Development and validation of blood-based predictive biomarkers for response to PD-(L)-1 checkpoint inhibitors: evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications

Abstract

Unprecedented advantages in cancer treatment with immune checkpoint inhibitors (ICI) remain limited to a subset of patients. Systemic analyses of the regulatory 3D genome architecture linked to individual epigenetics and immunogenetic controls associated with tumour immune evasion mechanisms and immune checkpoint pathways reveals a highly prevalent patient molecular profiles predictive of response to PD-(L)1 immune checkpoint inhibitors. A clinical blood test based on the set of 8 3D genomic biomarkers has been developed and validated on several independent cancer patient cohorts to predict response to PD-(L)1 immune checkpoint inhibition. The predictive 8 biomarker set is derived from prospective observational clinical trials, representing 229 treatments with Pembrolizumab, Atezolizumab, Durvalumab, in diverse indications: melanoma, non-small cell lung, urethral, hepatocellular, bladder, prostate cancer, head and neck, vulvar, colon, breast, bone, brain, lymphoma, larynx cancer, and cervix cancers. The 3D genomic 8 biomarker panel for response to immune checkpoint therapy achieved high accuracy up to 85%, sensitivity of 93% and specificity of 82%. This study demonstrates that a 3D genomic approach could be used to develop a predictive clinical assay for response to PD-(L)1 checkpoint inhibition in cancer patients.

Whole Genome 3D Blood Biopsy Profiling of Canine Cancers: Development and Validation of EpiSwitch Multi-Choice Array-Based Diagnostic Test

“…The EpiSwitch profiling, apart from delivering robust biomarker modality, also provides invaluable insight into high level integrated network regulation, as reflected in systemic readouts 48,62 . Similarly, to the analysis of the previous applications in human biology, identified network of 3D genomic canine biomarkers is directly linked to the genomic loci they modulate, providing insights into affected genes and pathways.…”

“…Custom microarrays were designed using the EpiSwitch pattern recognition algorithm, which operates on Bayesian-modelling and provides a probabilistic score that a region is involved in long-range chromatin interactions. The algorithm was used to annotate the CanFam 3.1 canine genome assembly across ∼1.1 million sites with the potential to form long-range chromosome conformations 48,62 . The most probable interactions were identified and filtered on probabilistic score and proximity to protein, long non-coding RNA, or microRNA coding sequences.…”

“…Emerging liquid biopsy and molecular testing platforms are addressing this unmet need 47 . Here, we report on the first evidence of a novel liquid biopsy biomarker modality focused on the changes in 3-dimensional genomic architecture (3D genomics) in peripheral blood cells – already utilized in DLBCL and other oncological applications in humans 19,48–51 – to establish the presence of the canine cancers described above, as well as to report on cancer indications in training. Exploration of higher-order genomic architecture has revealed that the 3D configuration of chromatin plays a critical role as an epigenetic regulator of gene expression in pathological and non-pathological phenotypes 52,53 .…”

“…The heart of the platform is the unification of high-throughput, high-resolution screening with the EpiSwitch Explorer microarray platform, machine learning algorithms, testing on independent validation cohorts, and a PCR-based format for stratifying biomarker signature 19,49,51,56–58 . This well-established phenomenon of CCSs being the multi-omics integrator and regulatory interface of the cell has been validated in the EpiSwitch platform in an extensive range of indications including detection of disease (pre-symptomatic and symptomatic), prognosis, and predictive response to treatment 19,48–51,56,59–65 . Two of the EpiSwitch blood-based biomarker applications are practiced today in US and UK as reimbursable clinical tests: a Checkpoint Inhibitor Response Test (CiRT) for prediction of treatment response in immuno-oncology 48 , and a prostate cancer screening test (PSE) 50 .…”

Omics and Multi-Omics Analysis for the Early Identification and Improved Outcome of Patients with Psoriatic Arthritis

“…In the case of PsA, it can assist with a definitive diagnosis and prognosis in the context of comorbidities and overlapping symptoms, without resorting to biopsy. This technique has already delivered biomarkers that predict the response to methotrexate treatment in RA patients [ 43 ], that predict the response to immune checkpoint inhibitors in cancer [ 44 ], and that are prognostic for severe outcomes of COVID-19 based on individual patient immune health profiling [ 45 ]. The markers profiled by EpiSwitch technology are governed by all forms of genetic and epigenetic variation, and their combined influence has a major impact on the regulation of gene expression by controlling access to chromatin.…”