Cancer research beyond personalized medicine

Rapid advances in genome sequencing and biomolecular technologies over the past decade have revolutionized many areas of medicine, especially cancer treatment. Cancer displays extreme diversity, having hundreds of types and subtypes, originating in different organs and cell types, and having a wide variety of underlying genetic or environmental causes.

To add to this complexity, each patient has a unique genetic makeup and clinical disposition that interacts in a complex way with the disease, its progression and treatment.

New genomic information is now starting to shed light on why some patients respond to certain treatments and not others. This has given rise to the field of personalized medicine, where these accumulated genomic and treatment data are used to tailor treatments more precisely to achieve better efficacy, fewer side effects and improved outcomes.

Researchers from Japan’s National Cancer Center Research Institute (NCCRI) in Tokyo are now taking this approach a step further, and seeking to understand how the evolution of cancer cells and the genomic and immunological microenvironment over time can be exploited to effectively treat the disease.

“Over the past six years, we’ve brought together some of the best cancer researchers and established one of the world’s most valuable biobanks of tissues, bloods, cells and mouse models accompanied by an unmatched depth of data,” says Hiroyuki Mano, who was appointed the director of the NCCRI in 2016.

“We now have for the first time the tools, data and samples to look at how tumours and their microenvironment change, and how this can differ significantly from the biomarkers and genomics obtained from a patient’s macro data, such as standard blood tests.”

Unique resources

The NCCRI’s biobank is exceptional not only in size but also in its range. Its collection of more than 28,000 surgical tissue samples and 100,000 blood profiles captures both a broad spectrum of cancer types and stages and the sequential evolution of individual cancers over time complemented by blood, DNA and patient data.

“Over the past five years, we have analysed more than 3,000 cases in detail with tumour biopsy samples taken before, during and after treatment,” says Mano. “By combining these samples with the full clinical history and local and peripheral blood results, we can glean unprecedented genomic, immunological and pharmacological insights into cancer treatment.”

The NCCRI, which works with the NCC Hospital and NCC Hospital East, receives a steady flow of samples and patient data through the hospitals. It has conducted more than 1,000 clinical trials in the fiscal year of 2022, 133 of which are first-in-human trials of new drugs and treatments. The institute also hosts a unique mouse facility for pre-human trials — a collection of more than 600 patient-derived xenograft (PDX) mice that have been grafted with tumour cells from human patients.

“Our PDX collection is probably the largest in the world for a single institute, and it is also unique in that each PDX has a full health record and clinical history from the source patient,” says Mano. “Conventional isolated cancer cells lines have very low clinical accuracy for testing new drugs, as low as 5%, while PDX mice generally achieve 50% to 80% accuracy. Our PDX collection is thus a powerful resource for pharmaceutical companies to trial new therapies efficiently.”

New cell analytics

One of the most challenging aspects of cancer research is understanding the state of the tumour and the body’s response at any given time. Armed with such information, it is possible to adjust therapies and boost or suppress different immunological and biomolecular processes to target transient weaknesses in the tumour’s defences. Until now, however, only partial or macro-level information has been obtainable.

Hiroyoshi Nishikawa, chief of cancer immunology at NCCRI, and one of the global leaders Mano has brought to the centre, has developed a ground-breaking technique that makes it possible to isolate individual immune cells from minute tissue samples taken by needle biopsy¹.

“Using this new solubilized single-cell technique, we can construct a complete immune and genomic profile of a tumour, its local micro-environment, in normal tissue and in peripheral blood to get a complete picture of genetic alterations and changes in immune status over time,” says Nishikawa. “Another of our strengths is in the close collaboration of our team of immunologists and genomicists, who work together on a range of analyses to understand immunological pathways.”

This approach is revealing some of the previously hidden mechanisms behind the efficacy or inefficacy of certain immunotherapies. For example, this method has identified a biomarker for predicting the efficacy for a treatment known as PD-1/PD-L1 blockade², and it also revealed the molecular basis for hyper-progressive disease, which is sometimes observed on PD-1/PD-L1 blockade treatment. In liver metastases, where hyper-progressive disease is often observed, the resistance to PD-1/PD-L1 blockade was attributed to a novel mechanism of the PD-1 protein expression by immune-suppressive cells³.

“Combined with our immuno-genomic analysis platform, this new approach will change many areas of the life sciences,” says Nishikawa.

This platform, which also assimilates patient data from 13 other cancer hospitals in Japan and the broader hospital network, has enabled the world’s first ‘Immuno-Genome Atlas’ of cancer, which will subcategorize tumours based on the microenvironment to support improvements in cancer treatment globally.

Brilliant young scientists

“We now have this new and fast technique to see how treatment changes immune cells and tumour cells, which is an incredible tool for trials of new drugs and immunotherapies,” says Mano. “We have a remarkable team of brilliant young scientists, the leaders in their fields across immuno-oncology, RNA splicing anomalies, brain tumours, clonal evolution of non-cancerous cells, haematological malignancies and bioinformatics, and we’re ready to collaborate.”

Mano believes that over the next decade it will become possible to prevent cancer in a highly predictive way based on accumulated knowledge of the Atlas project and factors such as epigenetic changes to gene expression, the microbiome, and deeper genomic links, brought together with computational methods and artificial intelligence — an area that Mano is turning his attention to.

“I’d like to see the NCCRI become a global hub not just for cancer drug development but also for cancer prevention — the next important frontier in cancer research,” he says.