The idea of turning the immune system against cancer has a long history. This is the story of the scientific development of cell therapy

In Greek mythology, the “chimera” was a fire-breathing hybrid of a lion, snake and goat, who struck terror into all who encountered it. This was the image that Zelig Eshhar – an Israeli immunologist – had in mind when he developed the idea of a ‘T-body’: a hybrid immune agent engineered to combine the attacking activity of a person’s T cells with the recognition and binding abilities of their antibodies.

Initially, his PhD student Gideon Gross had reservations: “I wondered whether embarking on such a project would work; would it lead me to a valid thesis?” says Gross, now at the MIGAL Galilee Research Institute in northern Israel. “However, as we went along it became clear to both of us that this could be a tool to redirect T cells at potentially any target– and the obvious target was cancer cells.”

It is now thirty years since these researchers announced that they’d assembled the first such hybrid agent. In that time, the idea of reprogramming the body’s immune system to attack cancer has gone from a distant dream to an emerging reality, and T-bodies – today called CAR T cells – are at the cutting edge of this field, now researched and manufactured by many organisations around the world.

In 2018, the American Society of Clinical Oncology (ASCO) named CAR T cell immunotherapy as its ‘Advance of the Year’. Efforts are now underway to turn CAR T cells against multiple types of cancer, including blood cancers and solid tumours.
The idea of turning the immune system against cancer has a long history. Nearly 130 years ago, an American surgeon called William Coley showed that deliberately injecting cancer patients with bacteria to stimulate their immune systems could cause their tumours to recede. However, the approach was gradually forgotten as others failed to replicate his results.

Today though, cancer immunotherapy is firmly back on the agenda. A critical turning point was the development of monoclonal antibodies – molecules that can be designed to recognise and bind to antigen targets, expressed on cells, including cancer cells.

For instance, antibodies can be designed to bind to a molecule called CD20 on the surface of a type of white blood cell called B cells. This triggers a process that may recruit other immune cells to destroy them.

The other component is T cells. “The role of properly functioning T cells in the body is to find, attack and kill abnormal entities – whether it is a cell infected by a microbial entity, or your own cells that have degenerated into cancer cells,” says Dr Dominique Tonelli, Head of Medical Affairs, Oncology and Cell Therapy at Gilead Sciences in Europe.

But they aren’t as good at recognising cancer cells as antibodies. So Eshhar’s idea was to combine the two. “Early on, we realised that a T cell with the specificity of an antibody, could attack target cells,” he says. “Once we demonstrated that this was biologically possible, we thought it had a good chance of becoming a viable therapy.”

That demonstration came in 1989, when the Israeli team announced they had genetically engineered T cells to kill cancer. In this way, they created the first engineered T cells capable of recognising key targets. In the following decades, these CAR T cells were gradually refined, first in the lab, then in animal models before being tested in humans.

Efforts are now focused on making CAR T therapy available for more types of cancer with fewer side effects and improving the production process. Additional research is underway to ensure therapy is given to patients most likely to benefit.

“Physicians have much to learn.” says Max Topp, who heads the haematology department at the University Hospital of Wurzberg. “We have to understand how to preselect the patients a bit better, and how to manage the serious adverse events, toxicity and the logistics as well.”

At the same time, the healthcare infrastructure for administering these therapies needs to be ready. Hospitals have to be qualified to deliver this therapy and this takes time. In many places, the infrastructure has yet to catch up to make this happen.

 

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