Aug 2026· Transplant International· Vol 39· 1 citation· 63 references
TL;DR
This review summarizes current strategies for engineering immune-evasive grafts that simultaneously suppress adaptive and innate immune responses and outlines the safety considerations and remaining limitations in immune evasion that must be addressed to enable clinical implementation.
Abstract
The growing gap between organ demand and clinical availability has renewed interest in immune-evasive graft strategies, yet rejection and lifelong immunosuppression remain major barriers to durable success. Advances in genome editing enable immune-evasive cell platforms designed to avoid immune recognition while replacing missing function in allogeneic settings. This review summarizes current strategies for engineering immune-evasive grafts that simultaneously suppress adaptive and innate immune responses. We discuss how coordinated modulation of antigen presentation and immune checkpoint pathways can protect transplanted allogeneic cells and tissues from T, NK, and macrophage-mediated rejection. We also present the emerging concept of integrating hypoimmune engineering with genetically modified porcine donors, where extensive genome editing has reduced, but not eliminated, xenogeneic immune barriers. Combining donor genome modification with immune-evasive graft design represents a promising conceptual advance toward xenograft survival, though whether full elimination of systemic immunosuppression is achievable remains to be established clinically. We further examine how the regulatory landscape for these products is evolving across major jurisdictions, and how differences in approval pathways, manufacturing standards, and long-term surveillance requirements shape the path to clinical translation. Finally, we outline the safety considerations and remaining limitations in immune evasion that must be addressed to enable clinical implementation.
This review systematically delineates the mechanisms underlying bidirectional immune rejection and comprehensively summarizes state-of-the-art mitigation strategies and highlights the development of alternative, inherently hypoimmunogenic cell sources as a fundamental approach to circumventing these immunological barriers.
Lu Ding, Lianfeng Zhao, Mengting Zhang et al.· Biochimica et biophysica act...· 0 citations
Targeted immunotherapies have transformed the treatment of hematologic malignancies, yet their clinical utility is often constrained by on-target, off-tumor toxicity arising from shared antigen expression between malignant cells and essential healthy tissues. An early approach to mitigate this limitation involved the knockout (KO) of the target antigen in donor hematopoietic stem and progenitor cells (HSPCs). However, this strategy is restricted to markers that are dispensable for normal hematopoietic function. Epitope engineering has emerged as an alternative paradigm to decouple therapeutic susceptibility from physiological function by modifying the target antigen on healthy cells while preserving biological activity. In this review, we discuss recent advances in base and prime editing approaches used for epitope editing. We examine recent preclinical and emerging translational studies of this strategy in both malignant and non-malignant contexts. Finally, we discuss challenges related to editing efficiency, off-target effects, delivery strategies, and long-term safety in hematopoietic stem cells. Collectively, epitope engineering of hematopoietic stem cells represents a versatile platform to expand the therapeutic window of precision immunotherapies and may enable safer, more effective combinatorial treatment strategies for both non-malignant and malignant hematologic conditions.
Joanne Baek, G. Casirati, Pietro Genovese et al.· Blood Advances· 0 citations
Cell therapy has longstanding roots in haematopoietic stem cell transplantation and early immune cell transfers in infectious disease and transplantation, where patient- or donor-derived cells have achieved therapeutic benefit in selected contexts. The modern era has been driven largely by oncology, with engineered modalities such as tumour-infiltrating lymphocytes, CAR-T cells and TCR-engineered T cells delivering transformative responses but requiring complex, costly manufacturing. These platforms are now being adapted for autoimmune diseases to induce durable, antigen-specific immune tolerance, yet broad application is limited by safety concerns, process complexity and access. Non-engineered cell therapies for autoimmunity, including mesenchymal stem cells, polyclonal regulatory T cells and tolerogenic dendritic cells, have shown acceptable safety and proof-of-principle for immune re-education, but clinical responses have been modest and inconsistent, with limited scalability. Engineered approaches such as CAR-T cells can induce reversible B cell depletion in B cell-mediated rheumatic diseases but only addresses antibody-driven pathology and not T cell-mediated autoimmunity. TCR-engineered Tregs have emerged as a promising antigen-specific strategy, offering localized, antigen-linked suppression with bystander tolerance. Preclinical and early clinical data suggest superior potency, stability and disease control compared with polyclonal Tregs at similar or lower doses, but translation is constrained by the rarity and fragility of Tregs and by labour-intensive, CAR-T-like manufacturing. This review highlights emerging solutions for closed, automated and decentralised production, and discusses allogeneic approaches using gene-edited or banked Tregs with HLA engineering or matching. Together, these advances support the development of scalable, "off-the-shelf" TCR-Treg products with potential to provide safe, affordable tolerance-restoring therapies for autoimmune disease.
Cheng Rui Peh, T. Nguyen-Dumont, Y. Ting et al.· Autoimmunity Reviews· 1 citation
Summary Solid organ transplantation (SOT) is a life-saving procedure for patients with end-stage organ failure; however, lifelong immunosuppressant use is needed to prevent allograft rejection. These drugs increase the risk of non-Hodgkin lymphoma, liver, kidney, and lung cancers, and heighten susceptibility to oncogenic viruses, including hepatitis B and Epstein-Barr virus. The usage of chimeric antigen receptor (CAR) regulatory T (Treg) cells is a promising approach to induce transplant tolerance while minimizing dependence on immunosuppressants. The CAR Tregs offer the potential to enhance graft survival and quality of life by reducing immunosuppressant-related morbidity and mortality. Despite remarkable progress in transplantation tolerance, challenges remain owing to a limited understanding of Treg biology and technical barriers. This review discusses the implications of immunosuppression, CAR and CAR Treg biology, mechanisms of Treg-mediated tolerance, CAR Treg manufacturing, clinical trials, optimization strategies, and existing challenges and future directions for CAR Treg-based therapies in SOT.
M. S. Alwethaynani· Saudi Medical Journal· 0 citations
The 30-year evolution of autologous gene therapy as a vital alternative to allogeneic hematopoietic stem cell transplantation for IEIs is explored, tracing the transition from early gamma-retroviral gene addition - which successfully restored immunity in severe combined immunodeficiency but carried high risks of insertional mutagenesis and leukemogenesis - to the adoption of safer self-inactivating lentiviral vectors.
Jasmeen Dara, Claire Booth· Expert Opinion on Biological...· 0 citations
Systemic immunosuppression to prevent allograft rejection or treat autoimmune disease can risk infection and malignancy. To uncouple therapeutic immunosuppression from systemic toxicity, we engineered Location-Specific T-cell Inhibitory Molecules (LoSTIMs), Fc-silent bispecific antibodies that activate PD-1 and inhibit T-cells only when they engage a predefined tissue surface antigen. We hypothesized that tissue-selective PD-1 agonism could protect allografts from rejection while sparing systemic immunity.
We profiled PD-1 agonism, epitope specificity, and binding kinetics of anti-PD-1 antibodies, then engineered Fc-silent bispecific LoSTIMs. We evaluated antigen-dependent PD-1 agonism in Jurkat reporter assays and inhibition of T-cell activation in primary T cells. We tested a donor MHC class I (H-2Kb)-specific LoSTIM in fully mismatched heterotopic cardiac transplant models, assessing graft survival and immune cell phenotype by flow cytometry and spatial transcriptomics.
LoSTIMs acted as conditional PD-1 agonists, inhibiting T cells only when engaging target antigen, and were FcγR independent, enabling Fc-silent designs that do not deplete PD-1+ T-cells and preserve physiologic immunity outside the target tissue. Systemic treatment with H-2Kb-specific LoSTIM durably prevented rejection of C57BL/6 allografts in BALB/c recipients, whereas monospecific anti-PD-1 or anti-H-2Kb did not. Flow cytometry and spatial transcriptomics showed reduced donor-specific priming and graft infiltration, loss of effector function in graft-infiltrating CD8+ T cells, and a shift toward less inflammatory, regulatory/progenitor-like T-cell populations. Third-party C3H cardiac allografts (H-2Kk) lacking the H-2Kb surface antigen were not protected, consistent with tissue-selective immunosuppression.
LoSTIMs provide systemically administered, tissue-restricted PD-1 agonism that prevents allograft rejection without global immune suppression and may be generalizable to other immune diseases.
ASCO Young Investigator Award (JT), Claudia Adams Barr Fellowship in Innovative Basic Cancer Research (JT)
Transplantation Immunology (TRAN)
J. Torchia, Minxue Liao, Nitzan Shakartzi Kaminsky et al.· Journal of Immunology· 0 citations
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