Minor histocompatibility antigens (MiHA) are polymorphic peptides derived from proteins with genetic variants that differ between donor and recipient and are presented by HLA molecules on recipient cells after allogeneic hematopoietic cell transplantation (allo-HCT). Because some MiHA are restricted to hematopoietic tissues, they provide a means to selectively target residual recipient hematopoiesis and malignant cells while sparing most nonhematopoietic tissues. This selective targeting underlies the therapeutic rationale for exploiting MiHA as immunologic targets to augment graft-versus-leukemia effects after transplantation.
Engineering donor T cells to express high-affinity, MiHA-specific T-cell receptors (TCR-T) is an emerging strategy to deliver precise post-transplant immunotherapy. The review frames MiHA-directed TCR-T as a genetically precise adjunct to HCT with the potential to decrease relapse and improve relapse-free survival when successfully translated to clinical practice.
The discovery of relevant MiHA combines forward and reverse immunology approaches. These processes converge on functional validation criteria to confirm that candidate polymorphic peptides are presented by relevant HLA alleles and are recognized by T cells with antigen-specific cytotoxicity. The review emphasizes an end-to-end workflow from identification through functional validation as foundational to selecting targets suitable for TCR-T development.
Once a MiHA-specific TCR is isolated and validated, it is cloned and introduced into selected donor T cells. The review describes both viral vector–based gene transfer and nonviral gene editing methods such as CRISPR-Cas9–mediated knock-in as routes to generate engineered T cells. Optional construct-level enhancements can be applied to improve safety and efficacy; manufacturing workflows include quality control steps to ensure product identity and potency prior to infusion. The schematic workflow presented in the full text links MiHA discovery with downstream engineering, manufacturing, and clinical deployment.
Early-phase clinical trials targeting HA-1 and HA-2 MiHA with TCR-T products are noted in the review. These trials have demonstrated safety, persistence of the engineered T cells, and durable antileukemic activity in patients with high-risk or relapsed hematologic disease. Specific trial identifiers are reported (ClinicalTrials.gov NCT-06492707, NCT-07098364, NCT-06588660). The abstract summarizes these early results but does not provide detailed numerical outcomes, eligibility criteria, or statistical estimates in the excerpt.
The review outlines how MiHA-directed TCR-T could be integrated into the transplant care pathway. For donor selection, screening can identify donors who lack a recipient’s MiHA or who lack the restricting HLA allele, enabling selective targeting post-transplant. Regarding timing of therapy, TCR-T cells may be infused while the patient is in deep remission to prevent recurrence, as a preemptive treatment upon detection of measurable residual disease (MRD), or as salvage therapy for overt relapse. The review highlights that lymphodepleting regimens favor in vivo persistence and expansion of engineered T cells.
A figure in the article depicts the patient journey and emphasizes tailoring adjunctive therapies—such as debulking and agents to counter immune escape—based on disease burden and prior therapies.
Operationally, lymphodepletion is identified as a strategy to support persistence and expansion of infused TCR-T cells. Debulking therapy and combining TCR-T with agents that address immune escape mechanisms are recommended to match treatment intensity to post-HCT disease burden and patient status. The review suggests that platform trial designs and inclusion of combination arms will be important to evaluate interactions with other therapies and improve efficiency of clinical testing.
To accelerate translation, the authors recommend expanding TCR-T development to additional MiHA targets to broaden HLA and population coverage. Integration of MiHA genotyping into donor selection practices is proposed to facilitate appropriate patient–donor pair identification. The review also advises developing platform clinical trials that can enroll patients across diverse MiHA/HLA genotypes and permit testing of combination therapies efficiently. These measures aim to make MiHA-directed TCR-T a more widely applicable and routine adjunct to HCT.
The abstract frames MiHA-directed TCR-T as a potentially routine, genetically precise adjunct that could strengthen graft-versus-leukemia effects and improve relapse-free survival if the field succeeds in expanding targets, integrating genotyping, and designing efficient clinical trials.
The review discloses conflicts of interest: E.F.K. reports clinical trial funding from PromiCell, Inc and prior trial funding from ElevateBio. M.B. is an inventor on an HA-1 T-cell receptor patent previously licensed to ElevateBio and recently licensed to PromiCell, Inc; M.B. also reports research funding from HighPass Bio and financial interests in HighPass Bio and PromiCell, Inc. Trial registrations cited in the abstract are ClinicalTrials.gov NCT-06492707, NCT-07098364, and NCT-06588660.
The article is a review published in Blood Advances (2026 Sep 22;10[18]:6064-6078) with PMID 42392183, PMCID PMC13578979, and DOI 10.1182/bloodadvances.2025018015. The abstract and figures summarize concepts and early clinical experience; further numerical trial results and detailed methods are available in the full text but are not included in the abstract excerpt provided here.