Latest developments in chimeric antigen receptor therapy
We recently sat down with Prof. Richard Boyd BSc (Hons) PhD* for an update on chimeric antigen receptor (CAR) cell therapy.
Progression of cancer treatment
Until the 1980s, cancer treatment was essentially limited to traditional methods of surgery, radiotherapy and chemotherapy. Since that time, significant advances in cancer research have led to a focus on engaging the power and specificity of the immune system to tailor treatment to a cancer patient’s specific clinical circumstances.
A pivotal advance in this precision medicine research was the development of cell-based immunotherapy centred on the breakthrough discovery of chimeric antigen receptor (CAR) immune cell therapy. CARs contain a cancer recognising component linked to cell activation molecules. The CAR enables binding to the cancer cell followed by activation and killing.
This CAR cell therapy has revolutionised cancer treatment, as an alternative to traditional chemotherapy and radiotherapy, with specific cancer killing capabilities and less side effects for the patient. Some blood cancer patients have even been ‘cured’. Whereas traditional chemotherapy and radiotherapy are effective only for the rapidly dividing cells, ‘resting’ cancer cells escape and can later lead to relapse. With CAR cell therapy, the re-engineered cells target both rapidly dividing cancer cells and dormant cancer stem cells.
Currently there are two main types of CAR cell therapies: CAR T-cell and CAR Natural Killer (NK) cell.
CAR T-cell therapy
T cells are the main effector cells of the immune system. They are produced within the thymus from bone marrow-derived blood stem cells. A major subclass of T cells, called killer cells, are a potentially powerful means of destroying cancers and have the important property of proliferating inside the patient to ensure long-term cancer attack. The challenge is that each T cell has only one unique specificity, so by chance they very rarely recognise a particular cancer.
The advent of CAR technology has overcome this major ‘roadblock’. By genetically editing T cells with a CAR, this serves as a ‘GPS-like tracking system’ enabling all treated T cells to seek and destroy cancer cells. T cells are collected from the patient’s blood and genetically engineered in the laboratory by inserting a CAR to recognise and bind to specific molecules (antigens) on the surface of cancer cells. Millions of CAR T cells are grown in the laboratory and then intravenously infused back into the patient to seek out the cancer cells and kill them. Since these T cells are derived from the patient’s own blood, this is called ‘autologous’ therapy. Whilst this is the safest approach, there are several practical problems: the T cells are low in number and function because of prior chemotherapy and are exhausted from attacking the cancer. The process is time consuming (weeks), putting patients at risk, and is very expensive (approx. $500,000).
Unfortunately, unless every single cancer cell is killed off, some rogue cells may be left behind as they mutated when the cells were dividing. When cells mutate, they can lose the marker which the re-engineered CAR cell is identifying and therefore the cancer cells cannot be recognized.
Accordingly, until recently, a CAR T cell was engineered with only one additional specificity but now researchers have discovered that the re-engineered cells could have multiple specificities known as dual-targeted CAR cell therapy, to overcome cancer escape by mutation.
Natural Killer (NK) cells
The success of CAR T-cell therapy led to research using natural killer (NK) cells as an alternative to T cells.
NK cells differ from T cells in that they have the ability to kill cancer cells without any priming or prior activation, in contrast to T cells which need priming by antigen presenting cells.
NK cells also have multiple natural receptors which can help identify cancer cells, in comparison to T cells that have only one specificity.
Additionally, T cells divide and increase in number when become stimulated and they will live for a long time, whereas NK-cells don’t divide and are short lived.
While T cells live longer and divide in vivo, they are considered to be less safe than NK cells because they may overproduce cytokines (immune stimulants) which can lead to organ failure. NK cells, however, are less aggressive.
What is the future of CAR cell therapy?
While CAR cell therapy is developing at a rapid rate, the manufacturing of the re-engineered cells needs to dramatically increase to cope with demand. The commercialisation of immunotherapy is robust, but it is imperative to increase the number of bio reactors for clinical scale production.
Another advance in therapy has recently emerged and initial clinical trials are underway. Whereas, conventional CAR cell therapy modifies a patient’s own blood cells, a new approach of re-engineering healthy donor cells has emerged. Methods are being developed to produce CAR cells from induced pluripotential stem cells (iPSC). iPSC can be genetically edited (e.g. addition of multiple CARs, and factors which increase CAR cell killing and longevity; deletion of immune suppressive genes), cloned to uniformity and differentiated continually to CAR T cells or CAR NK cells. Scale-up production of ultra-sterile iPSC derived CAR NK cells (CAR iNK cells) is resulting in multiple clinical trials; development of CAR T cells from iPSC (CAR iT cells) is more complex but success is on the horizon.
This new ‘off-the-shelf’ approach enables a patient to receive the therapy in a matter of days compared to a month or longer if using the patient’s own cells.
Researchers are continuing to develop the optimal treatment where a combination of both T cells and NK cells are used to ensure there is enough immune power to kill the cancer while also controlling the risk of side effects.
With the multiplicity of therapies available and the rapid development of CAR cell therapy, these treatments may be successful for solid tumours as well as autoimmune and infectious diseases.
“Blood cancer treatment research is developing rapidly with advances occurring almost daily. A combination of multiple therapies is the ideal to achieve the optimal result. The capability of engineering immune cells to kill any cancer is at our doorstep,” said Prof. Richard Boyd.
The Snowdome Foundation continues to support cutting-edge research which is critical in delivering next-generation treatments and make hope real for blood cancer patients.
* Prof. Richard Boyd BSc (Hons) PhD is Chief Scientific Advisor of Cartherics Pty Ltd, a cancer immunotherapy company, and a Snowdome Foundation Director.