---
title: "Minor histocompatibility antigen TCR-T: MiHA-directed T-cell therapy in allo-HCT"
id: "pubmed-42392183"
canonical_url: "https://medichelpline.com/clinical-feed/pubmed-42392183"
content_type: "clinical_feed_article"
specialty: "Pharmacology"
source_name: "PubMed / NCBI"
source_url: "https://pubmed.ncbi.nlm.nih.gov/42392183/"
doi: "10.1182/bloodadvances.2025018015"
published_at: "2026-09-22T00:00:00.000Z"
evidence_level: "Journal Article"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Minor histocompatibility antigen TCR-T: MiHA-directed T-cell therapy in allo-HCT
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/pubmed-42392183
- **Specialty:** [Pharmacology](https://medichelpline.com/clinical-feed/pharmacology.md)
- **Primary Source:** PubMed / NCBI
- **Source URL:** [Original Journal Publication](https://pubmed.ncbi.nlm.nih.gov/42392183/)
- **DOI:** [10.1182/bloodadvances.2025018015](https://doi.org/10.1182%2Fbloodadvances.2025018015)
- **Published At:** 2026-09-22T00:00:00.000Z
- **Evidence Rating:** Journal Article
## Executive GIST (TL;DR)
- Minor histocompatibility antigens (**MiHA**) are polymorphic peptides presented by HLA on recipient cells after allogeneic hematopoietic cell transplantation (**allo-HCT**) and derive from proteins with genetic variants that differ between donor and recipient. - Hematopoietic-restricted MiHA permit selective targeting of residual recipient hematopoiesis, including malignant cells, enabling graft-versus-leukemia effects without widespread off-target tissue damage. - Engineering donor T cells with high-affinity, MiHA-specific T-cell receptors (**TCR-T**) enables targeted immunotherapy after transplant; both viral and nonviral methods (including CRISPR-Cas9 knock-in) are described as part of development and manufacturing workflows. - Early-phase clinical trials of **HA-1**- and **HA-2**-specific **TCR-T** have demonstrated safety, persistence, and durable antileukemic activity in high-risk or relapsed disease according to the source review. - To broaden clinical applicability, the field should expand development to additional MiHA targets to increase HLA and population coverage, incorporate MiHA genotyping into donor selection, and design platform trials to include diverse MiHA/HLA genotypes and test combination therapies efficiently. - Practical integration into the post-transplant pathway can include donor selection strategies, timing of infusion (prophylactic in remission, preemptive at MRD, or salvage at relapse), and adjunctive measures such as lymphodepletion and debulking to favor TCR-T persistence and overcome immune escape. - The review notes trial registrations: ClinicalTrials.gov NCT-06492707, NCT-07098364, NCT-06588660. Specific trial outcomes beyond statements of safety, persistence, and durable activity are not detailed in the abstract. - Conflicts of interest reported: E.F.K. has clinical trial funding from PromiCell, Inc and prior funding from ElevateBio; M.B. is named on an HA-1 TCR patent with licensing history and reports research funding and financial interests related to industry entities. - The authors conclude MiHA-directed **TCR-T** could become a genetically precise adjunct to routine **HCT**, strengthening graft-versus-leukemia activity and improving relapse-free survival if translation and access are accelerated.
## Clinical Analysis & Structured Key Points
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Affiliations Expand ### Affiliations * 1 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA. * 2 Department of Medicine, University of Washington, Seattle, WA. * 3 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA. * 4 Department of Pediatrics, University of Washington, Seattle, WA. * PMID: **42392183** * PMCID: [ PMC13578979 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13578979/) * DOI: [ 10.1182/bloodadvances.2025018015 ](https://doi.org/10.1182/bloodadvances.2025018015) Item in Clipboard Review # Minor histocompatibility antigen TCR-T Elizabeth F Krakow et al. Blood Adv. 2026. Show details Display options Display options Format Abstract PubMed PMID Blood Adv Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Blood+Adv%22%5Bjour%5D&sort=date&sort_order=desc) * [ Search in NLM Catalog ](https://www.ncbi.nlm.nih.gov/nlmcatalog?term=%22Blood+Adv%22%5BTitle+Abbreviation%5D) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42392183/) . 2026 Sep 22;10(18):6064-6078. doi: 10.1182/bloodadvances.2025018015. ### Authors [Elizabeth F Krakow](https://pubmed.ncbi.nlm.nih.gov/?term=Krakow+EF&cauthor_id=42392183)[ 1 ](https://pubmed.ncbi.nlm.nih.gov/42392183/#short-view-affiliation-1 "Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA.")[ 2 ](https://pubmed.ncbi.nlm.nih.gov/42392183/#short-view-affiliation-2 "Department of Medicine, University of Washington, Seattle, WA."), [Marie Bleakley](https://pubmed.ncbi.nlm.nih.gov/?term=Bleakley+M&cauthor_id=42392183)[ 3 ](https://pubmed.ncbi.nlm.nih.gov/42392183/#short-view-affiliation-3 "Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA.")[ 4 ](https://pubmed.ncbi.nlm.nih.gov/42392183/#short-view-affiliation-4 "Department of Pediatrics, University of Washington, Seattle, WA.") ### Affiliations * 1 Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA. * 2 Department of Medicine, University of Washington, Seattle, WA. * 3 Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA. * 4 Department of Pediatrics, University of Washington, Seattle, WA. * PMID: **42392183** * PMCID: [ PMC13578979 ](https://pmc.ncbi.nlm.nih.gov/articles/PMC13578979/) * DOI: [ 10.1182/bloodadvances.2025018015 ](https://doi.org/10.1182/bloodadvances.2025018015) Item in Clipboard Full text links Cite Display options Display options Format Abstract PubMed PMID ## Abstract Minor histocompatibility antigens (MiHA) are polymorphic peptides presented by HLA molecules on recipient cells in allogeneic hematopoietic cell transplantation (allo-HCT) and are derived from proteins with genetic variants that differ between recipient and donor. After allo-HCT, hematopoietic-restricted MiHA enable selective targeting of residual recipient-derived hematopoiesis, including malignant cells. Advances in engineering T cells with high-affinity, MiHA-specific T-cell receptors (TCR; TCR-T) are enabling clinical translation of MiHA T-cell immunotherapy. Early-phase trials of HA-1- and HA-2-specific TCR-T demonstrate safety, persistence, and durable antileukemic activity in high-risk or relapsed disease. To accelerate translation, the field should expand TCR-T development to additional MiHA targets to broaden HLA and population coverage, integrate MiHA genotyping into donor selection, and devise platform trials to include patients with various MiHA/HLA genotypes and to efficiently test combination therapies. MiHA-directed TCR-T represents a genetically precise, potentially routine HCT adjunct that promises to fortify graft-versus-leukemia effects and improve relapse-free survival. **Trial registration:** ClinicalTrials.gov NCT-06492707 NCT-07098364 NCT-06588660. © 2026 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved. [PubMed Disclaimer](https://pubmed.ncbi.nlm.nih.gov/disclaimer/) ## Conflict of interest statement Conflict-of-interest disclosure: E.F.K. reports clinical trial funding from PromiCell, Inc and previously received trial funding from ElevateBio. M.B. is an inventor on a patent describing HA-1 T-cell receptor T cells that was previously licensed to ElevateBio and has recently been licensed to PromiCell, Inc; reports research funding from HighPass Bio, an ElevateBio portfolio company; and financial interests in HighPass Bio and PromiCell, Inc. ## Figures [ ![None](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21b/13578979/cac9ac917741/BLOODA_ADV-2025-018015-C-ga1.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21b/13578979/39d484a6b6e6/BLOODA_ADV-2025-018015-C-ga1.webp) ** Graphical abstract ** ** Graphical abstract ** **Graphical abstract** [ ![Figure 1.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21b/13578979/dfd240995515/BLOODA_ADV-2025-018015-C-gr1.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21b/13578979/861491fc1782/BLOODA_ADV-2025-018015-C-gr1.webp) ** Figure 1. ** **Integration of MiHA-directed TCR-T cell…** ** Figure 1. ** **Integration of MiHA-directed TCR-T cell therapy into allo-HCT.** (A) Donor selection. For a… **Figure 1.** **Integration of MiHA-directed TCR-T cell therapy into allo-HCT.** (A) Donor selection. For a patient with a specific HLA (eg, HLA-A∗02:01) and MiHA (eg, HA-1H or HA-2V), screening to find a donor lacking the recipient’s MiHA (eg, HA-1R/R or HA-2M/M) or a donor lacking the restricting HLA allele allows for selective HLA/MiHA targeting with engineered TCR-T cell products after transplant. (B) Patient journey. After HCT, TCR-T cells may be infused while the patient is in deep remission to prevent cancer recurrence, or as preemptive treatment upon detection of MRD, or as salvage therapy to treat overt relapse or persistent hematologic malignancy. Lymphodepleting therapy favors in vivo persistence and expansion of the engineered T cells. Debulking therapy and the application of other agents that may counter immune escape mechanisms should be tailored to the post-HCT disease burden and the patient’s clinical status and treatment history. Figure was created with biorender.com. Krakow E.F. (2026). https://biorender.com/Irqb4xd. HAPLO, haploidentical donor; HCT, hematopoietic cell transplantation; SNP, single nucleotide polymorphism. [ ![Figure 2.](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21b/13578979/4162eb301f5e/BLOODA_ADV-2025-018015-C-gr2.gif) ](https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b21b/13578979/5d3ad450b5b3/BLOODA_ADV-2025-018015-C-gr2.webp) ** Figure 2. ** **From MiHA discovery to targeted…** ** Figure 2. ** **From MiHA discovery to targeted therapy.** (A) MiHA discovery and validation workflow. Forward… **Figure 2.** **From MiHA discovery to targeted therapy.** (A) MiHA discovery and validation workflow. Forward and reverse immunology approaches converge on shared functional validation criteria. (B) TCR-T engineering and manufacturing workflow. The MiHA-specific TCR is isolated, cloned, and introduced into selected donor T cells via viral vector or nonviral CRISPR-Cas9–mediated knock-in. Optional construct enhancements improve safety and efficacy. Figure was created with biorender.com. Krakow E.F. (2026). https://biorender.com/i1wobcg and https://biorender.com/sqxave3. APCs, antigen-presenting cells; heme, hematopoietic; HCT, hematopoietic cell transplantation; iC9, inducible caspase 9; MHC-I, major histocompatibility complex class 1; QC, quality control; SNP, single nucleotide polymorphism; TGFβ, transforming growth factor beta. [See this image and copyright information in PMC](https://pubmed.ncbi.nlm.nih.gov/42392183/) ## Similar articles * [ [Modification of Cytotoxic Lymphocytes with T Cell Receptor Specific for Minor Histocompatibility Antigen ACC-1Y]. ](https://pubmed.ncbi.nlm.nih.gov/31184611/) Pilunov AM, Kuchmiy AA, Sheetikov SA, Filkin SY, Romaniuk DS, Rosov FN, Efimov GA.Pilunov AM, et al.Mol Biol (Mosk). 2019 May-Jun;53(3):456-466. doi: 10.1134/S0026898419030145.Mol Biol (Mosk). 2019.PMID: 31184611Russian. * [ T-cell receptor repertoires against HLA class I-restricted minor histocompatibility antigens are highly diverse with a small subset of public clonotypes. ](https://pubmed.ncbi.nlm.nih.gov/42624530/) Fuchs KJ, van de Meent M, Kester MGD, Hagedoorn RS, Khatri I, van Balen P, Heemskerk MHM, van den Akker EB, Falkenburg JHF, Griffioen M.Fuchs KJ, et al.J Immunother Cancer. 2026 Aug 20;14(8):e015350. doi: 10.1136/jitc-2026-015350.J Immunother Cancer. 2026.PMID: 42624530Free PMC article. * [ Development of T-cell immunotherapy for hematopoietic stem cell transplantation recipients at risk of leukemia relapse. ](https://pubmed.ncbi.nlm.nih.gov/29051183/) Dossa RG, Cunningham T, Sommermeyer D, Medina-Rodriguez I, Biernacki MA, Foster K, Bleakley M.Dossa RG, et al.Blood. 2018 Jan 4;131(1):108-120. doi: 10.1182/blood-2017-07-791608. Epub 2017 Oct 19.Blood. 2018.PMID: 29051183Free PMC article. * [ Strategies for the identification of T cell-recognized tumor antigens in hematological malignancies for improved graft-versus-tumor responses after allogeneic blood and marrow transplantation. ](https://pubmed.ncbi.nlm.nih.gov/25459643/) Zilberberg J, Feinman R, Korngold R.Zilberberg J, et al.Biol Blood Marrow Transplant. 2015 Jun;21(6):1000-7. doi: 10.1016/j.bbmt.2014.11.001. Epub 2014 Nov 20.Biol Blood Marrow Transplant. 2015.PMID: 25459643Free PMC article.Review. * [ Minor Histocompatibility Antigen-Specific T Cells. ](https://pubmed.ncbi.nlm.nih.gov/32582592/) Summers C, Sheth VS, Bleakley M.Summers C, et al.Front Pediatr. 2020 Jun 3;8:284. doi: 10.3389/fped.2020.00284. eCollection 2020.Front Pediatr. 2020.PMID: 32582592Free PMC article.Review. [ See all similar articles ](https://pubmed.ncbi.nlm.nih.gov/?linkname=pubmed_pubmed&from_uid=42392183) ## References 1. 1. Bleakley M, Riddell SR. Molecules and mechanisms of the graft-versus-leukaemia effect. Nat Rev Cancer. 2004;4(5):371–380. - [PubMed](https://pubmed.ncbi.nlm.nih.gov/15122208/) 2. 1. Biernacki MA, Sheth VS, Bleakley M. T cell optimization for graft-versus-leukemia responses. JCI Insight. 2020;5(9) - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC7253012/) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/32376800/) 3. 1. Griffioen M, van Bergen CA, Falkenburg JH. Autosomal minor histocompatibility antigens: how genetic variants create diversity in immune targets. Front Immunol. 2016;7:100. - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC4791598/) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/27014279/) 4. 1. Murata M, Warren EH, Riddell SR. A human minor histocompatibility antigen resulting from differential expression due to a gene deletion. 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J Clin Invest. 2005;115(12):3506–3516. - [PMC](https://pmc.ncbi.nlm.nih.gov/articles/PMC1297240/) - [PubMed](https://pubmed.ncbi.nlm.nih.gov/16322791/) Show all 116 references ## Publication types * Review Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Review%22%5Bpt%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Review) * [ Add to Search ](https://pubmed.ncbi.nlm.nih.gov/42392183/) ## MeSH terms * Animals Actions * [ Search in PubMed ](https://pubmed.ncbi.nlm.nih.gov/?term=%22Animals%22%5BMeSH%5D&sort=date&sort_order=desc) * [ Search in MeSH ](https://www.ncbi.nlm.nih.gov/mesh?term=Animals) * [ Add to Search ](https://pubmed.ncbi.nlm.n
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