically engineered T cells is performed using conventional methods, then T cells can be introduced to target cancer antigens, but T cell proliferation, survival, and function are insufficient leading to suboptimal therapeutic efficacy
Solution Approach 1:
The patent applies parameter changes by modifying T cell function through genetic engineering. Specifically, the T cells are engineered to express modified checkpoint receptors (anti-programmed cell death 1, anti-programmed cell death ligand 1, anti-cytotoxic T-lymphocyte-associated protein 4, and anti-lymphocyte-activation gene 3) which alter the immunological parameters of T cell activation, proliferation, and survival. This genetic modification transforms the T cells from conventional to enhanced functionality, directly addressing the insufficient proliferation and therapeutic efficacy mentioned in the contradiction.
2Duration of action of stationary object
If conventional adoptive transfer methods are used, then T cell introduction is feasible, but T cell survival and persistence in the host are limited
Solution Approach 1:
The patent applies preliminary action by pre-engineering the T cells with modified checkpoint receptors before adoptive transfer. The T cells are prepared ex vivo with enhanced survival and persistence capabilities through genetic modification, then introduced into the host. This preliminary genetic engineering ensures that the T cells are pre-equipped with the necessary functional enhancements to overcome host immune suppression and achieve prolonged persistence, directly addressing the limited survival and persistence issue.
3Productivity
If T cells are engineered with checkpoint inhibitors to improve function, then T cell activation and proliferation are enhanced, but the complexity of genetic engineering increases
Solution Approach 1:
The patent applies universality by developing a platform technology that uses a common genetic engineering approach (CRISPR/Cas9-based editing) to introduce multiple checkpoint inhibitor receptors into T cells. The same core genetic engineering mechanism is used to deliver various modified checkpoints (anti-PD-1, anti-PD-L1, anti-CTLA-4, anti-LAG-3), making the system universally applicable across different cancer types and T cell products. This multi-functional platform reduces the relative complexity by standardizing the engineering process while achieving enhanced T cell proliferation and function.
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
Enhances the efficacy of T cell-based cancer immunotherapy by improving T cell persistence, proliferation, and function, particularly in solid tumors, addressing the limitations of current therapies.
Implementation Method 1
Utilizing CRISPR/Cpf1 system-mediated gene editing to knockout or alter specific T-cell expressed genes such as FAS, BID, CTLA4, PDCD1, CBLB, PTPN6, B2M, TRAC, and TRBC
Data Source
AI summary
CRISPR/Cpf1-related compositions and methods for treatment of cancer.