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At least 19 recordsLinked to original sources
PubMed2016

Immunodominant Dengue Virus-Specific CD8+ T Cell Responses Are Associated with a Memory PD-1+ Phenotype.

UNLABELLED: Dengue disease is a large public health problem that mainly afflicts tropical and subtropical regions. Understanding of the correlates of protection against dengue virus (DENV) is poor and hinders the development of a successful human vaccine. The present study aims to define DENV-specific CD8(+)T cell responses in general and those of HLA alleles associated with dominant responses in particular. In human blood donors in Nicaragua, we observed a striking dominance of HLA B-restricted responses in general and of the allele B*35:01 in particular. Comparing these patterns to those in the general population of Sri Lanka, we found a strong correlation between restriction of the HLA allele and the breadth and magnitude of CD8(+)T cell responses, suggesting that HLA genes profoundly influence the nature of responses. The majority of gamma interferon (IFN-γ) responses were associated with effector memory phenotypes, which were also detected in non-B*35:01-expressing T cells. However, only the B*35:01 DENV-specific T cells were associated with marked expression of the programmed death 1 protein (PD-1). These cells did not coexpress other inhibitory receptors and were able to proliferate in response to DENV-specific stimulation. Thus, the expression of particular HLA class I alleles is a defining characteristic influencing the magnitude and breadth of CD8 responses, and a distinct, highly differentiated phenotype is specifically associated with dominant CD8(+)T cells. These results are of relevance for both vaccine design and the identification of robust correlates of protection in natural immunity. IMPORTANCE: Dengue is an increasingly significant public health problem as its mosquito vectors spread over greater areas; no vaccines against the virus have yet been approved. An important step toward vaccine development is defining protective immune responses; toward that end, we here characterize the phenotype of the immunodominant T cell responses. These DENV-reactive T cells express high levels of the receptor programmed death 1 protein (PD-1), while those from disease-susceptible alleles do not. Not only does this represent a possible correlate of immunodominance, but it raises the hypothesis that PD-1 might be a regulator that prevents excessive damage while preserving antiviral function. Further, as this study employs distinct populations (Nicaraguan and Sri Lankan donors), we also confirmed that this pattern holds despite geographic and ethnic differences. This finding indicates that HLA type is the major determinant in shaping T cell responses.

Alleles↗
PubMed2026

Artificial intelligence for translational personalized neoantigen cancer vaccine development.

Personalized neoantigen cancer vaccine is a promising strategy for precision immunotherapy by targeting patient-specific and mutation-derived tumor antigens. Early clinical studies have demonstrated the feasibility, safety, and immunogenicity of these vaccines across multiple solid tumors, with encouraging outcomes particularly when combined with immune checkpoint blockade. However, broader clinical translation remains limited by sequential bottlenecks across the vaccine development pipeline, including false-positive neoantigen selection,  imperfect modeling of antigen processing and HLA presentation, limited prediction of T-cell receptor recognition, and challenges in formulation, delivery, and manufacturing. Artificial intelligence and advanced computational workflows are increasingly integrated into this pipeline to improve candidate prioritization and support more reproducible decision-making. In this review, we summarize clinical progress and key translational barriers in personalized neoantigen vaccination, and discuss how AI-enabled approaches may contribute across four major stages: multi-omics integration for neoantigen discovery, processing-aware HLA presentation prediction, structure-aware and TCR-informed immunogenicity modeling, and data-driven formulation optimization, particularly for lipid nanoparticle-based delivery systems. These approaches are able to help narrow biological and chemical search spaces, improve prioritization, and provide mechanistic insights into antigen presentation and immune recognition rather than replacing experimental validation. This articlefurther addresses future implementation challenges, including dataset diversity, model interpretability, prospective benchmarking, manufacturing traceability, and evolving regulatory frameworks for individualized mRNA cancer immunotherapies. Integrating computational innovation with rigorous immunological validation, scalable manufacturing, and regulatory oversight will be essential for advancing personalized neoantigen vaccines toward broader clinical implementation.

Cancer Vaccines↗
PubMed2026

CRISPR-Engineered CAR-T Cell Therapy for Epstein-Barr Virus-Associated Nasopharyngeal Carcinoma: A Review of Emerging Therapeutic Prospects.

Epstein-Barr virus (EBV)-associated nasopharyngeal carcinoma (NPC) remains a clinically challenging malignancy, particularly in recurrent or metastatic disease where durable responses to chemoradiotherapy and immune checkpoint blockade are limited. The viral aetiology of NPC provides a strong biological rationale for immune-based treatment; however, translation of chimaeric antigen receptor (CAR) T-cell therapy into this solid tumour setting is constrained by poor tumour trafficking, antigen heterogeneity, limited surface accessibility of EBV latent antigens, T-cell exhaustion, and an immunosuppressive tumour microenvironment. This review critically evaluates the emerging therapeutic prospects of CRISPR-engineered CAR-T cell therapy for EBV-associated NPC. It synthesises evidence on EBV latency biology, NPC immune evasion, solid-tumour CAR-T limitations, and genome-engineering strategies including conventional CRISPR-Cas9, base editing, prime editing, and double-strand-break-sparing targeted integration. Particular attention is given to genotoxicity, chromosomal rearrangements, chromosome loss, bystander and off-target editing, manufacturing heterogeneity, and the regulatory and biological barriers that currently separate technical feasibility from NPC-specific clinical implementation. Available clinical evidence from checkpoint blockade, EBV-specific adoptive T-cell therapy, base-edited CAR-T cells in haematologic malignancy, and early CRISPR-edited T-cell trials supports the feasibility of immune and genetic redirection but does not establish efficacy of a clinically validated CRISPR-engineered CAR-T platform for NPC. Future development should prioritise surface-accessible antigen validation, fit-for-purpose selection of editing technology, genomic safety, scalable manufacturing, and biomarker-driven early-phase trials.

Humans↗
PubMed2026

Reprogramming of TLR-Ferroptosis Signaling and Immunometabolic Pathways Overcomes Myeloid Suppression to Improve Checkpoint Blockade in Prostate Cancer.

UNLABELLED: The limited efficacy of immunotherapies in advanced prostate cancer stems from a tumor microenvironment (TME) in which myeloid-driven immune suppression, stromal remodeling, and metabolic barriers converge to limit antitumor immunity. In this study, we characterized the immunometabolic properties of an ultrasmall prostate-specific membrane antigen-targeting silica particle therapy as a first-in-class strategy to reprogram the Toll-like receptor (TLR)-ferroptosis axis in MYC-driven prostate cancer. As single agents, these particles suppressed lipid and steroid biosynthesis, disrupted lipid peroxidation control, and impaired nutrient flux, sensitizing tumors to ferroptosis. Coordinated redox remodeling, stromal reprogramming, and innate immune activation reversed myeloid suppression and promoted CD8+ T-cell infiltration. When combined with CSF-1R inhibition and immune checkpoint blockade, the particles suppressed tumor growth, extended survival beyond 100 days, and achieved up to 50% complete remission in MYC-overexpressing models. These findings position TLR-ferroptosis axis remodeling as a mechanistic blueprint for rational, particle-driven immunotherapies with broad translational potential in prostate cancer and other immunologically refractory malignancies. SIGNIFICANCE: Clinically validated, PSMA-targeted ultrasmall core-shell silica particles reprogram immunometabolic pathways via a TLR-ferroptosis axis, enabling tumor microenvironment remodeling and potentiating checkpoint blockade in prostate cancer, with translational implications for treatment-resistant disease.

Male↗
PubMed2026

An Update on Inborn Errors of V(D)J Recombination.

V(D)J recombination is the fundamental process by which developing T and B lymphocytes generate diverse antigen receptors, enabling adaptive immunity. This tightly regulated program operates exclusively in lymphoid precursors during G1 phase and depends on the lymphocyte-specific RAG1-RAG2 recombinase to introduce programmed DNA double-strand breaks at recombination signal sequences, followed by repair through the classical nonhomologous end joining (c-NHEJ) pathway. Disruption of any step in this molecular choreography compromises antigen receptor diversity and underlies a spectrum of inborn errors of immunity (IEIs), ranging from severe combined immunodeficiency (SCID) to immune dysregulation with autoimmunity and granulomatous disease. In this review, we place disorders of V(D)J recombination within the broader framework of T-cell development, detailing the temporal waves of recombinase activity, chromatin accessibility, and DNA damage responses that guide thymocyte differentiation. We discuss pathogenic variants affecting the cleavage phase [RAG1, RAG2, and the recently identified RAG cochaperone NudC domain-containing 3 (NUDCD3)], end processing (ARTEMIS), ligation and repair (LIG4, XLF, XRCC4, PRKDC), and genome surveillance pathways (ATM, MRN complex, RNF168), highlighting genotype-phenotype correlations and mechanisms driving immune deficiency and dysregulation. We briefly review recent diagnostic advances, including newborn screening using T-cell receptor excision circles, repertoire sequencing, and functional assays, alongside current therapeutic strategies. Finally, we outline key unanswered questions and argue that continued integration of clinical observation with molecular discovery is essential to improve outcomes and deepen understanding of adaptive immune development.

Humans↗
PubMed2025

Transitioning from native to synthetic receptors: broadening T-cell engineering and beyond.

T-cell immunotherapy has progressed rapidly, evolving from native T-cell receptor biology to the development of innovative synthetic receptors that extend therapeutic applications beyond cancer. This review explores engineering strategies, ranging from natural TCRs to synthetic receptors, that increase T-cell activation and therapeutic potential. We begin by highlighting the foundational role of native receptors in the T-cell response, emphasizing how these structural and functional insights inform the design of next-generation synthetic receptors. Comparisons between CAR and TCR-like synthetic receptors underscore their respective advantages in specificity, efficacy, and safety, as well as potential areas for further improvement. In addition, gene editing technologies such as CRISPR-Cas9 enable precise modifications to the T-cell genome, enhancing receptor performance and minimizing immunogenic risks. In addition to tumors, these engineered T cells can be directed against viral infections, autoimmune disorders, and other diseases. We also explore advanced strategies that engage multiple immune cell types to achieve synergistic, durable responses. By demonstrating how native and synthetic receptors collectively drive innovation, this review aims to inspire new research directions and ultimately expand the scope of T-cell engineering for universal therapeutic applications.

Humans↗
PubMed2026

Detection of cytokine release syndrome using wearables and cytokine profiling following CAR-T therapy for myeloma.

BACKGROUNDChimeric antigen receptor T-cell (CAR-T) therapies have revolutionized treatment for relapsed/refractory multiple myeloma (RRMM). However, cytokine release syndrome (CRS), a common and potentially severe complication, requires inpatient monitoring, limiting access and increasing costs. Wearable devices could support outpatient CAR-T delivery, but feasibility for CRS detection versus standard care remains unproven.METHODSWe conducted a prospective, single-center observational pilot study to assess the feasibility of using wearable devices for monitoring vital signs and detecting CRS. Thirty patients receiving idecabtagene vicleucel (ide-cel) or ciltacabtagene autoleucel (cilta-cel) were enrolled; 25 with sufficient monitoring data were evaluable. Sensors collected skin and axillary temperature, oxygen saturation, respiratory and heart rate, and motion. Peripheral blood cytokines were analyzed pre- and postinfusion using a multiplex proteomic platform. The primary outcome was feasibility, assessed by CRS detection sensitivity and specificity; secondary outcomes included adherence, lead time, and performance of models integrating wearable and cytokine data.RESULTSCRS occurred in 20 of 25 patients. The best-performing wearable model detected 18 or 20 CRS episodes with a sensitivity of 0.72 (mean 0.75; 95% CI 0.60-0.91) and a specificity of 0.80 (mean 0.76; 95% CI 0.68-0.84), and a median lead time of 7:00 hours before nursing recognition. Median adherence during high-risk periods was 71%. Cytokine changes paralleled temperature elevations, and IFN-γ emerged as a consistent biomarker.CONCLUSIONWearable devices are feasible for early CRS detection and may support outpatient CAR-T care. Larger outpatient studies are warranted.TRIAL REGISTRATIONThis study did not meet the criteria for ClinicalTrials.gov registration.

Humans↗
PubMed2026

Efficient and precise programmable DNA knock-in without double-strand breaks.

Programmable gene knock-in holds substantial promise for treating genetic diseases and advancing cell therapies. However, achieving precise and efficient kilobase-scale DNA fragment integration remains challenging1,2. Here we report CRISPR kilobase-scale nickase-targeting (KNIT) editing for efficient, precise and programmable kilobase-scale DNA insertion without double-strand DNA cleavage, which is enabled through the coupling of a Cas9 nickase with a DNA donor recruiting system. KNIT editing facilitates programmable integration of DNA fragments from 0.7 kb to more than 10 kb and is effective across genomic loci and cell types. It achieves up to 89% efficiency and markedly reduces unintended insertion-deletion mutation (indels) rates, translocations and off-target editing. The system supports repeated insertion editing and multiloci gene knock-in with minimal translocations. Its enhanced version, KNIT editor 2, further improves efficiency via a single transfection. Moreover, in mutant cells with a pathological mutation, KNIT editing restores normal gene expression by inserting a therapeutic gene into a safe harbour locus or its native locus. Notably, KNIT editing enables non-viral and programmable chimeric antigen receptor T cell (CAR-T cell) engineering without double-strand breaks and with clinically relevant efficiencies. Moreover, the engineered CAR-T cells exhibit effective antitumour activity in vitro and in mouse models. Therefore, by achieving programmable and site-specific kilobase-scale DNA insertions without double-strand breaks while reducing unintended outcomes, KNIT editing provides a versatile platform for advancing personalized medicine.

Animals↗
PubMed2026

Tracking GAD-specific T-cell expansions in Type 1 diabetes by intradermal GAD-Alum challenge.

Identifying and monitoring autoreactive T cells that drive beta cell destruction remains a major obstacle to developing effective immunotherapies for type 1 diabetes (T1D). These cells are extremely rare in peripheral blood and cannot be accessed directly from the pancreas. We used intradermal injection of Glutamic Acid Decarboxylase (GAD)-Alum to recruit GAD-specific T cells to accessible sites in the skin and skin-draining lymph nodes (LNs), sampled by skin suction blisters and ultrasound-guided LN aspiration. Peripheral blood samples obtained before GAD injection were restimulated with GAD in vitro to detect reactive CD4+ T cells. Single-cell RNA sequencing (scRNAseq) followed by re-expression of selected T cell receptors (TCRs) confirmed antigen specificity. Up to 70% of T cells at the skin injection site were clonally-expanded and 4 of 14 (28%) re-expressed TCRs were GAD-reactive. In LNs 1 of 14 (4%) clonally-expanded TCRs was GAD-reactive, representing ~0.08% of all T-cells. GAD-reactive cells across compartments displayed Th1 and Th17-associated transcription signatures. These results demonstrate the intradermal autoantigen challenge and scRNAseq, enable direct identification and molecular profiling of autoreactive T cells in vivo. This minimally invasive approach provides a powerful platform for tracking antigen-specific T cells to monitor disease activity and evaluate immune interventions in T1D.

Autoimmunity↗
PubMed2026

Chemical Complementarities of Neuroblastoma Tumor-Resident TCR CDR3s and CMV Antigens are Associated with a Better Outcome.

A likely immune response to a virus can be detected via the presence of TCR CDR3s that (a) exactly match CDR3s known to bind viral antigens or (b) represent chemical complementarity to viral antigens. Previous studies, based on genomics approaches to characterizing anti-CMV TCR CDR3s in patient blood samples, have indicated the possibility that a systemic CMV infection is associated with worse outcomes for NBL, as well as for breast cancer. Thus, the association of NBL tumor-resident anti-CMV TCR CDR3s and patient outcomes was evaluated here, with results indicating that high levels of chemical complementarity between tumor-resident TCR CDR3s and CMV antigens represented a better outcome. This is in apparent contrast to results obtained via the previous study of blood sourced, anti-CMV TCR CDR3s representing a worse outcome. This study identified gene expression values associated with the tumor-specific anti-CMV TCR CDR3s, representing exact matches to known anti-CMV TCR CDR3s, which may assist in identifying a potential underlying mechanism effecting the better outcomes associated with the tumor-resident, anti-CMV TCR CDR3s. Overall, results here raise the question of whether an anti-CMV response directly against the tumor, or within the tumor microenvironment, is involved in reductions in tumor progression or responsiveness to treatment?

Humans↗
PubMed2026

The future of TCR-Treg therapies is renewables.

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.

Humans↗
PubMed2014

Distinct contributions of Aire and antigen-presenting-cell subsets to the generation of self-tolerance in the thymus.

The contribution of thymic antigen-presenting-cell (APC) subsets in selecting a self-tolerant T cell population remains unclear. We show that bone marrow (BM) APCs and medullary thymic epithelial cells (mTECs) played nonoverlapping roles in shaping the T cell receptor (TCR) repertoire by deletion and regulatory T (Treg) cell selection of distinct TCRs. Aire, which induces tissue-specific antigen expression in mTECs, affected the TCR repertoire in a manner distinct from mTEC presentation. Approximately half of Aire-dependent deletion or Treg cell selection utilized a pathway dependent on antigen presentation by BM APCs. Batf3-dependent CD8α⁺ dendritic cells (DCs) were the crucial BM APCs for Treg cell selection via this pathway, showing enhanced ability to present antigens from stromal cells. These results demonstrate the division of function between thymic APCs in shaping the self-tolerant TCR repertoire and reveal an unappreciated cooperation between mTECs and CD8α⁺ DCs for presentation of Aire-induced self-antigens to developing thymocytes.

Animals↗
PubMed2026

An immunoinformatics-based multi-epitope vaccine candidate confers cross-protection against two Actinobacillus pleuropneumoniae serovars.

Porcine contagious pleuropneumonia (PCP) is caused by Actinobacillus pleuropneumoniae (APP) and inflicts heavy economic losses on the swine industry. However, existing inactivated vaccines provide limited cross-protection, highlighting the need for improved vaccine strategies. In this study, we combined pangenome analysis with subtractive proteomics to screen the APP core genome and identified 11 potential antigens. Seven of them showed immunoreactivity by ELISA and Western blotting. These antigens, together with the ApxI-III toxins, were used for T and B cell epitope prediction. On this basis, a multi-epitope fusion protein MVAPP was constructed. In silico molecular docking with swine immune receptors and immune simulations suggested that MVAPP has the potential to induce immune responses. In the mouse model, that MVAPP elicited specific antibody responses, shifted the splenic T-cell subset distribution toward CD4+ T cells, and provided partial protection against challenge with strains from two serovars. In conclusion, MVAPP represents a potential multi-epitope vaccine candidate for further development against APP.

Animals↗
PubMed2026

Receptor-defined targeting of a genomically unique melanoma-enriched noncanonical antigen.

Effective T cell-based immunotherapies require functional receptors that can be engineered and redeployed to recognize tumor-restricted antigens. Noncanonical peptides arising from transcription outside annotated protein-coding regions expand the antigenic landscape of cancer; however, systematic strategies to biologically prioritize and functionally validate such targets remain underdeveloped. Here, we integrated de novo transcript analysis, exon-resolved quantification, RNA in situ hybridization, and immunopeptidomics to identify melanoma-associated noncanonical transcripts and advance candidates through receptor-level validation. Among three recurrent melanoma-associated transcripts, EVA003 emerged as a lead target based on its distinct repeat-enriched genomic architecture, consistent tumor-enriched exon-level expression across independent datasets, and a genomically unique immunogenic core sequence. We demonstrate endogenous presentation of EVA003-derived peptides on HLA-A*03:01 and detect specific reactivity in patient-derived tumor-infiltrating lymphocytes. Single-cell transcriptomic profiling identified a dominant peptide-reactive clonotype, enabling isolation of a naturally occurring T cell receptor. Transfer of this receptor into healthy donor T cells conferred antigen-dependent activation and cytotoxicity against both peptide-pulsed targets and melanoma cells expressing EVA003 endogenously. Together, these findings establish a biologically informed strategy for prioritizing noncanonical tumor antigens and demonstrate that genomically unique, tumor-enriched noncanonical peptides can be presented to molecularly defined receptors capable of mediating cancer cell killing. These findings support the integration of prioritized noncanonical antigens into engineered T cell therapeutic strategies.

Humans↗
PubMed2015

Dengue virus infection elicits highly polarized CX3CR1+ cytotoxic CD4+ T cells associated with protective immunity.

Dengue virus (DENV) is a rapidly spreading pathogen with unusual pathogenesis, and correlates of protection from severe dengue disease and vaccine efficacy have not yet been established. Although DENV-specific CD8(+) T-cell responses have been extensively studied, the breadth and specificity of CD4(+) T-cell responses remains to be defined. Here we define HLA-restricted CD4(+) T-cell epitopes resulting from natural infection with dengue virus in a hyperepidemic setting. Ex vivo flow-cytometric analysis of DENV-specific CD4(+) T cells revealed that the virus-specific cells were highly polarized, with a strong bias toward a CX3CR1(+) Eomesodermin(+) perforin(+) granzyme B(+) CD45RA(+) CD4 CTL phenotype. Importantly, these cells correlated with a protective HLA DR allele, and we demonstrate that these cells have direct ex vivo DENV-specific cytolytic activity. We speculate that cytotoxic dengue-specific CD4(+) T cells may play a role in the control of dengue infection in vivo, and this immune correlate may be a key target for dengue virus vaccine development.

Adult↗
PubMed2024

Aire mediates tolerance to insulin through thymic trimming of high-affinity T cell clones.

Insulin is a central autoantigen in the pathogenesis of T1D, and thymic epithelial cell expression of insulin under the control of the Autoimmune Regulator (Aire) is thought to be a key component of maintaining tolerance to insulin. In spite of this general working model, direct detection of this thymic selection on insulin-specific T cells has been somewhat elusive. Here, we used a combination of highly sensitive T cell receptor transgenic models for detecting thymic selection and sorting and sequencing of Insulin-specific CD4+ T cells from Aire-deficient mice as a strategy to further define their selection. This analysis revealed a number of unique t cell receptor (TCR) clones in Aire-deficient hosts with high affinity for insulin/major histocompatibility complex (MHC) ligands. We then modeled the thymic selection of one of these clones in Aire-deficient versus wild-type hosts and found that this model clone could escape thymic negative selection in the absence of thymic Aire. Together, these results suggest that thymic expression of insulin plays a key role in trimming and removing high-affinity insulin-specific T cells from the repertoire to help promote tolerance.

Animals↗
PubMed2026

EPIC: multi-objective guided diffusion for epitope design in TCR-pMHC complexes.

MOTIVATION: T cell receptor (TCR) recognition of peptide-major histocompatibility complex (pMHC) complexes is central to adaptive immunity, yet rational design of immunogenic epitopes remains elusive due to complex triplet binding constraints and data scarcity. No existing method can generate epitopes satisfying simultaneous requirements for antigenicity, MHC presentation, and TCR specificity. RESULTS: We present EPIC, a multi-objective diffusion framework that decomposes TCR-pMHC binding into three biologically grounded sub-tasks, enabling training-free gradient guidance without end-to-end retraining. By integrating ESM-based classifiers with a peptide diffusion generator, EPIC leverages heterogeneous immunological interaction datasets to generate diverse, context-aware epitopes. EPIC-designed top-three epitopes achieve lower predicted interface energies compared to ground-truth epitopes in 78.31% of test cases, while maintaining 80.1% sequence novelty and comparable structural confidence. Generated epitopes exhibit 100% uniqueness, high diversity (64.05%), and high antigenicity scores (0.4723). To our knowledge, EPIC is the first computational framework capable of de novo epitope design while explicitly integrating the triplet constraints of TCR-pMHC binding. This paradigm shift from discovery to design unlocks new potential for personalized cancer vaccines, precision adoptive T cell therapy, and rapid response to emerging infectious diseases. AVAILABILITY AND IMPLEMENTATION: The source code of EPIC is available at https://github.com/Octopus125/EPIC and archived on Zenodo (DOI: 10.5281/zenodo.18537646).

Receptors, Antigen, T-Cell↗
PubMed2026

[Development of universal off-the-shelf T cell therapies derived from ES/iPS cells for leukemia and COVID-19].

Cancer immunotherapy using patient-derived T cells genetically modified in vitro has been demonstrated to be effective. However, issues such as cost, time, and unstable quality must be resolved. To overcome these barriers, we developed the TCR-PS cell method, in which a specific TCR gene is introduced into pluripotent stem cells (PS cells), such as ES cells or iPS cells, and T cells are generated from those PS cells. We are currently preparing for a clinical trial in acute myeloid leukemia, targeting the WT1 antigen, with iPS cells provided by the CiRA Foundation as the starting material. In parallel, we are also investigating this approach for viral infections and preparing for clinical trials in COVID-19, with HLA-deficient ES cells as the starting material. This method should enable stockpiling of T cell therapies against known viruses such as SARS or avian influenza. Even for outbreaks caused by unknown viruses, it should be possible to produce T cell therapies within 100 days after the virus genome is defined.

Humans↗