From crude surgery to gene editing: how cancer treatments evolved over the years

Highly sophisticated technologies and treatments helped to reduce relative cancer deaths by 15 per cent over the past 30 years

A little more than two centuries ago, an English novelist named Frances Burney endured a "terrible operation" to remove a tumour after having breast cancer diagnosed.
Burney spent more than 17 agonising minutes under the scalpel as her surgeon in Paris cut away at her breast – all without anaesthetic.
She was 58 when the mastectomy was performed and lived another three decades, a happy outcome that went against the terrible odds faced by cancer patients at the time.
Fast forward to today and the cancer treatments being contemplated by Prof Dan Peer at Tel Aviv University in Israel are as sophisticated and precisely targeted as the one Burney suffered was crude.

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I feel privileged to stand at the edge of what could be the biggest biomedical revolution in our lifetime


Prof Peer and his team in the Laboratory of Precision NanoMedicine are working at one of cancer research's most exciting frontiers: gene editing.
They package a gene editing tool called Crispr-Cas9 into tiny lipid nanoparticles (LNPs) that bond specifically to receptors found only in cancer cells.
The LNPs contain two types of RNA genetic material: messenger RNA (mRNA) that encodes for the Cas9 enzyme, which can cut DNA and alter a cell's genome; and single-guide RNA (sgRNA) that guides it to the correct location within a specific gene in the cancer cells. The end result is that a gene, called PLK1, which is often overactive in cancer cells, is taken out.
"We cut the gene out. This is a gene that's important for the proliferation of cancer cells. It's highly expressed in the tumours," Prof Peer said.
"The tumour cells will die and will not recover from this. That's one less tumour cell."

Professor Dan Peer of Tel Aviv University (photo courtesy of Prof Peer)

Survival rates in mice with ovarian and brain cancer increased when treated with the targeted LNPs, and Prof Peer is hopeful that trials with people could happen.
"We are eager to move this into the clinic," he said. "We would expect, if we had everything in place, within two years we could push this into clinical trials."
Taking out a specific gene in cancer cells could be a suitable approach for cancers including pancreatic, prostate and some melanomas.
Trials have started on other cancers using Crispr-Cas9, which is part of the growing field of gene-based approaches to cancer therapy.
For all the improvements in treatment, cancer's toll continues to rise with about 10 million people a year dying – up two thirds on 1990, although population growth and reductions in other causes of death explain the increase.

The actual cancer death rate, taking into account changes in the age profile of the world's population, has fallen 15 per cent over the past three decades and the hope is that technologies such as Crispr-Cas9 could lead to further improvements.
The treatment options available for cancer are wide ranging and more than one are typically used in a patient. 
Surgery is often combined with systemic treatments (medications that travel through the body) such as chemotherapy, targeted therapy and immunotherapy, or with radiotherapy.

About half of cancer patients receive radiotherapy, where ionising radiation is used to destroy cancer cells, and better computing and engineering technology has made it more targeted, reducing damage to healthy tissue.
Chemotherapy, the use of drugs, may still cause severe side effects lasting months or longer, because, in aiming for cells replicating their DNA and dividing, it destroys healthy cells too.
In recent decades the trend is to greater use of targeted drugs exploiting the genetic differences of cancer cells to pick them out more selectively.

Targeted therapy, sometimes used as the main treatment for leukaemia and advanced melanoma, often has fewer side effects than standard chemotherapy because of its greater precision.
Another major field is immunotherapy, which may involve strengthening the patient's immune responses or augmenting them with lab-grown substances, such as monoclonal antibodies that attach to the surface of cancer cells. Immunotherapy treatments specific to the genetic characteristics of the patient's tumour are being developed.

The German biotechnology company BioNTech, which shot to global fame last year by developing an mRNA Covid-19 vaccine with Pfizer, is at the cutting edge in this field.
"We are convinced that there is an innovative way to treat cancer by developing cancer immunotherapies based on the genetic features of the individual tumours, aiming to enable each person's immune system to fight the diseases," a company representative said.
The company is using a range of approaches, including therapeutic mRNA vaccines against cancer, several of which are in clinical trials.
Therapeutic cancer vaccines – the term vaccine is widely used even if the aim is to treat rather than to prevent disease – typically stimulate the immune system to attack particular cancer cells.
Another emerging form of immunotherapy is Car T-cell therapy, in which T cells (a type of white blood cell central to the functioning of the immune system) are collected from a patient's blood.
These cells are then genetically engineered in the laboratory to become Car (chimeric antigen receptor) T-cells, which can target a cancer cell protein.
Multiplied in a lab before being given to the patient through a drip, they identify and attack cancer cells. Clinical trials for this treatment are under way.
The genetic engineering process can be much more efficient if carried out using Crispr-Cas9 and, last year, researchers wrote in Briefings in Functional Genomics that the technology holds "immense promise" for improving ways in which Car T-cells are used.

Dr Sam Kulkarni, CEO of CRISPR Therapeutics (photo courtesy of CRISPR Therapeutics)

"I think cell therapies will transform the treatment of cancer," said Dr Sam Kulkarni, chief executive of Crispr Therapeutics, a US and Swiss company with three ongoing clinical trials of Car T-cell cancer therapies based on Crispr-Cas9 gene editing.
"We're going from small-molecule pills to antibodies to intelligent cells that know how to recognise a cancer cell and eliminate it.
"Crispr is the best way to manipulate these cells to make them recognise and kill the cells. Over time they're going to become more and more intelligent.
"They're going to find ways to [monitor] so the cancer doesn't come back, to find ways to make sure there's no metastases."
Crispr Therapeutics takes cells from healthy young adult donors and genetically engineers them so that they will kill cancer cells but not be recognised by the immune system of the patient who subsequently receives them.
Trials, which began in 2019, have so far been promising with nearly half of patients showing significant improvements.
Now that the technology has been shown to be safe, the cells can be made more potent, which should result in better outcomes for patients, and commercialisation could happen within the next three to four years.
"My prediction ... is that by 2030 nearly one third of cancers will be treated with cell therapies, the large majority of which will use Crispr-Cas9," he said.
"Beyond that, the sky's the limit. I think cell therapies will overtake antibodies ... it's a great sense of excitement. I also feel privileged to stand at the edge of what could be the biggest biomedical revolution in our lifetime."

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