Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs are developed that harness endogenous ADAR1 to direct precise adenosine-to-inosine (A-to-I) editing at selected transcript sites and demonstrate the generation of immunogenic neoepitopes through RNA editing at the transcript level, termed editopes.
Abstract
Neoepitope-based therapies hold great promise for cancer immunotherapy because they target tumor-specific mutations and elicit potent anti-tumor T-cell responses. However, their clinical implementation remains limited by the complexity of neoepitope discovery and uncertainty regarding presentation by tumor cells. A potential alternative is the generation of immunogenic neoepitopes directly within cancer cells through programmable RNA editing. Here, we develop Short Precise-Encodable ADAR Recruiting (SPEAR) gRNAs that harness endogenous ADAR1 to direct precise adenosine-to-inosine (A-to-I) editing at selected transcript sites. Using these gRNAs, we demonstrate the generation of immunogenic neoepitopes through RNA editing at the transcript level, termed editopes. In a proof-of-concept model based on the melanoma antigen MART-1, SPEAR-mediated RNA editing restored antigen-specific T cell recognition and enabled tumor control in vivo. Finally, we developed a computational pipeline to identify candidate tumor-selective neoepitopes across multiple cancer types amenable to guided RNA editing. Our findings establish programmable RNA editing as a strategy for engineering immunogenic editopes and provide a framework for neoepitope-directed cancer immunotherapy.
This review outlines the molecular mechanisms driving neoantigen generation in CRC, including frameshift mutations, single-nucleotide variants, alternative RNA splicing, and circular RNA-derived epitopes, and evaluates neoantigen-directed therapeutic platforms, encompassing personalized neoantigen vaccines and adoptive T-cell therapies that are engineered to recognize neoantigen-derived epitopes.
Na Wang, Yi-Meng Xia, Ping Wang et al.· Medical Oncology· 0 citations
The strongest current signal supports use in adjuvant, perioperative, and minimal residual disease settings, usually in combination with checkpoint blockade or other immune-modifying strategies, usually in combination with checkpoint blockade or other immune-modifying strategies.
Minglu Ge, Ning Wu· Cancer Treatment and Researc...· 0 citations
This efficient engineering process of Iterative Nicking for Synchronous Engineered Reprogramming of T cells (INSERT) establishes a safe, simplified platform for advanced therapeutic CAR T engineering.
Joseph G. Skeate, Nicholas J. Slipek, Walker S. Lahr et al.· Molecular Therapy· 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
Aberrant pre-mRNA splicing in cancer generates protein sequences that are rare or absent in normal tissues, creating a rich source of tumor-specific neoantigens for immunotherapy. These splicing-derived neoantigens arise through diverse mechanisms, including recurrent somatic mutations in core spliceosome components (SF3B1, SRSF2, U2AF1, and ZRSR2), epigenetic derepression of transposable elements that give rise to chimeric exon-TE junctions, and coordinated dysregulation of splicing regulatory networks in cancers lacking spliceosome coding mutations. These processes produce two major classes of immunotherapeutic targets: 1) MHC class I-restricted neopeptides that can be recognized by T-cell-based therapies, and 2) extracellular neoepitopes (ExNeoEpitopes) within transmembrane proteins that are accessible to HLA-independent antibody-based modalities, including monoclonal antibodies (mAbs), bispecific engagers (BiTEs), antibody-drug conjugates (ADCs), and chimeric antigen receptor (CAR)-T or CAR-NK cells. Despite their strong immunogenic potential, effective therapeutic exploitation requires overcoming key immunological barriers, including T-cell exhaustion, impaired antigen presentation through MHC-I downregulation, and suppression within the tumor microenvironment. Recent advances in computational neoantigen prediction, immunopeptidomics, surface proteomics, long-read and single-cell isoform sequencing, and AI-guided therapeutic design are enabling more systematic discovery and validation of splicing-derived targets. This review integrates current understanding of the biological origins, immunological barriers, target classes of splicing neoantigens, and the technologies that enable their advancement in cancer immunotherapy.
Mu-Tian Tang, H. L. Grimes, Nathan Salomonis· Frontiers in Immunology· 0 citations
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