Israel-based NovellusDx and IBBL entered into a collaboration to test and validate a novel platform that holds great promises for the diagnosis and personalised treatment of cancer patients. Dr. Gabi Tarcic, Vice President of R&D at NovellusDx, explains the hows and whys of the project and provides insight into the current challenges of personalised cancer care.
Interview by Federica Amato (FA).
FA: Innovative start-ups and SMEs such as NovellusDx are often the driving force behind breakthroughs in biomedical research and cancer care. Can you briefly present your company and its services?
GT: Indeed! Though a young company – it was founded in 2011 – I can confidently say that NovellusDx is one of the leading functional oncology companies. This means that we go beyond simply ‘reading’ the DNA sequence of cancer patients. We actually test the exact function of the mutations that are identified in the patient and analyse the response to given drugs. We therefore deliver evidence-based clinical insights that allow oncologists to treat every type of cancer and every patient with the most precise treatment, while also supporting pharmaceutical companies with the life cycle of their drugs.
FA: To put the importance of your work into context, can you give us some background information regarding the unmet need or research question that has prompted the project?
GT: In essence, the state-of-the-art in cancer diagnostics and treatment today is the sequencing of tumour biopsies through Next-Generation Sequencing (NGS) to understand the genetic characteristics of the tumour and consequently administer a specifically tailored treatment. However, the response rates to such targeted treatments and the progression-free survival (PFS) have remained essentially unvaried and relatively low. This is because the function and role of most mutations identified through NGS are often unknown and therefore the physician cannot factor them in when prescribing the treatment, leaving them untreated. For instance, some mutations of uncharacterised function (known as Variants of Unknown Significance – VUS) result in a large number of ‘resistance’ mechanisms in the tumours, which make them immune to the treatments. Moreover, even if the effect of a specific mutation might be known, the combined effect of two or more mutations is often disregarded when selecting the treatment course. That is why at NovellusDx we decided to test each and every mutation inside the cells and study how it reacts to drugs.
FA: That sounds enthralling. Could you explain what solution you propose and how it works?
GT: To address the challenges I described above, we have developed NovellusDx’s Functional Annotation for Cancer Treatment™, a novel, live‐cell based platform that functionally characterises mutations and their role in cancer, allowing us to recommend a tailored-made treatment. Conceptually, the solution is very simple. The patient gets his/her tumour sequenced and we receive the sequencing report. We then do a bit of ‘gene manipulation’, meaning that we reproduce (synthesise) the actual mutated genes, re-sequence them to ensure we have an exact match to what was found in the patient and then insert them into live cells. The cells then act as our live ‘test tubes’: they process the mutated genes which can then cause the cells to behave differently. Our microscopy system and machine learning methods detect these behavioural abnormalities, so that we can subsequently tell the physician what the result of each mutation is. In other words, we are able to describe the oncogenic activity of each of the patients’ individual mutations as well as their mechanism of action. We also repeat the same process in the presence of drugs so that we can analyse their effect on cell behaviour and report back to the physician which drug was the most effective.
FA: So, in a nutshell, by characterising the mutations in a given tumour, you are able to select the best treatment possible out of the spectrum of currently available therapies.
GT: That is exactly right.
FA: Can you tell us more about the project that you conducted with IBBL’s support?
GT: We launched the project with the aim of testing the NovellusDx platform and demonstrating the significant added‐value it brings to NGS-based diagnostics. No matter how innovative and revolutionary, every novel product needs to be supported by a solid validation process. Specifically, we sought to provide evidence for the ability of the platform to accurately confirm the mutations found by traditional NGS diagnostic tools, functionally characterise unknown mutations (VUS) and elucidate their mechanism of action.
FA: How was the project set up and how did the collaboration with IBBL take place?
GT: The key steps of the project were to obtain and process tumour samples, sequence them and test the identified mutations for oncogenic activity. Concretely speaking, we wanted to test our platform on lung and colon cancer specimens, which is where IBBL came in. Indeed, IBBL specialists identified the relevant frozen tissue samples of the cancer types of interest. These samples – 80 in total – were then sent to us for analysis, together with the relevant associated clinical data. However, IBBL’s role was not simply limited to supplying us with the biospecimens. In fact, during the process of analysis, IBBL’s scientific team provided continuous information and help as required, to ensure the successful completion of the project. I would say that IBBL acted both as a sample supplier and as an ‘adviser’, sharing with us their knowledge regarding the clinical, regulatory and scientific aspects within ‘precision’ oncology.
FA: That sounds like a winning partnership! Is there anything that you particularly appreciated in IBBL’s work?
GT: We found IBBL to be a professional but also ‘friendly’ partner. The team played an important part from the very beginning, bringing their insight and contributions to feed our discussions. They represented the EU view of patient care and brought considerable valuable knowledge to trial design. I am happy to say that many members of the team even became good friends of ours during the process! Last but not least, we were particularly satisfied with the quality of the samples provided. Indeed, this is of paramount importance, especially for validation tests such as this one, since even small alterations in the biology of the tissues could skew the measurements of the oncogenic activity of the mutations. Basically, ‘precision’ oncology goes hand in hand with ‘precision’ biobanking and preanalytics!
FA: Could you sum up the main benefits of the platform?
GT: In essence, our platform provides a simple solution to optimise the treatment administered to a specific cancer patient. A ‘trial-and-error’ approach to therapy is not the way forward – patients do not have the time to undergo different treatment options, which can often also be unnecessarily painful, and the healthcare system does not have the financial resources to pay for ineffective treatments. That is why it is crucial to find the correct treatment for each patient from the very beginning. In addition, the benefits of the system include its scalability and processing capacity of thousands of patient samples at a competitive cost.
FA: Now that the effectiveness of the platform has been proven, what are the next steps?
GT: The solution is already integrated into clinical practice, but we are now working on our scale-up from 6,000 tests per year to 60,000 tests per year. We are also starting distribution in Japan and are partnering directly with the best hospitals in the US and EU.
FA: To sum up, NovellusDx is revolutionising the way cancers are treated, but the road towards a fully personalised cancer care is still long. What are some of the main challenges that remain to be addressed?
GT: Personalised cancer care is a very broad topic. At NovellusDx for instance, we are focusing only on targeted therapies, but even within our field there is so much more to do. Immunotherapy is certainly one of the biggest challenges in the industry. It has provided astonishing results but only to a small fraction of patients, so it is fundamental that we be able to say in advance which patients will respond to it and which ones will not. We currently have several projects in the pipeline investigating this question… but this will be a topic of discussion for another time!
FA: Thank you very much Dr. Tarcic for taking the time to answer my questions. We look forward to many more fruitful collaborations in the near future.
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 PFS: the length of time, during and after the treatment, during which a patient lives with the disease but it does not worsen.
 Preanalytics: the collection and handling steps of a sample (collection, transportation, processing) prior to its analysis.