The proposal to CIRRP is a public/private partnership which will involve clinicians and academics from the Universities of Oxford and Birmingham, Imperial Healthcare NHS Trust, Norfolk and Norwich Universities NHS Trust, and OBD, to build on the successful translation to clinical practice of a proven predictive tool for response to immune checkpoint inhibitors (ICI) provided by OBD.

In the proposal to the UK government, a successful Cancer Immunotherapy Response Research platform (CIRRP) outcome will accurately predict a patient’s clinical response to current ICIs to inform clinical treatment decisions, focus on optimization of NHS resources, be applicable to and scalable across many cancers, be flexible and adapt to new ICIs, identify new immunological targets and treatment regimes, account for comorbidities and provide insights into mechanisms of response.

If the proposal is accepted, the consortium will:

1. Establish the CIRRP platform within an existing OBD ISO15189/UKAS accredited clinical laboratory to offer UK-based EpiSwitch CiRT and HiRT clinical screening on at least 350 patients - in prostate, colorectal, breast, ovarian and lung cancers, initially at the NHS trusts within the consortium, and then across NHS networks across the UK, using an established transparent cost per patient sample model.

2. Create real-world impact data within NHS clinical practice for prediction of ICI response and prognosis of Hyperprogressive disease (HPD). The initial focus will be NHS patients considered for or currently receiving anti-PD-1 or anti-PD-L1 ICI treatment for prostate, colorectal, breast, ovarian and lung cancers. Understanding the distinct Objective Response Rate to ICIs means precise understanding of rates of response/non-response to treatment, immune-related adverse events (irAEs) or HPD becomes critical.

3. Advance the understanding of genetic, metabolomic and epigenetic mechanisms behind clinical outcomes, acquired resistance and remission. The world-class expertise of the research team will be guided through the multiomic complexity of genomes by focusing on the functional genomic footprints of networks of 3D EpiSwitch biomarkers strongly associated with clinical outcomes of ICI treatments.

EpiSwitch? Checkpoint inhibitor Response Test (CiRT)

Cancer does not exist in isolation. The most successful approaches for treating cancer will need to consider the larger systemic picture, comprising a combination of the tumour, its interaction with its environment, the immune system, and a patient’s genome and epigenome.^[1,2] Most current predictive biomarker tests focus on specific genetic markers such as (i) tumour mutation burden (TMB), which measures the extent of DNA mutations in a tumour acting as a proxy for how readily an engaged immune system may recognize the tumour, or (ii) protein markers, such as expression of PD-L1 protein in the tumour, a direct target of ICI. These tests rely on retrieving a biopsy or resections from a tumour, but these tumour-based methods show limited success at predicting who will benefit from ICI treatment. A recent retrospective analysis that systematically evaluated all clinical trials leading to FDA approvals of ICIs from 2011 to 2019, found that the most studied marker, tumour PD-L1 expression, was predictive in only 24.4% of cases.^[1,2] Unfortunately, the data does not support either tool as a good predictor of response to ICI treatment, as ICIs reset the immune system of the host to fight the cancer and they do not directly target the tumour.

The EpiSwitch? CiRT is a first-of-its-kind blood test that accurately predicts an individual cancer patient's therapeutic response to immune checkpoint inhibitors (ICIs), providing unique benefits for physicians in treatment planning and navigating complex decisions.^[3,4] ICIs offer a real hope of durable disease control for some patients. Despite pre-screening with current standard tests such as tumor PD-L1 expression, these ICIs offer a long-term survival advantage to less than 1 in 4 patients, and many may become seriously ill and require hospital admission.

An important consideration is the high cost of treatment with an ICI. The anti-PD-1 and anti-PD-L1 therapies represent some of the most expensive therapies employed today. In order to allow equitable access by NHS patients to this technology, with the promise of a disease-free future, better prediction of responders, non-responders and informed clinical decision-making as to whether ICI treatments should be continued or ended will have a significant impact on costs and thus the number of patients who can be treated.

EpiSwitch Hyper-progressive Immune Response Test (HiRT)

Treatment with an ICI elicits a spectrum of side-effects and immune related adverse events, including a subgroup of patients with hyperprogressive disease (HPD). HPD patients demonstrate significantly reduced progression free survival (PFS<2mo) and overall survival (OS<5mo), with increased tumour growth rates and underlying molecular trends of genomic amplifications (MDM2, etc.) and lesion accumulation. A retrospective analysis of 24 studies and 3,109 patients revealed that the incidence of HPD varies from 5.9% to 43.1% across different cancers, with an average of 12%.^[5]

With a special award from the Partnership for Accelerating Cancer Treatment (PACT), Washington DC, OBD has developed the prognostic HiRT, demonstrating over 85% accuracy for the first 60 participants in the independent validation cohort. When combined with CiRT calls for response/non-response to ICI, it offers highly specific prospective identification of patients who are likely to 1) respond to ICI therapy and 2) accurately identify patients likely to exhibit an HPD response to ICI treatment, both extremely useful for clinical patient management and potentially leading to reduced costs, socioeconomic benefits and improved patient outcome.

Dr Alexandre Akoulitchev, CSO at OBD, said: "The EpiSwitch platform and its systemic biomarkers have already delivered the most accurate test, as of today, for predicting response to ICIs treatment – CiRT. The test has been adopted by a growing number of institutions and practicing clinicians, and patients in the USA and in private UK care have been benefiting from its accuracy for many months now.

"The other benefit our consortium is offering is the power of the EpiSwitch platform to capture the systemic aspects of cancer biology. With the guidance from our academic and clinical world-class experts, we can combine genetic, epigenetic and metabolic specifics of every patient. We can gain insights into predispositions to immune related adverse events (irAEs), side effects to immune oncology treatment. Their burden is significant and should not be overlooked. The CIRRP initiative is focused on the challenge that could propel the UK as a world leader in cancer treatment. We believe our consortium can help make it happen."

Professor E. Jane Mellor, Department of Biochemistry, University of Oxford, said: "It is a real privilege to be involved in this potentially transformative initiative, to work with visionary clinicians, entrepreneurs and basic scientists, and to see how this disruptive technology, which combines epigenetics and metabolomics, is being applied for the benefit of patients within the NHS."

References

[1] Hunter, E., et al. (2023). Development and validation of blood‐based predictive biomarkers for response to PD‐1/PD-L1 checkpoint inhibitors: evidence of a universal systemic core of 3D immunogenetic profiling across multiple oncological indications, Cancers 15(10), 2696. https://www.mdpi.com/2072-6694/15/10/2696

[2] Zhao, B.; Zhao, H.; Zhao, J. (2020). Efficacy of PD-1/PD-L1 blockade monotherapy in clinical trials, Therapeutic Advances in Medical Oncology, Vol. 12. https://doi.org/10.1177/1758835920937612

[3] Oxford BioDynamics Plc. (2022). EpiSwitch CiRT. https://www.mycirt.com

[4] Oxford BioDynamics Plc. (2023). Half-year report. HY results link

[5] Park, H. J.; Kim, K. W.; Won, S. E.; Yoon, S.; Chae, Y. K.; Tirumani, S. H.; Ramaiya, N. H. (2021). Definition, Incidence, and Challenges for Assessment of Hyperprogressive Disease during Cancer Treatment with Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis, JAMA Network Open, Vol. 4, No. 3. doi:10.1001/jamanetworkopen.2021.1136

For more information, please visit OBD’s website, www.oxfordbiodynamics.com, or follow the Company on Twitter (@OxBioDynamics) and LinkedIn.

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