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    Myeloma Novel Drug Targets and agents

    Category: Myeloma Novel Drug Targets and agents

    Uncovering shared cancer-restricted cryptic antigens as T cell targets in Multiple Myeloma patients treated with Dendritic Cell/Myeloma fusion vaccine

    (PA-298) Uncovering Shared Cancer-restricted Cryptic Antigens as T Cell Targets in Multiple Myeloma Patients Treated with Dendritic Cell/Myeloma Fusion Vaccine

    Wednesday, September 17, 2025
    Introduction: Identifying novel tumor-specific antigens for T cell therapy is a critical step in developing next-generation immunotherapies for Multiple Myeloma (MM). Cryptic peptides from untranslated regions, tumor-specific splice variants, retroelements, and non-coding RNAs aberrantly translated in MM may represent a potent yet underexplored class of neoantigens. Studying primary myeloma cells from patients in a cancer vaccine trial (CTN 1401), we discovered shared tumor antigens, including retroviral-derived epitopes, as potential targets for cellular immunotherapy.

    Methods: We developed a discovery framework integrating whole-exome sequencing, RNAseq, ribosome profiling, and single-cell immunoprofiling (gene expression + TCRseq) to identify (neo+cryptic) antigens that are transcribed, translated, and predicted to be antigenic. We applied this to 16 MM patient samples from the BMT CTN 1401 trial (NCT02728102). Detected peptides were prioritized using a machine learning algorithm trained on thousands of validated antigens. Prioritized antigens were confirmed for plasma cell specificity via single-cell RNAseq, and MHC-I presentation potential assessed using public immunopeptidomic datasets. Top antigens are being validated and matched with cognate TCRs using single-cell multiomics (gene expression, TCRs, and antigen binding) with DNA-barcoded dCODE MHC-I Dextramers. 

    Results: Of the over 2,000 cryptic and mutation-derived peptides identified through our framework, 69 high-confidence, cancer-restricted cryptic antigens were prioritized. These antigens originated from 3′/5′ UTRs, retrotransposons, and endogenous retroviruses. Notably, six novel shared antigenic retroelements were identified, originating from the L1, L2, and ERV1 subfamilies, with the L2 element being consistently detected across 10 patients. Most remaining prioritized antigens arose from non-canonical ORFs in the 3′/5′ UTRs of plasma cell-associated genes, including BCMA, SLAMF7, and emerging candidates such as EGR1, TRIB1, and UBE2J1, likely generated through alternative splicing or aberrant transcription. Additionally, novel shared neoantigens were identified from UCHL1 and TPTE, two genes found to be aberrantly expressed in malignant plasma cells. Single-cell immunoprofiling revealed significant α/β TCR clonotypic expansion associated with high cryptic antigen abundance, suggesting active T cell engagement. We are currently conducting dCODE MHC-I Dextramer profiling to evaluate the intrinsic and vaccine-induced T cell responses against these tumor-specific targets. 

    Conclusions: This study reveals a novel repertoire of shared, cancer-restricted cryptic antigens in MM, many arising from retroelements and previously annotated non-coding regions. These peptides are immunogenic and tumor-specific. Integration with dCODE profiling and TCR tracking provides a roadmap for identifying clinically relevant T cell targets and optimizing vaccine-based immunotherapies in MM.