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Leveraging on Technology for Tomorrow’s Cancer Treatment

think-09-08-Leveraging on Technology for Tomorrow's Cancer Treatment-Featured Image

Cancer is a common disease affecting mankind and remains a significant cause of death, especially in many developed countries. Besides inflicting immense pain and suffering to patients, it also poses a huge economic burden to societies, necessitating a relook at how to fight this disease burden on many fronts. In 2020, the incidence of cancer is estimated to be approximately 19.3 million/100,000 years, and this figure is projected to increase by 47% in the year 2040.1

 

Cancer research is key to mitigating the sufferings caused by cancer and also to providing potential cures for some patients. Several advances have been accomplished to that end, especially with the developments of cancer immunotherapy strategy which have galvanised its re as the fourth pillar of cancer treatment (beyond surgery, radiation and chemotherapy). At the same time, technological advances have enabled clinicians to dive deep into cancer cell biology at the single cell level, and deepened our understanding of the cancer cell, cancer microenvironment, and cancer-host interactions.

 

In this article, I hope to provide a personal perspective on some of these developments which may impact the cancer treatment paradigm and its delivery of care to patients.

 

CANCER IMMUNOTHERAPY

The human immune system is a complex, highly interconnected system that is capable of detecting transformed cells, such as mutations or genetic changes in the cell. Once engaged, these transformed cells are quickly eradicated by highly trained killer cells such as Natural Killer cells and cytolytic T cells from the innate and adaptive immune cells respectively. This early engagement of the host immunity is paramount to curbing further transformation of cancer clones, thereby preventing the eventual development of cancer.

 

Unfortunately, transformed cells can acquire mechanisms to evade the host immune system. For examples, cancer may masquerade as normal or ‘self’ tissues to escape immune detection and destruction; or secrete or acquire receptors to inactivate activating signals that ‘turn on’ the anti- tumour immunity. In 2018, Dr James P. Allison and Dr Tasuku Honjo were awarded the Nobel Prize for their discovery of checkpoint receptors (CBRs) of CTLA-4 and the PD-1 molecule respectively. These CBRs elucidate the mechanism whereby cancer cells render cytolytic T cells exhausted or ineffective to kill cancerous cells. With these discoveries, anti-CTL4 and anti-PD1 antibodies have been developed and are currently approved to treat a wide variety of cancers.

 

Another means of cancer immunotherapy is to arm T cells and Natural Killer cells to effect cancer killing. These killer cells can be isolated from the blood of patients and reactivated in a specialised laboratory before they are re-infused to treat cancer. This form of adoptive cell therapy (ACT) has proven to be useful in some cancers, and more recently, T cells can even be harvested and isolated from the tumour tissue itself, termed tumour infiltrating lymphocytes (TILs). Several possible advantages of TILs over blood-derived T cells are that, firstly, these TILs have acquired memory (termed memory T cells) against the tumour and are potentially better killer cells, and secondly, TILs may have overcome some of the inhibitory signals preventing T cells from homing to the tumour, compared to the blood-derived T cells. Beyond these options, genetically modified T cells, termed chimer antigen T cells or CAR T cells, have also been shown to induce durable complete responses in patients with blood cancers. The development of ACT, including CAR T cells in solid cancers is currently undergoing intense research.

Vaccine-based immunotherapy from novel nanoparticle systems

Researchers at the Texas Center for Cancer Nanomedicine are creating particle-based vaccines for cancer therapy. The particles carry molecules that stimulate immune cells and cancer antigens (proteins) that direct the immune response. This scanning electron microscope image shows dendritic cells, pseudo-coloured in green, interacting with T cells, pseudo-coloured in pink. The dendritic cells internalise the particles, process the antigens, and present peptides to T cells to direct immune responses. Photo: National Cancer Institute

CANCER PREVENTION VIA SCREENING AND VACCINATION

Worldwide, approximately 15% of all cancers are related to viruses, with examples such as the Epstein-Barr Virus (EBV), human papillomavirus (HPV), Hepatitis B virus (HBV) and Hepatitis C virus (HCV).2 In theory, some of these cancers may be preventable through vaccination. As a proof of concept, the adoption of pre-adolescent HPV vaccination programmes among females has resulted in a dramatic reduction of HPV- related cervical cancers3. This pre-exposure protection against cancer-causing strains of HPVs has also reduced the incidence of genital warts and pre-cancerous lesions of the genital tract4. Comparatively, there is currently no vaccination against the EBV which is another important cause of nasopharyngeal cancer (NPC), lymphoepithelial cancer and some gastric cancers.

 

 

Beyond prevention of cancers through vaccination, virally associated cancers can be monitored or screened for early cancer development or relapse through detection of viral genetic fragments in plasma, termed liquid biopsy. This technology is epitomised by highly sensitive assays that are capable of detecting minute fragments of circulating EBV in plasma. These assays are currently being utilised in both screening and surveillance of EBV-driven NPC5 with the overarching goal being to detect early cancer before they cause symptoms. This early detection of cancer will lead to timely treatments so as to improve clinical outcomes. Furthermore, these liquid biopsy assays have been shown to precede clinically detectable cancer, and further developments are in progress to further increase the sensitivity of these assays.

Three-dimensional landscape of genome

HIPMap (high-throughput imaging position mapping) accurately determines the position of a gene in the three-dimensional (3D) space of the cell nucleus. In this illustration, images of genes (red, green, and blue spots within the nuclei of HeLa cells) are artificially superimposed on images of multi-well plates. Photo: National Cancer Institute

DEEPER INSIGHTS INTO THE CANCER CELL

Technologies have also enabled researchers to understand the cancer cell at single cell resolution and to interrogate interactions or interplay between various components of the cancer microenvironment (such as immune, cancer and stromal cells). Over the past decade, remarkable advances have enabled researchers to dive deeper into the cancer microenvironment. Previously, when researchers see an abundance of lymphocytes surrounding the tumour on pathology slides, they are uncertain about the roles of these lymphocytes. Are these lymphocytes attempting to kill the cancer cells, or are these cells by- standers or even contributing to the cancer development in the environment? With improved technologies, various types of lymphocytes have been characterised based on their function(s), and they can even be spatially identified in relation to other cells such as tumour or stromal cells so as to identify their interactions with these other cells in the cancer microenvironment. Similarly, high throughput assays can generate large datasets using genomics (genes), proteomics (proteins) and RNAs (ribonucleic acids) of cancers and have seen tremendous growth and capability. Using these sequencing platforms can generate large amounts of data about the cancer and can be used to correlate with relevant clinical parameters or outcomes.

DNA fragmentation

A dye marker on agarose gel used to separate DNA by a scientist. The smaller fragments move faster, the larger ones move slower. This separation process is used to analyse the size of DNA fragments, to map DNA, to separate fragments of DNA to create clones. Photo: National Cancer Institute

DIGITAL HEALTH / ARTIFICIAL INTELLIGENCE

With these huge databases derived from the sequencing platforms, there need to be accompanying technologies to integrate them with the aim of providing holistic care to cancer patients. To this end, Artificial Intelligence (AI) expertise will come in handy to help clinicians make sense of these large data. The AI specialist will require a highly curated database (with the relevant patients’ characteristics and outcomes) in order to generate an algorithm. Once this is accomplished, subsequent datasets may be used as a validation cohort to assess the reliability of this algorithm according to the cancer type. This work is exciting, as the value of AI in healthcare has been shown to be equivalent or superior to diagnosing various conditions using pattern recognition of radiological and pathological images of various disease conditions. Pushing the AI frontiers towards curating these huge datasets will be helpful in integrating these data and provide actionable information towards cancer care management and delivery.

 

Presently, clinical practice has transited to the digital age, with clinical notes, radiology and pathology images being made available on digital format. These innovations can complement clinical cancer data to provide a wealth of data to track cancer patients’ progress throughout their treatment. Similarly, AI platforms can help to curate these datasets to assist clinicians with identifying any potential cancer ‘phenotypes’ that are more resistant or susceptible to cancer treatment. Additionally, this information can guide population health, the prioritisation of healthcare resources and aid in personalising the care of cancer patients.

DNA genotyping and sequencing

A bioinformatician analyses DNA integration data from human papillomavirus (HPV) at the Cancer Genomics Research Laboratory. Storing, analysing, integrating and visualising large amounts of biological data and related information, as well as providing access to it, from the focus of bioinformatics. Photo: National Cancer Institute

PRECISION CANCER SURGERY

Surgery remains a cornerstone of cancer treatment. The advantage of surgical treatment is that the entire resected surgical sample can be used to provide deeper insights into the cancer biology. Rather than having a small cancer biopsy, the entire surgical sample can be interrogated to identify adverse pathological features that are not available on a single tumour biopsy, and provide a comprehensive overview of the tumour.

 

One of the challenges of cancer surgery is ensuring that the entire cancer is removed with a rim of ‘normal’ tissue, termed a surgical margin. Patients with a positive surgical margin (defined by presence of cancerous cells at the resected margin) have a significantly higher risk of cancer relapse. Therefore, surgeons have traditionally relied on frozen section pathology reports to determine and confirm adequate cancer resection. Optical biopsy is a field which utilises various biophysical properties of tissues as an adjunct to determine the properties of the tissue. These differences can be correlated with the actual histology diagnoses and provide real time tissue analyses. For example, Raman spectroscopy is an optical technical tool which relies on the differential scattering properties of light by tissues which can be captured and analysed in real time. These differential scattering properties, termed Raman signatures, can be correlated to the tissue composition of proteins, amino acids and/or lipids. Our research experience (in collaboration with NUS) has validated the use of Raman spectroscopy as an adjunct to analyse cancer margins in head and neck cancers. This area of optic tissue biopsy is emerging, with many other tools being developed to assist precision surgery for cancer with the ultimate goals of minimising positive surgical margins and ‘over-resection’ that may affect the functional outcomes of cancer patients receiving surgery for treatment.

Breast cancer advancements

From nanotechnology to improved tests, researchers have made amazing breakthroughs in diagnosing and treating breast cancer in the past decade. These include HER2-directed therapies, gene expression testing, hormonal therapy, less invasive surgery, and healthy lifestyle choices aimed at prevention. Photo: Dreamstime

CHALLENGES AND ADOPTION

Despite these current and emerging technological advances, translating novel technologies to be integrated into cancer care need to follow a systematic process. Beyond the presence of robust scientific rationale and validity, implementation of these strategies requires a concerted effort involving many stakeholders such as patients, clinicians, researchers, cancer centres, pharmaceutical companies, and ethical and regulatory boards. Behavioural modifications of both clinicians and patients are also necessary to embrace adoption of new technologies into healthcare practice. A cost-benefit analysis is fundamental to providing value-based healthcare reforms across all societies.

 

SUMMARY

Technological advances have emerged through rigorous research and have shown much promise in enhancing cancer healthcare. Continual warfare against cancer is still greatly needed because cancers do develop resistance with repeated treatments and newer trends of cancer will inevitably develop over time. Regardless, the age-old wisdom of the great physician Sir William Osler is still very much relevant today: “The good physician treats the disease; the great physician treats the patient who has the disease.” Empathy, compassion and love are fundamental qualities of a great physician, who recognises that managing the cancer patient’s fears and emotions are equally, if not more, important than what these technological advances can provide.

DR LIM CHWEE MING

Dr Lim Chwee Ming graduated from the Faculty of Medicine at the National University of Singapore and subsequently underwent residency in Otolaryngology in Singapore. He decided to pursue head and neck surgery as his subspeciality and was awarded the Ministry of Health Overseas Training award to undergo Head and Neck Oncologic Fellowship at the University of Pittsburgh Medical Center in the United States of America. Presently, he is a surgeon scientist funded by the National Medical Research Council, Singapore, to translate novel cellular immunotherapies in head and neck cancer. He is practising in the Department of Otolaryngology – Head and Neck Surgery at the Singapore General Hospital. On the research front, he leads a team at the translational head and neck cancer immunotherapy lab at Academia (SGH) and is Director of the Department of Clinical Translational Research. He is an Associate Professor with the Duke-NUS Medical School.

DECEMBER 2021 | ISSUE 9

Tomorrow's Technology Today

  1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4. PMID: 33538338.

  2. Zapatka, M., Borozan, I., Brewer, D.S. et al. The landscape of viral associations in human cancers. Nat Genet 52, 320–330 (2020). https://doi.org/10.1038/s41588-019-0558-9

  3. Jiayao Lei, A Ploner, M Elfstrom, et al. HPV vaccination and the risk of invasive cervical cancer. New Eng Journal of Medicine 2020, 383,1340-8.

  4. M Falcaro, A Castanon, B Ndlela, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepiithelisal neoplasia incidence : a register-based observational study. The Lancet Nov 2021, doi 10.1016.

  5. Tan R, Phua SKA, Soong YL, Oon LLE, Chan KS, Lucky SS, Mong J, Tan MH, Lim CM. Clinical utility of Epstein-Barr virus DNA and other liquid biopsy markers in nasopharyngeal carcinoma. Cancer Commun (London). 2020 Nov;40(11):564-585. doi: 10.1002/cac2.12100. Epub 2020 Sep 28. PMID: 32989921; PMCID: PMC7668470.

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Leaders and changemakers of today face unique and complex challenges. The HEAD Foundation Digest features insights and opinions from those in the know addressing a wide range of pertinent issues that factor in a society’s development. 

Informed opinions can inspire healthy discussions and open up our imagination to new possibilities. Interested in contributing? Write to us at info@headfoundation

Stay updated on our latest announcements on events and publications

About

Leaders and changemakers of today face unique and complex challenges. The HEAD Foundation Digest features insights and opinions from those in the know addressing a wide range of pertinent issues that factor in a society’s development. 

Informed opinions can inspire healthy discussions and open up our imagination to new possibilities. Interested in contributing? Write to us at info@headfoundation

Stay updated on our latest announcements on events and publications

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Stay updated on all the latest news and events

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