Tumour-Specific T Cell Preparation via Clonotype Isolation
Solution Overview
Problem
Current cancer treatments using autologous T cell transfer lack high tumour-specificity and reactivity, resulting in moderate and imperfect immune responses due to the general nature of transferred T cells.
Innovation Solution
A method is developed to determine and prepare tumour-specific T cell receptors by isolating and characterizing T cell clonotypes from tumour samples, sequencing their CDR3 regions, and expressing these specific receptors in T cells for targeted cancer treatment through adoptive transfer.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If autologous T cells are transferred to treat cancer, then the treatment can be personalized to the patient, but the tumour-specificity and reactivity of the transferred cells are insufficient
Solution Approach 1:
The patent extracts and isolates specific tumour-reactive T cell clonotypes from the patient's tumour tissue, separating them from the broader T cell population. This extraction process involves identifying and isolating only the T cell clones that specifically recognize tumour antigens, thereby achieving high tumour-specificity while maintaining personalization.
Solution Approach 2:
The patent segments the T cell receptor repertoire into specific clonotypes based on their tumour reactivity. By analyzing T cell receptors and identifying distinct clonotypes with specific tumour-reactive properties, the method creates segmented, highly specific T cell populations rather than using a homogeneous mixture of T cells.
2Productivity
If broad T cell populations are transferred, then the treatment process is simpler, but the immune response against tumour is moderate and imperfect
Solution Approach 1:
The patent performs preliminary analysis of the patient's tumour tissue to identify tumour-reactive T cell clonotypes before preparing the therapeutic T cell product. This preliminary characterization allows for targeted expansion and preparation of only the relevant clonotypes, improving immune response effectiveness while streamlining the preparation process.
Solution Approach 2:
The patent applies local quality by customizing the T cell preparation to match the specific tumour characteristics of each patient. Instead of using a generic T cell product, the method creates patient-specific T cell populations with localized specificity to their individual tumour antigens, thereby improving effectiveness.
3Reliability
If T cell receptors are engineered to be tumour-specific, then tumour reactivity is enhanced, but the manufacturing process becomes more complex
Solution Approach 1:
The patent uses copying by synthesizing and expressing specific T cell receptor sequences that have been identified from tumour-reactive T cells. The identified TCR sequences are copied into expression vectors and introduced into T cells, creating engineered T cells with enhanced tumour reactivity without requiring de novo design of the receptors.
Solution Approach 2:
The patent applies parameter changes by modifying the T cell receptor parameters (specificity, affinity) based on the identified tumour-reactive clonotypes. The method changes the receptor sequence parameters to match the specific tumour antigens, thereby enhancing tumour reactivity while using a systematic approach to manage the engineering complexity.
Data Source
AI summary
Described herein are methods for providing a tumour-specific T cell preparation of use for treating cancer. The method encompasses, determining which T cell receptors are most likely to be reactive to a cancer in a patient, then preparing a T cell population expressing these specific T cell receptor genes from expression constructs transferred into a preparation of T cells, and administering these engineered T cells into the patient.