MR1-Restricted TCRs for Broad Cancer Immunotherapy
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Solution Overview
Problem
Current cancer immunotherapy approaches are limited by the polymorphism of MHC genes, making them applicable only to patients expressing specific MHC alleles, and often face challenges with tumor escape variants under immune pressure, while targeting non-polymorphic antigen-presenting molecules like MR1 could provide a broader applicability and complementary anti-tumor responses.
Innovation Solution
Identification and utilization of MR1-restricted tumour-reactive T cell receptor (TCR) sequences isolated from T cells that recognize tumour-associated antigens presented by MR1, enabling their expression in patient T cells for adoptive cell immunotherapy, allowing specific recognition and targeting of MR1-expressing cancer cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If tumour-associated antigens are targeted using polymorphic MHC molecules, then specific anti-tumour immune response is induced, but the therapy is limited to patients expressing specific MHC alleles
Solution Approach 1:
The patent employs non-polymorphic MR1 molecules as antigen-presenting structures, which are universally expressed across different human populations regardless of MHC allele variations. This allows the TCR-engineered T cells to recognize and target tumour-associated antigens presented by MR1 in a broad range of patients, eliminating the restriction imposed by polymorphic MHC molecules while maintaining specific immune response induction
2Reliability
If tumour antigens are targeted using polymorphic MHC molecules, then MHC-presented peptide antigens are recognized, but tumour escape variants may develop under immune pressure
Solution Approach 1:
The patent changes the antigen-presenting parameter from polymorphic MHC molecules to non-polymorphic MR1 molecules, thereby altering the recognition paradigm. By engineering T cells with TCRs specific for MR1-presented tumour-associated antigens, the system achieves stable and consistent antigen recognition across different patients and tumour types, reducing the likelihood of tumour escape variant development
3Reliability
If multiple tumour antigens are targeted simultaneously, then tumour escape variants are minimized, but the complexity of TCR engineering increases
Solution Approach 1:
The patent utilizes the universal MR1 molecule as a common platform for presenting multiple different tumour-associated antigens. By engineering T cells with TCRs that recognize MR1-presented antigens, the system can target multiple tumour antigens simultaneously through a unified approach, avoiding the need for separate complex engineering procedures for each antigen while achieving comprehensive anti-tumour coverage
Data Source
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AI summary
The invention relates to a method of isolating a T cell that expresses a T cell receptor capable of binding specifically to an antigen presented by a cancer cell in association with an MR molecule. The method comprises the steps of (a) providing a preparation of T cells, (b) contacting the preparation with cancer cells expressing MR1 protein; (c) isolating a T cell that is specifically reactive to said cancer cells. The invention further relates to a method of preparing a T cell preparation expressing select MR1 recognizing T cell receptors from transgene expression vectors, the use of such T cell preparations in treatment of cancer, and to collections of MR1 reactive T cell receptor encoding nucleic acids and cells.