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Next Generation

In December 2012, the Chinese Food and Drug Administration – the regulatory agency for the largest of all emerging markets – approved its first circulating tumour cells (CTC) diagnostic test (1). The approval, and the willingness to accept assessment and analysis of CTC, places China in a strong position to take part in the next generation of oncology development and treatment.

Although CTC testing first rose to prominence in the early 2000s, it has only entered the drug development mainstream in the past few years. Growing acceptance of the test as a useful tool culminated at the 2012 American Society of Clinical Oncology (ASCO) meeting with a section dedicated to CTCs. As interest has risen, the pipeline of CTC tests has expanded. For example, the CellSearch® breast cancer diagnostic has recently been approved in China, and other similar technologies are now looking to join the market.

Oncology in China

Companies are developing CTC methodology in response to industry demand for novel drug development approaches designed for the new era of targeted therapeutics in oncology (2). Advanced technologies now allow us to accurately diagnose disease, define its parameters and predict patient outcomes to specific treatments. Current and next-generation CTC tests can perform all these tasks with just a blood sample, giving researchers a non-invasive means by which to assess the status of a cancer patient. It has long been possible to interrogate and analyse cells from liquid tumours, and now with CTC testing the same capabilities are becoming available for solid tumours.

The arrival of CellSearch technology in China comes at a time when the country is experiencing a rising incidence of oncological diseases. Cancer has been the leading cause of death in Beijing every year since 2007, when it displaced cardiovascular disease as the city’s biggest killer. The Beijing Cancer Prevention and Control Research Office has compiled data which indicates that, by 2020, three million people will die of cancer in China every year, up from 2.5 million today (3). If the biopharmaceutical industry is to help reduce the number of cancer-related deaths, clinical trial evolution and in-depth understanding of the genetic factors involved in cancer development in China are needed. The use of CTC technology could become a major factor to help in both of these areas.

Tracking Drug Efficacy

CTC tests such as CellSearch offer an early, strong indicator of whether a drug is effective. The tests work by analysing cancer cells that have separated from a solid tumour site and are circulating in the bloodstream. These cells are responsible for the metastases that eventually result in the deaths of many cancer patients. If the number of such cells falls after the administration of a drug, it is a sign that the treatment is working. CTC count has been shown to correlate with patient survival – at least as well as serial radiographic assessment – and is more reproducible than radiologic evaluation. The higher the CTC count, the less optimistic the prognosis. Having access to an accurate, non-invasive method for assessing a drug’s efficacy throughout a trial can provide information that helps improve the treatment. For example, a stubbornly high CTC count could indicate a drug’s ineffectiveness or that larger/more frequent doses of the drug are needed.

Once a trial ends, CTC testing takes on new functions. If the treatment has been successful and patients have fewer CTCs, continual monitoring of these cells may give insights into the longer-term prognosis or the effectiveness of a maintenance therapy. Such information is particularly valuable given payers’ new focus on longer-term health outcomes data.

CTC Take-Up

These capabilities have seen CTC tests incorporated into a growing number of clinical trial protocols, but the lack of local testing facilities in much of the world could limit utilisation of the technology. Without local capacity, clinical trial investigators face having to export samples for CTC testing. This means navigating local export laws, adding to the logistical complexity and timeline of a trial. Countries will need to add testing capabilities to stay at the forefront of cancer research, particularly as CTC testing becomes more embedded into novel oncology drug development and cancer treatment.

Efforts to establish the role of CTC tests in clinical trials in the US are under way. CTC enumeration is yet to be approved as a surrogate endpoint in cancer clinical trials – a fact many in the industry would like to see change. As it stands now, indications such as prostate cancer use overall survival or progression free survival as endpoints. Trials designed around this must continue for a long period of time after the initial treatment ends in order to obtain this information and data. Having to run extremely long trials can delay the drug approval process and its availability for clinical treatment, while adding significantly to the cost of the study.

Having CTC enumeration as the endpoint may result in a trial ending sooner, cutting costs and time to market. Efforts in this area are ongoing. Janssen Diagnostics has sent data on the use of CTCs as an efficacy response biomarker for castration-resistant prostate cancer to the US Food and Drug Administration (FDA) (4). Johnson & Johnson (J&J) recorded CTC counts in its Phase 3 trial of the prostate cancer drug Zytiga. The data showed CTC numbers are predictive of favourable and unfavourable overall survivals, prompting J&J subsidiary Janssen Diagnostics to submit the information to the FDA to demonstrate that this biomarker is accurate and reliable.

The submission is part of the oncology biomarker qualification initiative set up by the FDA and other agencies. Data from this trial forms one quarter of the Phase 3 CTC data requested by the FDA. Janssen Diagnostics has completed the other three trials and is now preparing to submit the final data. If successful, CTC enumeration may be accepted as a surrogate endpoint in future clinical trials for evaluating castration-resistant prostate cancer drugs.

Facilitating Personalised Medicine

While CTC enumeration is undoubtedly a very useful tool for cancer research and treatment, it falls short of realising the full potential of such testing. A CTC count is a simple way of analysing CTC numbers in the blood sample of a cancer patient. More advanced analyses can assess genetic information, critical growth pathways or receptor expression contained in and on the CTCs. Such characterisation of CTCs could show that a patient’s tumour is positive for a specific gene mutation and, in the era of more targeted, personalised medicines, this can shape and/or predict effectiveness of drug treatment regimes.

If an experimental drug is effective by targeting a certain activated pathway, or works by interfering with a surface receptor such as HER2, patients with cancers that have these characteristics can be identified in clinical trials. In this regard, CTC testing could be used to help stratify patient populations and identify potential clinical trial participants who meet very specific inclusion criteria. Then, if a drug reaches the market, the CTC test has the potential to become a companion diagnostic and used to identify which patients might benefit from the treatment. In addition, the sensitivity of advanced CTC testing may result in early cancer detection, increasing the likelihood that the treatment will be effective.

CTC testing can provide clinicians with all this information about a patient’s tumour without the need to perform a biopsy. For solid tumour therapy, CTC technology has tremendous potential as a non-invasive tool for patient selection and designing effective drug treatment protocols.

Such stratification of patients can increase the likelihood of success for a novel therapeutic compound that is in development. It is about delivering the right drug to the right patient, as opposed to the onesize-fits-all approach taken in the past. Without CTC testing and other advanced scientific applications, this tailored approach is impossible, meaning its acceptance is reliant on the rollout of the technology around the world.

One month after regulatory approval of CTC testing, the LabCorp facility in Beijing became the first Chinese clinical reference laboratory to offer the service, giving study organisers a new way to measure drug efficacy and positioning the country to take part in the new era of oncology drug development. As the understanding and characterisation of CTCs advances, the tests could play a more central role in all solid tumour clinical trials. CTC technology aligns well with the new paradigm of targeted oncology drug development and can facilitate the shift towards a more advanced biological approach to therapeutic endpoints in China and worldwide.

Next-Generation Technology

CTC technology has progressed significantly over the past decade (2). Although CTCs were first identified in an autopsy back in 1869, applications for them in drug development and patient therapies came much later. Progress in this area accelerated after the first CTC in vitro diagnostic application was introduced in 2004. Towards the end of the last decade, researchers began to characterise CTCs at the ribonucleic acid and DNA levels, which then paved the way for the next generation of oncology tests and the utilisation of CTC testing.

The CellSearch research team is responsible for some of the latest innovations (2). In 2011, Veridex (now Janssen Diagnostics) began working with Massachusetts General Hospital on its next-generation CTC technology platform (5). The publication of a paper earlier this year details the focus of the collaboration and gives an idea of the near-term future of CTC testing (6).

Microfluidics is at the heart of this developmental CTC technology. The new system – called the CTC-iChip – is designed to ‘filter’ out CTCs from a cancer patient’s blood sample. When whole, unmanipulated blood enters the chip, the cellular components are sorted by size. This process sifts out red blood cells, platelets and other large blood components, leaving a mix of CTCs and white blood cells. In the next step, the chip filters out white blood cells using inertial focusing – a microscale hydrodynamic process.

Depending on testing application requirements, the next-generation technology can have two approaches: CTCs can be labelled with magnetic beads and isolated (positive selection), or the white blood cells can be tagged and removed from the mix (negative selection) to purify the CTC population. Each approach is expected to play a major role in the utility of next-generation CTC technology, with certain applications being better suited to one or the other.

Isolating all CTCs, regardless of phenotype, counters criticisms of current approaches that only identify and capture epithelial cell adhesion molecule (EpCAM) positive cells. The next-generation technology works to purify the CTC population and enables the interrogation of various types of CTCs that may be undergoing epithelial mesenchymal transition. Since the technology is no longer based on EpCAM selection exclusively, all non-epithelial-based cells will also be captured, enumerated and characterised, expanding our understanding of the various subtypes of CTCs associated with tumorigenesis.

Commercial Capabilities

It is important that CTCs retain their phenotype after going through processing, so researchers can gather as much information from them as possible. Early data suggests that isolated cells retain these biomarkers after passing through CTC-iChip (6). To verify this, studies were performed to compare CTCs obtained by the iChip to those captured using fine-needle aspiration – an approach for removing cells directly from the tumour. Breast cancer cells recovered by both procedures were shown to retain and equally express the receptors for oestrogen and progesterone, as well as sensitivity to those hormones. Likewise, another study demonstrated that prostate cancer cells obtained after CTC-iChip enrichment maintained the TMPRSS2-ERG gene fusion alteration. Both of these examples confirm that after processing on the Next-Gen-CTC-iChip, CTCs should retain the characteristic of the primary tumour, as well as the cellular integrity and stability required for additional advanced testing.

These capabilities, which were not possible a decade ago, are now nearing commercialisation. In the next few years, advances in CTC technology will allow physicians and drug developers to fully characterise a tumour in a cancer patient without using an invasive procedure. This, in turn, will help to determine patient treatment and open up opportunities for targeted oncology drug development with a more advanced biological approach to endpoints. For China and the rest of the world, the potential of CTC technology to improve cancer drug development and patient care is immeasurable.

References

1. Visit: www.cellsearchctc.com/news-events/cellsearch%C2%AE-liquid-biopsy-approved-china

2. Pennline K, Unger M and Izmailova E, Circulating tumor cells as a biomarker approach in oncology, White paper showcase presented at the DIA 49th Annual Meeting, June 2013

3. Visit: http://chinadigitaltimes.net/2013/04/cancer-beijingsbiggest-killer

4. Visit: www.cellsearchctc.com/significance-ctcs/ctc-clinical-studies

5. Visit: www.cellsearchctc.com/news-events/next-generationcirculating-tumor-cell-test-demonstrates-high-efficiencyand-accuracy

6. Ozkumur E, Shah AM, Ciciliano JC et al, Inertial focusing for tumor antigen-dependent and -independent sorting of rare circulating tumor cells, Sci Transl Med 5: p179, 3rd April 2013


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Ken Pennline, Vice President and Global Head of Cytometry Services for LabCorp Clinical Trials, received his PhD in Immunology from OhioStateUniversity in 1977. Previously, he has held positions as a faculty member in the Department of Pathology and Director of the Immune Monitoring Laboratory at Georgetown University, Washington, DC; as Senior Principal Scientist and Director of Core Flow Cytometry at Schering Plough, New Jersey; and as Global Director of Operations in Oncology/Cell Analysis for Esoterix Clinical Trials Services.

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