Skip to main content

Liquid biopsies and Imaging for improved cancer care

Periodic Reporting for period 2 - LIMA (Liquid biopsies and Imaging for improved cancer care)

Reporting period: 2019-07-01 to 2020-12-31

Patients with advanced cancer are typically treated using a combination of methods. If possible, surgical removal is attempted first, followed by chemotherapy to eradicate any remaining disease. Each step increases the chances of patients to survive the disease, but also increases their risk of severe side effects that may result in poor quality of life or even death.
To strike an appropriate balance between cure and quality of life, it is important to know in advance which individual patients will respond to chemotherapy and who will not. Physicians therefore sometimes switch the order of treatments, performing chemotherapy first, and surgery second. This is called “neoadjuvant chemotherapy”. It allows the tumor to be monitored on medical images during the chemotherapy in order to intervene quickly if the medication is ineffective.
Unfortunately, current methods to measure tumor response have limited accuracy. This is caused in part because medical images cannot visualize microscopic disease and because not all parts of the tumor respond equally well to the same medication.
A consortium of hospitals and industry has joined forces in the LIMA project to tackle this problem. They will develop new methods to increase the chances of cure without compromising quality of life. To allow results to be translated to patients as soon as possible, the study has been designed to follow the current clinical routine of doctors as closely as possible.
In patients with breast cancer and rectal cancer, magnetic resonance imaging (MRI) will be employed to study the biology of the tumor before and during the treatment using state-of-the-art technology. MRI uses magnetic fields and radio waves to create very detailed pictures of the tumor, its functional behaviour and chemical composition. Secondly, blood samples of the same patients will be analysed before and during treatment to automatically look for microscopic tumor cells and their characteristics. Finally, all available information will be combined with clinical information using machine learning techniques to predict as soon as possible after the start of the treatment whether the treatment will eradicate all cancer.
As such the promise of LIMA is that more patients will get the right targeted drugs early on in their therapy, opening the route to more effective treatment.
During the first reporting period (M1-M18):
Focus was on setting up the workflows for liquid biopsy measurement (ct-DNA and CTCs) as well as setting up the MRI imaging protocols to be used in the two clinical trials which will be run for breast and rectal cancer, respectively. In addition, the protocols for both clinical trials have been drafted and submitted. Some of the key results achieved so far are:
- Panels of DNA mutations, enabling the monitoring of a general patient population for rectal and breast cancer patients, have been developed.
- The multiplexing capabilities of Stilla’s digital droplet PCR system has been increased twofold by the implementation of a 6-colour instrument. (See attached picture of the Naica system.)
- An automated cell-picking instrument for clinical use for picking specific cells from a patient blood draw has been made.

During the second reporting period (M19-M36):
Focus was on setting up the clinical trials for breast and rectal cancer. For this purpose IRB approval has been obtained as well as arranging all contracts required for data sharing during the duration of the LIMA project within the consortium and also through a public database after the LIMA project has ended. This took quite more time than originally anticipated as is described in more detail in this report. In summary clinical Trial progress was delayed by two factors: contract negotiations delayed the start of the clinical trials and COVID-19 brought patient recruitment down to zero in the first pandemic wave and was and still is relative small currently. A 6 month extension has been submitted to the EU to address the delay due to COVID-19 for both clinical trials. Official decision on the amendment is expect on March 12, 2021.
Some of the key results achieved so far are:
• IRB approvals for both clinical trials have been obtained and on 1 Jan. 2020 UMCU has started with recruiting the first breast cancer patient.
• Both Agena and Stilla have developed liquid biopsy mutation panels for breast and rectal cancer, which can be run on their systems (MassARRAY and Naica, respectively).
• On top of the originally planned objectives an additional breast cancer panel was developed by Agena based on methylation, since this was found to be needed to be able to track disease progression in the total breast cancer population, since with mutations only about 40 % of this population can be tracked.
• ALS has developed in the project a new product: their CellCelector Dx cell isolation system aimed at diagnostics application, which they are starting to market (they have already x interested consumers).
• Thus far a total of 5 patent applications and 3 scientific publications have been produced from this project, in addition to 3 presentations at a conference (2@CNAPS, 1@TRICON)

A set-back we discovered was:
• mRNA-based pathway analysis on isolated CTC does not seem possible with the envisioned approach. We had to abandon this idea and fall back to counting the CTC’s in the blood samples and isolating the CTCS so that DNA analysis can be done and mutation found compared with those found in ct-DNA.
LIMA will produce a comprehensive database of imaging and corresponding tissue and blood draw information from an unselected series of breast and rectal cancer patients before, during and after their treatment. This dataset will be important for future research in the medical sector, pharmacy, and education. LIMA is also expected to form a basis of new guidelines to standardize the interpretation of treatment response across the EU and worldwide. The current standard of tumor response criteria are based on the RECIST criteria or those from the World Health Organisation, both of which only address changes in the size of the tumor in response to therapy. Although they serve good general purpose, these standards are decades old and do not incorporate information from advanced imaging. Let alone their integration with synchronous information from tissue and blood draws. LIMA offers to interpret and combine this vast expanse of new information on the molecular properties of tumors in a consistent and reproducible manner. Due to this work, it is likely that patients will be diagnosed and treated differently and better across the EU and across the world, in the near future.

If successful, the project will have a considerable impact on the patients and the healthcare systems. E.g. the LIMA project provides the opportunity to both improve disease free and overall survival outcomes. Furthermore, it will result in reduced burden, less side effects for the patients, and increased cost-effectiveness of targeted therapies.

The project has already economic impact among the SME’s involved in the project:
• There is a relevant increase in the number of people employed.
• During the running of the project, Stilla completed their next funding round of 16 M€, enable further growth of the company.
• Furthermore ALS has developed its CellCelector Dx for diagnostic applications in the project and even: first of these systems already have been sold in the market.
CellCelector
Lima Logo
The Naica 6-color Crystal Digital PCR system developed in LIMA. Shown are the various elements.