Engineered MAIT Cells With Exogenous TCRs for Resistant Cancers
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Solution Overview
Problem
Current methods for treating cancer and conditions associated with HLA class I-restricted antigens using immunotherapy are limited, particularly for patient populations with primary or acquired resistance, and existing MAIT cell therapies face challenges in function and survival during adoptive transfer.
Innovation Solution
Genetically engineering MAIT cells from placental intervillous blood to express an exogenous T cell receptor (TCR) specific to tumor antigens like NY-ESO-1 and LAGE-1A, and using them in adoptive transfer cell therapy (ACT) to target HLA class I-restricted antigens.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional immunotherapy methods are used to treat cancer, then treatment is effective for some patients, but patient populations with primary or acquired resistance show poor outcomes
Solution Approach 1:
The patent changes the fundamental parameters of the immune cell by genetically engineering MAIT cells to express exogenous TCRs with altered specificity. This allows the cells to recognize tumor antigens that conventional T cells cannot detect, thereby overcoming resistance in patient populations who do not respond to standard immunotherapies
Solution Approach 2:
The engineered MAIT cells possess multi-functional capabilities: they retain their native ability to recognize microbial vitamin B metabolites presented by MR1 while simultaneously acquiring the ability to recognize tumor antigens through exogenous TCR expression. This dual functionality enables broad applicability across different patient populations including those with resistance to conventional therapies
2Reliability
If MAIT cells are used in adoptive transfer cell therapy, then they show promise for treating cancer, but they face challenges in function and survival during adoptive transfer
Solution Approach 1:
The patent creates a composite immune cell by combining MAIT cell characteristics with exogenous TCR specificity. This composite structure integrates the innate-like rapid response capabilities of MAIT cells with the antigen-specific targeting of conventional T cells, resulting in enhanced persistence and therapeutic effectiveness in adoptive transfer
Solution Approach 2:
The MAIT cells are pre-engineered with exogenous TCRs and activated ex vivo before adoptive transfer. This preliminary conditioning ensures the cells are primed and functional upon introduction into the patient, improving their survival and persistence in the in vivo environment compared to unprepared cells
3Measurement precision
If conventional T cells are used for cancer therapy, then they have exquisite specificity for individual peptides, but the frequency of any individual peptide-specific T cell is very low at first encounter with a pathogen
Solution Approach 1:
The patent merges two distinct T cell populations: conventional T cells with high antigen-specific frequency but limited specificity, and MAIT cells with restricted TCR repertoire but high frequency. The engineered MAIT cells combine the high frequency advantage of MAIT cells with the specific antigen recognition capability of conventional T cells through exogenous TCR expression
Data Source
AI summary
The present disclosure relates in general to the field of genetic engineering of immune cells, specifically to mucosal-associated invariant T (MAIT) cells genetically engineered to express an exogeneous T cell receptor (TCR) and uses thereof. More specifically, the invention in embodiments thereof relates to cell compositions adapted for adoptive transfer cell therapy (ACT) providing for improved therapeutic modalities.