J. Irlam and C.M.L. West

Translational Radiobiology Group, Division of Cancer Sciences, University of Manchester, Manchester Academic Health Science Centre, Christie Hospital NHS Foundation Trust, Manchester.

 

There can be a stigma to translating research into products and profit in academia. The prospect of commercialisation makes many of us uncomfortable. While industry partnerships are acceptable, our community has a poor track record of innovation via commercialising radiobiology research. When academics do spin-out companies, it can be perceived as driven by financial rather than patient benefit. However, it might be that failure to embrace commercialisation has hampered progress in translating research findings into the clinic.

Our research interest is in developing biomarkers to personalise radiotherapy. We develop and validate genomic signatures that assess tumour hypoxia [1]. The radiobiology community has explored approaches for measuring hypoxia since the 1960s. We know tumour hypoxia is an adverse prognostic factor but, despite years of research, there is no diagnostic test for assessing hypoxia in clinical use. To paraphrase Jens Overgaard [2], hypoxia biomarkers are “adored and ignored”. Research continues to develop and explore new ways of measuring hypoxia. There is a plethora of new biomarkers but failure to progress clinically is underpinned by false discovery (inadequate validation), poor assay performance (reproducibility, sensitivity, specificity) and no consideration of how a biomarker/test would be implemented clinically. As funders prioritise biomarker discovery over assay validation and technical delivery, we need to rethink strategies for clinical impact.

The global cancer biomarker market is forecast to reach ~$29.9B in 2026 [3]. Genomic technologies represent 30.8% of the market. Exemplars of RNA based signatures for oncology are the Oncotype DX® 21-gene and MammaPrint® 70-gene classifiers. Oncotype DX® predicts response to neo-adjuvant chemotherapy in ER-positive breast cancer patients and was developed by Genomic Health® as a diagnostic test run on a qPCR platform. The test is moving to a next generation sequencing (NGS) platform, which has the advantage of high throughput with sample multiplexing. The U.S. Food and Drug Administration (FDA) recently released guidelines for the design, development, and validation of NGS tests and approved several [4]. The MammaPrint® test produced by Agendia uses microarray technology to identify breast cancer patients with a high risk of recurrence. Both tests give binary results and are in widespread use, which was facilitated by commercialisation and investment into test delivery.

In an attempt to follow the examples from the breast oncology field, we are exploring commercialisation as a route to clinical implementation of RNA based hypoxia signatures. While recognising the importance of commercial innovation as a key step in the road to deliver benefit to patients, the route was unclear. Our work was motivated by the need to provide workflows for (1) future biomarker driven trials for the radiotherapy community, and (2) the clinical delivery of hypoxia signatures in routine care.

Mimicking Oncotype Dx we initially developed and validated a qPCR platform for measuring our head and neck signature [5, 6]. The platform was used in the UK NIMRAD trial that teststhe utility of the signature to select head and neck cancer patients for treatment with nimorazole [7]. After two years of exploring how to make our signatures available clinically, we spun out ManTRa Diagnostics in August 2021. We identified two approaches for test delivery that are not mutually exclusive. Both focus on using NGS, which we now consider will allow for widespread use and flexibility for adding new signatures. An NGS platform can measure multiple tumour-type specific hypoxia-associated signatures in a single test. The platform is also amenable to multiplexing with other classifiers, e.g., one that measures radiosensitivity.

Our first approach involves an international molecular diagnostics group, which integrates genomic technologies and services for precision medicine. The group works in partnership with global leaders in DNA technology to advance diagnostic science. The company is a full life-cycle partner for preclinical, clinical, and post-market development of new products and services. The company has a partnership programme for diagnostic development from launching a CE-marked in vitro diagnostic (CE-IVD) to obtaining FDA approval. This approach involves the partner company doing the work with ManTRa Diagnostics front- and back-ending delivery and with the expertise and drive the service needs of the radiotherapy community. While the partnering company has all the expertise to develop our signatures as a CE-IVD using NGS technology and to progress to regulatory approval, we now need to validate the utility of measuring our signatures using the platform in patients.

Our second approach involves a collaborative opportunity to work on a development project within the North West Genomics Hub. NHS England provides a genomic testing service delivered through a network of seven Genomic Laboratory Hubs (GLHs) that coordinate services at a regional level. The 100,000 Genomes Project aimed to develop the tools and expertise needed to take advantage of a revolution in genetic testing. Genomics England was announced at the NHS 65th anniversary celebrations in July 2013; it established the approach for future care. There are four key principals: extend current diagnostic scope of genomic testing, recruit from routine care, consent to share de- identified data for R&D & industry use and establish a model for transformational change. Our collaboration explores pioneering the translation of RNA based signatures using NGS technology. The novelty of a targeted RNA panel means that current work needs to develop optimal strategies to select endogenous controls, and for normalisation and assay verification.

Platform migration, validation and verification for clinical delivery is challenging. The work required is meticulous and demands scientific rigour as well as a flair for engagement. Connecting with the right development teams within the NHS takes time, negotiation, and patience. Incentives are needed on both sides to promote this drive route to the patient. Platforms developed within the academic laboratory may no-longer fit the demands of the clinical laboratories delivering tests. Collaboration across stakeholders to drive these routes forward require contractual agreements; material transfer, Non-disclosure agreements, these negotiations can take months and years to agree and are often the reason promising collaborations fail to progress. There is no established route to take translational academic science from the laboratory to the clinic for patient benefit. A disconnect exists between the academic, commercial, and clinical worlds that requires careful navigation and benefits from a combination of good science, good personal networks, tenacity, luck and a maverick nature.

Collaboration across multiple stakeholders should ensure that any test is seamlessly embedded within the NHS for delivery for radiotherapy patient benefit via the local Academic Health Science Network (AHSN). The AHSN was established in England to deliver a step-change in the way the NHS identifies, develops and adopts new technologies and are based on partnership working and collaboration between the NHS, academia, the private sector and other external partners. ManTRa Diagnostics will work with a partnering company to deliver a fee for service research use only laboratory derived test to ISO 15189 appropriate for use in clinical trials that will move through the development pipeline to full CE-IVD, extending into kit manufacture and sales.

Our relationships highlight the potential for separate enterprises to work collaboratively for the sole purpose of improving patient outcomes. Commercialisation helps to remove the disconnect that prevents biomarker research from reaching its full potential. Our collaborations as a new small medium enterprise (SME) trail-blaze the way for future translational science projects to engage to achieve a shared goal. Spinning out also means intellectual property (IP) was identified, which should attract investors to fund the work needed for exploitation. SME engagement opens the potential for knowledge sharing and working with commercial partners outside and within the NHS clinical delivery sphere.

Pharmaceutical companies increasingly recognise biomarker development as being key to the future of precision oncology. Collaboration with pharmaceutical companies would help drive this development forward whilst bridging the translational gap. Although knowledge/data sharing can be delayed due to contractual negotiations and legal teams finding agreements over IP, it is sample acquisition that is the most challenging / frustrating hurdle when collaborating with large commercial companies. Engagement as an SME should facilitate this route as the terms of engagement are similar, i.e., driven by both patient benefit and revenue generating.

Molecular classifiers are starting to aid disease classification. The radiotherapy community has a long track record of embracing biomarker discovery but a seemingly low interest in translating the research into patient benefit. Our experience informed us what is needed to spin out an SME for biomarker delivery in clinical trials and via the NHS. We learnt how to connect with others blend the skills needed for future bullet proofing and knowledge sharing across this diverse and rapidly evolving era of genomics. We hope to be an exemplar for real life innovation in action for radiobiology and trail blaze the need to spin out or lose out.

 

Acknowledgement

The authors are supported by the NIHR Manchester Biomedical Research Centre.

 

Conflict of interest

The authors are managing directors of ManTRa Diagnostics.

 

 

 

 

 

References

  1. Yang L and West CM. Hypoxia gene expression signatures as predictive biomarkers for personalising radiotherapy. Br J Radiol 2019; 92: 20180036.
  2. Overgaard J. Hypoxic radiosensitization: adored and ignored. J Clin Oncol 2007; 25: 4066-74.
  3. [cited 2021 30th November 2021]; https://www.acumenresearchandconsulting.com/cancer-biomarkers-market].
  4. Zhong Y, Xu F, Wu J, Schubert J and Li MM. Application of Next Generation Sequencing in Laboratory Medicine. Ann Lab Med 2021; 41: 25-43.
  5. Eustace A, Mani N, Span PN, Irlam JJ, Taylor J, Betts GN, Denley H, Miller CJ, Homer JJ, Rojas AM, Hoskin PJ, Buffa FM, Harris AL, Kaanders JH, and West CM. A 26-gene hypoxia signature predicts benefit from hypoxia-modifying therapy in laryngeal cancer but not bladder cancer. Clin Cancer Res 2013; 19: 4879-88.
  6. Betts GN, Eustace A, Patiar S, Valentine HR, Irlam J, Ramachandran A, Merve A, Homer JJ, Moller-Levet C, Buffa FM, Hall G, Miller CJ, Harris AL, and West CM. Prospective technical validation and assessment of intra-tumour heterogeneity of a low density array hypoxia gene profile in head and neck squamous cell carcinoma. Eur J Cancer 2013; 49: 156-65.
  7. Thomson D, Yang H, Baines H, Miles E, Bolton S, West C, and Slevin N. NIMRAD – a phase III trial to investigate the use of nimorazole hypoxia modification with intensity-modulated radiotherapy in head and neck cancer. Clin Oncol (R Coll Radiol) 2014; 26: 344-7.