Precision Medicine – Changing the DNA of Health Care

How precision medicine is changing the shape of health – by Alan Trounson

Human disease is generally a consequence of complex interaction between our genes and the environment. Traditionally, medical research focuses on creating therapies to treat specific diseases.

This can be very effective and these therapies can have universal benefits across the whole population: look at immunisation against specific pathogens, or how new antiviral medication has helped control the spread of HIV/AIDS.

However, many diseases defy simple drug solutions and strategies for population therapeutics. In our increasingly sophisticated and impatient society, there’s more demand than ever on biomedical research to develop therapies across a broad range of clinical conditions.

Diseases can have very different trajectories over the course of different people’s lives, and this has major health implications. Bioinformatic data analysis enables clinicians to work out a person’s likely response to medication and how urgently intervention is needed.

This is rather different to static, clinical diagnosis based solely on a patient’s symptoms that doesn’t take this broader information into account. Genetic and/or environmental factors can change the progression of clinical trajectories. Considering these factors can reduce the chance of catastrophic events that cause accelerated disability or premature death.

Given an individual can respond positively, negatively or not at all to therapy, there is increasing interest in personalised or precision medicine. This approach uses genomic and biological data to predict the probability a person will respond to a therapeutic option.

First, a consulting clinician needs to submit a patient’s e-health record to an informatics centre for detailed analysis. The centre then uses worldwide health and genomics data to identify the diagnostic cluster group a patient belongs to.This is used to compute a diagnosis and the probable best treatment options, which are then provided to the clinician in the form of summary data.

When combined with the patient’s molecular diagnostic information from pathology tests and specific patient examination, this data enables the clinician to determine personalised therapies that maximise likely benefit while reducing the chance of adverse events and failure.

So how can we make all this happen? The genomic and patient history data banks are being built, but we need detailed bioinformatics analyses to turn large amounts of complex data into useful information for busy clinicians. The outcomes of diagnosis and treatment then need to be verified and fed back into these data banks.

There is a role for the private sector to enter this space and help provide the needed specialist bioinformatics advice. Since the goal is to improve patients’ lives and reduce primary health care costs, government can also play a part.

Insurance policies and their coverage of therapy will need to be revised to ensure equal access to these new precision medicines. The overall economic benefits to the community will drive these processes in the health industry.

We will need to incorporate Artificial Intelligence (AI) into precision medical practice, because the growing mass of data for genomics, biologics, demographics and environmental variants will be beyond individual humans’ capacity for useful analysis. Machine learning will increase predictive power and improve accuracy, speed and workflow.

AI has already improved diagnostics through mammograms, colonoscopies, X-rays, brain CT scans, heart MRIs and more. New developments will further enhance the capacity and effectiveness of personalised medicine.

Deep neural networks of AI can accurately and rapidly detect complex patterns associated with genotypes, gene signalling, environmental cues, patient data and disease phenotypes. This will reduce the clinical errors, near-misses and lack of accuracy that often exist in present medical practice.

Gene therapy has helped us make critical advances in the treatment of inheritable genetic diseases, including:

• sickle cell anaemia
• Duchenne muscular dystrophy
• alpha and beta thalassemia
• spinal muscular atrophy
• leukocyte adhesion deficiency
• X-linked hypohidrotic ectodermal dysplasia
• X-linked chronic granulomatous disease
• adenosine deaminase-deficient severe combined immunodeficiency (SCID) and X-linked SCID
• cerebral adrenoleukodystrophy.

These genetic diseases are rare and are caused by inherited genetic errors – generally very specific monogenetic DNA mutations. They can be treated by editing the genes of blood or tissue stem cells, either inside or outside the patient’s body, to introduce a corrected version of the abnormal gene to reverse symptoms of the disease.

The microbiome is rapidly being incorporated into medical diagnostics and therapeutics as we increase our understanding of its association with disease. In the past, this aspect of patient variance hasn’t been considered critically for many conditions.

For example, anti-tumour immunity responses have been very clearly associated with microbiota changes in mice. Specific microbial strains can significantly boost immune responses to tumour cells and restricted tumour growth.

Similarly, the composition of patient’s gut microbiome can influence the success of cancer immunotherapy. Studies are underway that combine immune checkpoint therapy (ani-PD1 therapy) with oral doses of certain bacteria or fecal matter from melanoma patients who responded well to anti-checkpoint treatment. There is interest in adding this kind of information into the data sets for personalised therapy.

As genomics adopts new advances for identifying and confirming the role of gene signalling pathways in diseases, new drugs will be discovered and personalised medicine will evolve.

For example, large patient-donated samples of stem cells derived from adult tissue (induced pluripotent stem cells, or iPSCs) are being analysed to find out how various diseases respond to different drugs. Experts are connecting this data with gene-edited and genomic screens to develop and repurpose drugs and identify clusters of patients likely to benefit from them.

Similarly, researchers are designing personalised cell therapies for regenerative medicine by using iPSCs from individual patients or rare high-compatibility donors. These studies are entering clinical trials for numerous conditions including blindness, spinal cord injury, diabetes, heart disease, Parkinson’s disease and cancer.

The success of immune therapies has impacted the present approach to cancer therapeutics. Three particularly exciting developments are monoclonal antibodies, checkpoint inhibitors and chimeric antigen receptor technologies (CAR-T).

Monoclonal antibodies are a fascinating breakthrough. Antibodies are protective proteins in the immune system that attack “foreign” substances like viruses and bacteria. To do this, they recognise and latch onto proteins called antigens.

Thanks to genomics, we can now identify antigen markers specific to an individual cancer. This lets us design specific therapeutic antibodies to bind to and kill tumour cells. These are called “monoclonal antibodies” because they come from identical, cloned immune cells.

The precision sequencing of tumour DNA in patients’ blood is a very rapidly expanding area of diagnostics. It’s revealing important variations within cancers traditionally considered to be of a single cancer type. This allows us to design specifically targeted therapies that transform patients’ lives.

Personalised cancer vaccines are also rapidly evolving. These make use of dendritic cells: tree-shaped cells that present antigens to the immune system and instruct it to make antibodies and disease-fighting white blood cells.

Scientists make cancer vaccines by taking the patient’s own dendritic cells and activating them with synthesised molecules (peptides) that are based on the specific gene mutations in the patient’s tumour.

No two peoples’ tumours are identical: their likely malignancy and spread vary considerably. Additionally, the rapid growth of tumours means that multiple gene mutations in tumour-starting genes (oncogenes) can develop.

Inheritance, mutation, and environmental influence can cause abnormalities in oncogenes and their regulation, which in turn causes cancer. Since each situation is unique, personalising therapy makes a lot of sense.

Checkpoint inhibitor therapy is another exciting area of research. Tumours sometimes use the immune system’s own regulators to protect themselves from it. Molecules called checkpoint inhibitors block these regulators and activate the patient’s immune system to hunt down and destroy cancers. This is particularly effective against melanomas.

The most effective therapy for B cell blood cancers is CAR-T therapy. This involves genetically engineering tumour-recognising proteins called chimeric antigen receptors (CAR) into a patient’s own white blood cells. These CAR-T cells are multiplied in the lab then infused back into the patient.

When the CAR-T cells recognise and bind to the cancer cells in the patient, they signal the immune system to kill the tumour. CAR-Ts are incredibly effective and target a patient’s own specific tumour type. They are being studied for a wide range of cancers.

Presently, CAR-T therapy involves the recovery and genetic manipulation of the patient’s own disease-hunting killer T cells. However, cancer patients have usually had long and debilitating chemo- or radiotherapy and their immune systems are often severely impaired. This can make it difficult to obtain sufficient CAR-T engineered cells for successful therapy.

“Off-the-shelf” CAR-T therapy is emerging as a useful alternative. These approaches involve removing the major transplant barrier genes in donor cells, or selecting rare donors who are compatible with a high proportion of the population.

It’s now possible to generate stem cells from adult tissue that are the equivalent to primitive embryonic stem cells. These iPSCs make it possible to gene-edit very specific genomic designs, dramatically increasing the effectiveness of cancer-destroying immune cells. Using iPSCs with enhanced tumour cell-killing function to produce protective white blood cells (natural killer cells or T cells) is likely to be a powerful therapy for cancer.

A key advantage of the off-the-shelf CAR-T therapy is that it uses healthy donor cells (such as from umbilical cord blood) that have not been subjected to intensive chemotherapy. Production costs are also slashed because the cell therapy product doesn’t have to be manufactured for every individual patient.

Unfortunately, precision medicines often cost many hundreds of thousands of dollars for any treatment. While there may be tolerance for providing expensive funding for a few patients with rare diseases, when it comes to mass treatment, the cost of precision medicine will be onerous for present health care budgets.

The present health system won’t be able to provide public funding and insurance unless major changes are implemented. We need to remember that keeping people healthy also has economic benefits. Helping patients meet the increased costs of these personalised therapies is an investment that will drive down the long-term costs of disease care.

The other great challenge is in training clinicians to use major data resources. That means collecting and interpreting individual patient information to make better diagnoses and therapeutic recommendations.

Our community’s health will increasingly be a partnership between patients, consulting clinicians and therapeutic providers. These relationships will be different to what we’re used to. Patients’ decisions and data inputs will have a bigger role than ever before.

All these changes are already happening. Medical practice, public health, government, health insurance and the community need to come together to be ready for them. It’s up to us to create an economically rational, emotionally comfortable and socially just health care system.

Bio: Alan Trounson PhD LLD is a world-renowned embryologist with an expertise in stem cell research. Elected a Fellow in 2014, he is an Emeritus Professor at Monash University and Distinguished Scientist at the Hudson Institute of Medical Research. Professor Trounson is also the CEO of Cartherics, an immune stem cell cancer therapy company.