EORTC 2016-Genomic characterization of immune targets in patient-derived xenograft models for translational assessment of immunotherapy
Genomic characterization of immune targets in patient-derived xenograft models for translational assessment of immunotherapy
David Cerna1, Daniel Ciznadija1, Ido Ben zvi1, Ido Sloma1, David Sidransky2, and Angela Davies1, Neal Goodwin1 1 Champions Oncology, Baltimore, MD, USA. 2 Johns Hopkins University School of Medicine, Baltimore, MD, USA
Although oncology therapies reactivating the immune response by targeting checkpoints such as PD1 and PD-L1 are now FDA approved, development of therapeutics regulating other immune targets remains an area of active research. Differences between human and murine immune systems have generally limited the use of animal models in this setting. Whilst patient-derived xenograft (PDX) models are robust pre-clinical tools, whether they reflect human immune marker expression patterns remains unclear. Here we describe the genomic characterization of immunotherapy targets across a large panel of PDX models. This dataset is essential for planning downstream translational studies with PDX models in humanized mouse systems for evaluating immuno-oncology (IO) agents.
RNA sequencing was used on PDX models to determine the expression of genes considered targets for IO agents, including PD-L1, LAG3, IDO1 and 2, MUC1, and MUC4. Given the reported correlation between mutation load and response to IO agents, the total number of germline and somatic mutations (single nucleotide variations/small indels) in each PDX model was calculated from whole exome sequencing data. HLA locus analysis by </sequence-based typing (SBT) was performed for graft-host alignment.
PDX models are robust translational models; however, evidence of their utility for evaluating IO agents has been limited. We have now described the differential expression of various new and well-characterized immune targets in a large number of solid tumor PDX models. Such models may be reasonable surrogates for screening novel immunotherapies in human immune system (HIS) mice.