ScaiDigest Volume 3: Unveiling Immuno-Oncology's Next Frontier

“As a firm believer in our potential to solve biological problems, I identify single-cell and multi-omics technologies as a prime contender in the race to provide a whole new dimension of data that will answer open and complex biological questions. My confidence in the possibilities of these technologies  has been recently justified as two articles adopting multi-omic approaches to address unmet needs in immuno-oncology were published in the last several weeks.

The article by Tretter et al. in Nature Communications underscores the importance of a multi-omics approach for the discovery and assessment of neoantigens in various cancer types. It demonstrates the value of integrating RNA-based data and non-canonical HLA-binding peptides in immuno-oncology research. These trends highlight the ongoing advancements in single-cell multi-omics technologies for enhancing our understanding of tumor immunogenicity and the development of personalized cancer treatments.

Specifically, the study adopts a comprehensive multi-omics approach, including DNA and RNA sequencing, as well as MS-based immunopeptidomics of tumor specimens. This indicates a growing trend in utilizing multiple omics techniques to obtain a more holistic understanding of the molecular and immunological characteristics of tumors.

The primary focus of the study is on the discovery of neoantigens, which are unique antigens derived from tumor-specific mutations. The use of computational methods in combination with multi-omics data enables the identification of a large number of tumor-specific and tumor-associated antigens, enhancing our understanding of cancer immunogenicity.

Interestingly, the majority of neoantigen candidates are found to originate from variants identified in the RNA data set. This underscores the significance of RNA as a source of cancer antigens, challenging the traditional focus on DNA variants alone. This trend emphasizes the importance of integrating RNA-based data in immuno-oncology research.

Another study by Wong et al. published in Frontiers in Immunology emphasizes the integration of multi-omics technologies in a phase 1 clinical trial for relapsed/refractory multiple myeloma. The study showcases a bold approach to identifying predictive biomarkers through high-dimensional genomics and immune data analysis, contributing to the ongoing advancement of personalized treatment strategies in immuno-oncology.

Phase 1b Clinical Trial Design: The study focuses on a phase 1b clinical trial (NCT02431208) to evaluate the safety and efficacy of the anti-programmed death-ligand 1 monoclonal antibody atezolizumab (Atezo). A novel unsupervised integrative multi-omic analysis is conducted using RNA sequencing, mass cytometry immunophenotyping, and proteomic profiling of baseline and on-treatment bone marrow samples. This advanced analytical approach underscores the integration of various omics data sources to gain a comprehensive understanding of the disease and treatment effects.

The high-dimensional multi-omic profiling and integrative Similarity Network Fusion analysis reveal novel correlations between cellular and molecular features of the tumor and immune microenvironment. The integrative analysis’s findings have implications for patient selection and outcome assessment in future immunotherapy studies. 

These studies underscore the importance of incorporating advanced multi-omics strategies in research and clinical trial design to guide the development of novel therapies and treatment decisions.”

Proteogenomic analysis reveals RNA as a source for tumor-agnostic neoantigen identification.

Tretter C, de Andrade Krätzig N, Pecoraro M, Lange S, Seifert P, von Frankenberg C, Untch J, Zuleger G, Wilhelm M, Zolg DP, Dreyer FS, Bräunlein E, Engleitner T, Uhrig S, Boxberg M, Steiger K, Slotta-Huspenina J, Ochsenreither S, von Bubnoff N, Bauer S, Boerries M, Jost PJ, Schenck K, Dresing I, Bassermann F, Friess H, Reim D, Grützmann K, Pfütze K, Klink B, Schröck E, Haller B, Kuster B, Mann M, Weichert W, Fröhling S, Rad R, Hiltensperger M, Krackhardt AM.

Nat Commun. 2023 

Multi-omic analysis of the tumor microenvironment shows clinical correlations in Ph1 study of atezolizumab +/- SoC in MM

Sandy Wong, Habib Hamidi, Luciano J. Costa, Selma Bekri, Natalia Neparidze, Ravi Vij, Tina G. Nielsen, Aparna Raval, Rajan Sareen, Elisabeth Wassner-Fritsch, Hearn J. Cho

Front Immunol. 2023