MiHA Identification via Personalized Transcriptome Sequencing
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Solution Overview
Problem
Current methods for identifying minor histocompatibility antigens (MiHAs) are limited by their lack of specificity and efficiency, leading to unsatisfactory cancer immunotherapy outcomes due to unselective injection of allogeneic lymphocytes, which causes graft-versus-host disease and an attenuated graft-versus-tumor reaction.
Innovation Solution
A method involving the isolation and sequencing of MHC-associated peptides, followed by whole transcriptome and exome sequencing to identify single nucleotide variations, and in silico translation to determine peptide sequences, allowing for the identification of MiHA candidates and their use in priming CD8 T cells for targeted cancer therapy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If unselective injection of allogeneic lymphocytes is used for cancer immunotherapy, then the graft-versus-tumor effect is induced, but graft-versus-host disease occurs due to lack of specificity
Solution Approach 1:
The patent segments the broad allogeneic lymphocyte population into specific MiHA-reactive T cell subsets. By identifying and isolating T cells that react to specific minor histocompatibility antigens, the therapy targets only the desired graft-versus-tumor effect while excluding T cells that would cause graft-versus-host disease.
Solution Approach 2:
The patent applies local quality by making the immune response specific to particular MiHA targets. Instead of using homogeneous allogeneic lymphocytes, the method enriches for T cells with specific reactivity profiles against identified MiHAs, creating a heterogeneous population with localized specificity that distinguishes between tumor-targeting and host-attacking functions.
2Reliability
If conventional AHCT is used to treat cancer, then the graft-versus-tumor reaction is induced, but the reaction is attenuated because donor T cells are not primed against specific MiHAs
Solution Approach 1:
The patent applies preliminary action by pre-identifying and characterizing MiHA targets before conducting the adoptive T cell transfer. The method includes isolating T cells, testing their reactivity against various MiHAs, and selecting those with optimal reactivity profiles, thereby priming the therapeutic cells in advance to ensure potent graft-versus-tumor activity.
Solution Approach 2:
The patent employs feedback mechanisms by systematically testing donor T cell reactivity against a panel of MiHA-expressing cell lines and using this information to guide the selection and expansion of specific T cell populations. This feedback loop ensures that only T cells with desired specificity and potency are selected for therapy.
Data Source
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AI summary
A novel method for human minor histocompatibility antigen (MiHA) discovery, novel MiHAs identified using this method, as well as uses of the novel MiHAs, are described. One of the features of the novel method is the inclusion of personalized translated transcriptome and/or exome in the database used for peptide identification by mass spectroscopy (MS). Candidate MiHAs are identified by comparing the personalized transcriptome and/or exome to a reference genome and/or to the transcriptome and/or exome of an HLA-matched subject.