Universal CAR-T cell therapy: mechanisms and evasion strategies of bidirectional immune rejection.

Transient T cell therapies.

CAR-T and GvHD: Have We Engineered GvHD Out of Allogeneic CAR‑T Therapy?

BACKGROUND Autologous CAR-T has transformed lymphoma therapy, but 40-60% of patients still relapse, and manufacturing is slow/expensive. Allogeneic CAR-T cells (from healthy donors or iPSCs) could overcome these issues. They can avoid patient leukapheresis and reliance on heavily pretreated autologous T cells, reduce the need for bridging therapy, permit advance manufacture, and allow deliberate donor and cell-subset selection. However, they face two main immunologic barriers: (1) GvHD, in which donor T cells' native TCRs may recognize patient tissues as foreign, causing acute/chronic GvHD; and (2) host-versus-graft rejection, in which the patient's immune system may reject the donor cells2. In mismatched stem cell transplant (alloHCT), GvHD occurs in ∼50-80% of cases without intervention3. By analogy, unmodified donor αβ T cells with CARs might similarly attack HLA-mismatched host tissues. Thus, successful allogeneic CAR-T must reduce donor-to-host alloreactivity while managing the distinct host-versus-graft barrier. This focused Perspective asks whether GvHD directed engineering has made clinically significant product-associated GvHD rare.

CAR-T Cell Therapy: Manufacturing Platforms and Clinical Consequences.

Chimeric antigen receptor (CAR) T-cell therapy has transformed hematological cancer care, yet variability in efficacy, durability, and safety cannot be explained solely by antigen selection or patient factors. We propose that manufacturing platforms are active biological determinants of outcome. Viral vectors, used in all licensed products, provide stable genomic integration and durable expression but are limited by cost, cargo capacity, and centralized production. Nonviral strategies, including transposons, CRISPR knock-ins, and messenger RNA delivery, enable faster, less-expensive manufacturing with larger payloads, while introducing distinct safety and persistence profiles. This review presents a three-layer mechanistic framework that reframes manufacturing as biology: integration biology determines genomic risk and transgene stability; clonal fitness shapes persistence, dominance, and exhaustion; and epigenomic imprinting, influenced by gene transfer method, cytokines, and culture stress, preconfigures functional trajectories. Clinical observations link platform choice to immune recovery, where prolonged B-cell aplasia and delayed T-cell reconstitution contribute to infection-related nonrelapse mortality, and hematopoietic reserve at apheresis emerges as a practical predictor. Finally, manufacturing is positioned as the key to democratizing cell therapy. Decentralized, nonviral production aligned with regulatory standards may enable equitable access and transition CAR-T therapy from innovation to sustainable global care.

Targeting T-cell exhaustion and tumour immune evasion: a review of emerging strategies.

Adoptive T-cell therapies and immune checkpoint blockade have produced durable remissions in selected malignancies, yet most patients still fail to achieve lasting benefit. Two convergent obstacles underlie much of this failure: T-cell exhaustion and tumour immune evasion. T-cell exhaustion arises from chronic antigen stimulation in the tumour microenvironment (TME) and spans a hierarchy from reversible, stem-like progenitor-exhausted cells to terminally exhausted cells with limited functional recovery, which is a transition epigenetically enforced by transcription factors such as TOX and the NR4A family. In parallel, tumours evade recognition by silencing antigen-presentation pathways, including MHC class I. This review discusses a complementary therapeutic strategy that addresses both obstacles: engineering T cells for greater durability in the TME through knockout of exhaustion-associated transcription factors, and reprogramming tumour cells with DNA methyltransferase (DNMTi) and histone deacetylase (HDACi) inhibitors to restore immunogenicity. We also consider emerging evidence that metabolic and neuro-immune features of the TME, including nerve-to-tumour mitochondrial transfer, may contribute to immune resistance in some tumour contexts. Importantly, we emphasise that most supporting evidence derives from CAR-T and murine systems, and that direct validation in TCR-engineered T-cell (TCR-T) platforms is still required. We further outline a personalised, biomarker-guided framework that integrates T-cell signatures, the epigenetic landscape of the tumour, and tumour innervation density to match combination therapy to the individual patient. Integrating exhaustion-resistant T cells with a reprogrammed, immunologically visible tumour may help address mechanisms of immune resistance and improve therapeutic outcomes.

CAR T cell therapy beyond cancer: current status, challenges and future prospects

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized oncology, and its foundational logic—precise antigen recognition coupled with durable effector activity—extends naturally to chronic non-malignant diseases sustained by long-lived pathological cells. These include viral reservoirs, autoreactive B and plasma cells, activated fibroblasts, alloimmune clones, and senescent cells that remodel tissue niches and evade clearance by conventional therapies. This review highlights how CAR-based strategies can be adapted across diverse disease settings by redirecting engineered immune responses toward disease-sustaining cellular compartments. Co-stimulatory domains such as CD28, 4-1BB, and OX40 enhance persistence and effector function; programmed cell death protein 1 (PD-1)–CD28 switch receptors reverse inhibitory signaling; and cytokine-resistant CARs incorporating dominant-negative transforming growth factor-β (TGF-β) receptors maintain activity within suppressive microenvironments. We discuss these approaches across infections, including human immunodeficiency virus (HIV) and Epstein–Barr virus (EBV); autoimmunity involving CD19- and B-cell maturation antigen (BCMA)-directed depletion strategies and CAR-engineered regulatory T cells (CAR-Tregs); fibrosis targeting fibroblast activation protein (FAP); hemophilia using B-cell antibody receptor (BAR)-CARs against factor VIII and factor IX inhibitors; transplantation employing human leukocyte antigen (HLA)-specific CAR-Tregs; and senescence-associated pathologies targeting urokinase plasminogen activator receptor (uPAR) and natural killer group 2D ligands (NKG2DLs). Early clinical experiences in systemic lupus erythematosus, systemic sclerosis, myositis, and multiple sclerosis, together with preclinical successes in chronic infections and fibrotic disease, demonstrate both feasibility and durable disease modification. By extending CAR-T therapy beyond oncology, these applications position programmable cellular immunotherapy as a broadly adaptable platform for eliminating persistent pathological cells, remodeling diseased tissue environments, and restoring long-term immune homeostasis.

Hypoimmune platforms: from rejection to immune evasion and regulatory implications

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.