Valid-NEO: A Multi-Omics Platform for Neoantigen Detection and Quantification from Limited Clinical Samples

Terai, Yuri Laguna; Huang, Chun; Wang, Baoli; Kang, Xiaonan; Han, Jing; Douglass, Jacqueline; Hsiue, Emily Han‐Chung; Zhang, Ming; Purohit, Raj; deSilva, Taylor; Wang, Qing

doi:10.3390/cancers14051243

Cited by 7 publications

(7 citation statements)

References 31 publications

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“…Frozen pellets were sent to Complete Omics Inc for immunoprecipitation and antigen validation and quantification by mass spectrometry through the Valid-NEO platform. 51 Pellets were processed into single-cell frozen powder and then lysed. Peptide-HLA complexes were immunoprecipitated using the Valid-NEO neoantigen enrichment column preloaded with antihuman HLA-A, HLA-B, and HLA-C antibody clone W6/32 (BioXCell).…”

Section: Methodsmentioning

confidence: 99%

Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT

et al. 2023

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T-cell responses to minor histocompatibility antigens (mHAs) mediate graft versus leukemia (GvL) effects and graft versus host disease (GvHD) in allogeneic hematopoietic cell transplant (alloHCT). Therapies that boost T cell responses improve alloHCT efficacy, but are limited by concurrent increases in incidence and severity of GvHD. mHAs with expression restricted to hematopoietic tissue (GvL mHAs) are attractive targets for driving GvL without causing GvHD. Prior work to identify mHAs has focused on a small set of mHAs or population-level SNP association studies. We report the discovery of a large set of novel GvL mHAs based on predicted immunogenicity, tissue expression, and degree of sharing among donor-recipient pairs (DRPs) in the DISCOVeRY-BMT dataset of 3231 alloHCT DRPs. Total number of predicted mHAs varied by HLA allele, and total number and number of each class of mHA significantly differed by recipient genomic ancestry group. From the pool of predicted mHAs, we identified the smallest sets of GvL mHAs needed to cover 100% of DRPs with a given HLA allele. We used mass spectrometry to search for high population frequency mHAs for three common HLA alleles. We validated 24 novel predicted GvL mHAs that cumulatively are found within 98.8%, 60.7%, and 78.9% of DRPs within DISCOVeRY-BMT that express HLA-A*02:01, HLA-B*35:01, and HLA-C*07:02 respectively. We confirmed immunogenicity of an example novel mHA via T cell coculture with peptide-pulsed dendritic cells. This work demonstrates that identification of shared mHAs is a feasible and promising technique for expanding mHA-targeting immunotherapeutics.

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Section: Methodsmentioning

confidence: 99%

Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT

et al. 2023

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“…We assessed the presence of PR3 and PR5 peptides on HLA molecules on the surface of tumor cells. A targeted MS-based method using a highly sensitive technology ( 18 ) was developed to analyze peptides eluted from HLA molecules. This approach confirmed the presence of PR3 (but not PR5, data not shown) on HLA molecules on the surface of 8 out of 10 HLA-A2-positive tumor cell lines from the NCI-60 panel, representing various types of cancers (triple negative breast cancer, colon, ovarian, non-small cell lung cancer and melanoma) (Fig.…”

Section: Main Textmentioning

confidence: 99%

Targeting a shared neoepitope derived from non-canonical translation of c-MYConcogene in cancer cells

Baulu,

Bolon,

Etchegaray

et al. 2024

Preprint

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Cancer cells rely on alternative modes of translation for protein synthesis, promoting internal ribosome entry site (IRES)-dependent translation of mRNA encoding pro-oncogenic factors. Furthermore, ribosomes translate mRNA with lower fidelity in tumor cells. We proposed that these translational modifications in cancer produce shared tumor-specific epitopes derived from IRES-containing oncogenes. To identify such neoepitopes, we developed an in silico-based method that we applied to c-MYC. We showed that the non-canonical translation of c-MYC mRNA in cancer cells, involving a (+1) ribosomal frameshift, generates a shared neoepitope which induces high-avidity T cells able to kill tumor cells in vitro and in vivo while sparing normal cells. Our data provide preclinical rationale for developing immunotherapies targeting this c-MYC-derived neoepitope and validate a new type of shared translation-associated neoantigens.

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“…This PDF file includes: Materials and Methods Figs. S1 to S19 references (105)(106)(107)(108)(109)(110)(111)(112) Other Supplementary Material for this manuscript includes the following: Table S1 to S6 data file S1 Mdar reproducibility checklist…”

Section: Supplementary Materialsmentioning

confidence: 99%

Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities

Mog,

Marcou,

DiNapoli

et al. 2024

Sci. Transl. Med.

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Two types of engineered T cells have been successfully used to treat patients with cancer, one with an antigen recognition domain derived from antibodies [chimeric antigen receptors (CARs)] and the other derived from T cell receptors (TCRs). CARs use high-affinity antigen–binding domains and costimulatory domains to induce T cell activation but can only react against target cells with relatively high amounts of antigen. TCRs have a much lower affinity for their antigens but can react against target cells displaying only a few antigen molecules. Here, we describe a new type of receptor, called a Co-STAR (for costimulatory synthetic TCR and antigen receptor), that combines aspects of both CARs and TCRs. In Co-STARs, the antigen-recognizing components of TCRs are replaced by high-affinity antibody fragments, and costimulation is provided by two modules that drive NF-κB signaling (MyD88 and CD40). Using a TCR-mimic antibody fragment that targets a recurrent p53 neoantigen presented in a common human leukocyte antigen (HLA) allele, we demonstrate that T cells equipped with Co-STARs can kill cancer cells bearing low densities of antigen better than T cells engineered with conventional CARs and patient-derived TCRs in vitro. In mouse models, we show that Co-STARs mediate more robust T cell expansion and more durable tumor regressions than TCRs similarly modified with MyD88 and CD40 costimulation. Our data suggest that Co-STARs may have utility for other peptide-HLA antigens in cancer and other targets where antigen density may limit the efficacy of engineered T cells.

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Valid-NEO: A Multi-Omics Platform for Neoantigen Detection and Quantification from Limited Clinical Samples

Cited by 7 publications

References 31 publications

Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT

Shared graft-versus-leukemia minor histocompatibility antigens in DISCOVeRY-BMT

Targeting a shared neoepitope derived from non-canonical translation of c-MYConcogene in cancer cells

Preclinical studies show that Co-STARs combine the advantages of chimeric antigen and T cell receptors for the treatment of tumors with low antigen densities

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