Abstract LB-287: Combining immunomics and genomics for immunotherapy of refractory and rare cancers
Authors: Kosaloglu Zeynep , Zoernig Inka , Halama Niels , Koehler Bruno , Berger Anne Katrin , Springfeld Christoph , Ulrich Alexis , Schneider Martin , Lasitschka Felix , Glimm Hanno , Froehling Stefan , Brors Benedikt , Jaeger Dirk 
Published: July 2016

Abstract
Introduction: An underlying basis of cancer immunotherapy is the activation of the patient's own immune effector cells to specifically eradicate tumor cells. Different strategies of cancer immunotherapy have shown outstanding success in a number of patients across various tumor types. However, currently only a fraction of patients respond to immunotherapy, and therapy works only in a subset of tumors. To understand why, an integrated analysis of host and tumor factors is required. Fundamental issues in the analysis of key prognostic and predictive components include elucidating the complex interaction between tumors and their microenvironment, determining the type and densities of tumor-infiltrating immune cells, and understanding how the mutational load influences therapy outcome. Sophisticated analysis is required for patients with refractory or rare cancers to explore new therapeutic strategies. We established a systems medicine approach to obtain detailed data about tumor-host interactions, which may provide information on clinical outcome and help identify patients who are most likely to benefit from immunotherapy.
Methods and Results: Whole-exome sequencing of tumor and control samples is performed from freshly obtained patient samples. In addition, whole-transcriptome sequencing of tumor tissue is performed if possible. Single nucleotide variations (SNVs) are detected in each tumor. Sequence-based HLA typing and computational epitope prediction methods are used to assess the immunogenicity of each SNV. The grade of immune cell infiltration and the expression of selected immunomodulatory proteins, e.g. PD-1 and PD-L1, is assessed by immunohistochemical stainings of tissue samples. Additionally, cytokine and chemokine profiles are determined in the tumor microenvironment. The resulting data can aid in treatment decision, e.g. PD-1 blocking antibodies can be administered when elevated PD-1 expression is detected. Alternatively, peptide vaccination is considered if a sufficient number of immunogenic mutations is detected. Based on the mutational profiles, mutation specific 29mer peptides and corresponding wild type peptides are produced for ELIspot assays with patient PBMCs to assess mutation-specific T cell reactivity. To assess the changes over time, blood and tissue are obtained during therapy to monitor therapy-induced changes in the periphery and the tumor microenvironment.
Conclusion: Here we present our established workflow to systematically analyze tumor-host interactions in cancer patients and show preliminary data of different facets and clinical implications of these complex interactions. To evaluate and validate immunological and pathological characteristics of a tumor and the methods to assess its immunogenicity as well as its complex interplay with the microenvironment, comprehensive translational studies have to be conducted. Eventually, the obtained information will help to identify important subgroups and patients who are most likely to benefit from a certain type of immunotherapy.
Citation Format: Zeynep Kosaloglu, Inka Zoernig, Niels Halama, Bruno Koehler, Anne Katrin Berger, Christoph Springfeld, Alexis Ulrich, Martin Schneider, Felix Lasitschka, Hanno Glimm, Stefan Froehling, Benedikt Brors, Dirk Jaeger. Combining immunomics and genomics for immunotherapy of refractory and rare cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-287.