Cancer's Dark Matter: Lighting the Abyss Unveils Universe of New Therapies

Fox, Bernard A.; Urba, Walter J.; Jensen, Shawn M.; Page, David B.; Curti, Brendan D.; Sanborn, Rachel E.; Leidner, Rom S.

doi:10.1158/1078-0432.ccr-23-0422

Cited by 6 publications

(4 citation statements)

References 20 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Another group has explored the immunogenicity of non-canonical HLA-I tumor antigens identified through proteogenomics and shown that at least some of them are immunogenic (IFNg production and upregulation of 4-1BB) and shared across patients [ 82 ]. Their and our data reinforce the potential of TSAs as targets for off-the-shelf vaccines or TCR-based immunotherapies [ 83 ]. Furthermore, a multi-target approach in immunotherapy can enhance treatment effectiveness, improve patient outcomes, and decrease the likelihood of cancer recurrence [ 84 ], positioning immunogenic TSAs as appealing targets for designing multi-epitope vaccines.…”

Section: Discussionsupporting

confidence: 83%

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Hesnard,

Thériault,

Cahuzac

et al. 2024

Current Oncology

View full text Add to dashboard Cite

Epithelial ovarian cancer (EOC) has not significantly benefited from advances in immunotherapy, mainly because of the lack of well-defined actionable antigen targets. Using proteogenomic analyses of primary EOC tumors, we previously identified 91 aberrantly expressed tumor-specific antigens (TSAs) originating from unmutated genomic sequences. Most of these TSAs derive from non-exonic regions, and their expression results from cancer-specific epigenetic changes. The present study aimed to evaluate the immunogenicity of 48 TSAs selected according to two criteria: presentation by highly prevalent HLA allotypes and expression in a significant fraction of EOC tumors. Using targeted mass spectrometry analyses, we found that pulsing with synthetic TSA peptides leads to a high-level presentation on dendritic cells. TSA abundance correlated with the predicted binding affinity to the HLA allotype. We stimulated naïve CD8 T cells from healthy blood donors with TSA-pulsed dendritic cells and assessed their expansion with two assays: MHC-peptide tetramer staining and TCR Vβ CDR3 sequencing. We report that these TSAs can expand sizeable populations of CD8 T cells and, therefore, represent attractive targets for EOC immunotherapy.

show abstract

Section: Discussionsupporting

confidence: 83%

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Hesnard,

Thériault,

Cahuzac

et al. 2024

Current Oncology

View full text Add to dashboard Cite

show abstract

“…The combination of PD-1 inhibitor, multivalent DRibbles vaccine and GITR agonist has shown increased efficacy in preclinical models [63] and is being tested in a clinical trial of DRibbles vaccine ± GITR agonist, followed after two weeks by delayed anti-PD-1. DPV-001 (DRibbles vaccine) is an off-the-shelf multivalent autophagosomeenriched cancer vaccine that contains > 300 putative cancer antigens, including alternative cancer neoantigens-cancer's dark matter, DAMPS, HSPs and agonists for TLR 2, 4, 7, 8, and NOD2 [64]. INCAGN01876 (GITR agonist) is a recombinant, humanized IgG1 κ monoclonal antibody that selectively binds to the extracellular domain of human GITR (CD357 or TNRSF18).…”

Section: Preliminary Immunological Monitoring Of First-in-human Immun...mentioning

confidence: 99%

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st–3rd, 2022—Naples, Italy)

et al. 2023

Self Cite

View full text Add to dashboard Cite

Outcomes for patients with melanoma have improved over the past decade with the clinical development and approval of immunotherapies targeting immune checkpoint receptors such as programmed death-1 (PD-1), programmed death ligand 1 (PD-L1) or cytotoxic T lymphocyte antigen-4 (CTLA-4). Combinations of these checkpoint therapies with other agents are now being explored to improve outcomes and enhance benefit-risk profiles of treatment. Alternative inhibitory receptors have been identified that may be targeted for anti-tumor immune therapy, such as lymphocyte-activation gene-3 (LAG-3), as have several potential target oncogenes for molecularly targeted therapy, such as tyrosine kinase inhibitors. Unfortunately, many patients still progress and acquire resistance to immunotherapy and molecularly targeted therapies. To bypass resistance, combination treatment with immunotherapies and single or multiple TKIs have been shown to improve prognosis compared to monotherapy. The number of new combinations treatment under development for melanoma provides options for the number of patients to achieve a therapeutic benefit. Many diagnostic and prognostic assays have begun to show clinical applicability providing additional tools to optimize and individualize treatments. However, the question on the optimal algorithm of first- and later-line therapies and the search for biomarkers to guide these decisions are still under investigation. This year, the Melanoma Bridge Congress (Dec 1st–3rd, 2022, Naples, Italy) addressed the latest advances in melanoma research, focusing on themes of paramount importance for melanoma prevention, diagnosis and treatment. This included sessions dedicated to systems biology on immunotherapy, immunogenicity and gene expression profiling, biomarkers, and combination treatment strategies.

show abstract

“…In addition, among the nascent proteins, misfolded proteins and the population called short‐lived proteins (SLiPs) and defective ribosomal products (DRiPs) are also known to become antigen sources for HLA class I immunopeptides. 16 To trim these source proteins/peptides into a more desirable property as immunopeptides to make the HLA complex, proteasomal degradation and endopeptidase activity are required. More recently, the ubiquitin proteasome system (UPS)‐independent source supply has been also reported.…”

Section: Introductionmentioning

confidence: 99%

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy

Minegishi,

Haga,

Ueda

2024

Cancer Science

View full text Add to dashboard Cite

With significant advances in analytical technologies, research in the field of cancer immunotherapy, such as adoptive T cell therapy, cancer vaccine, and immune checkpoint blockade (ICB), is currently gaining tremendous momentum. Since the efficacy of cancer immunotherapy is recognized only by a minority of patients, more potent tumor‐specific antigens (TSAs, also known as neoantigens) and predictive markers for treatment response are of great interest. In cancer immunity, immunopeptides, presented by human leukocyte antigen (HLA) class I, play a role as initiating mediators of immunogenicity. The latest advancement in the interdisciplinary multiomics approach has rapidly enlightened us about the identity of the “dark matter” of cancer and the associated immunopeptides. In this field, mass spectrometry (MS) is a viable option to select because of the naturally processed and actually presented TSA candidates in order to grasp the whole picture of the immunopeptidome. In the past few years the search space has been enlarged by the multiomics approach, the sensitivity of mass spectrometers has been improved, and deep/machine‐learning‐supported peptide search algorithms have taken immunopeptidomics to the next level. In this review, along with the introduction of key technical advancements in immunopeptidomics, the potential and further directions of immunopeptidomics will be reviewed from the perspective of cancer immunotherapy.

show abstract

Cancer's Dark Matter: Lighting the Abyss Unveils Universe of New Therapies

Cited by 6 publications

References 20 publications

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Immunogenicity of Non-Mutated Ovarian Cancer-Specific Antigens

Perspectives in Melanoma: meeting report from the Melanoma Bridge (December 1st–3rd, 2022—Naples, Italy)

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy

Contact Info

Product

Resources

About