03 November 2023
Check Up #19 - Cancer immunotherapy
What are CAR T-Cells and what do they do?
Cancer immunotherapy is any treatment that uses our own immune system to fight cancer. There are several types of immunotherapy, some of which are already being used routinely, and others still mostly experimental. They are generally a second line of treatment, following chemotherapy, radiotherapy or surgery.
There are several types of immunotherapies. For instance, they can be drugs that block so-called “immune checkpoint inhibitors” (a normal part of the immune system), allowing immune cells to respond more strongly to cancer. They can be monoclonal antibodies, which are artificially-made immune system proteins that mark cancer cells so that they will be better detected and destroyed by the immune system. And they can be T-cell transfer therapies, which boost the natural ability of our T-cells (immune cancer-killing cells) to fight a cancer.
Over the last decade, immunotherapy has become what many now call the "fifth pillar" of cancer treatment – after surgery, chemotherapy, radiotherapy, and targeted therapy (see https://fchampalimaud.org/news/check-up-6-chemotherapy-radiotherapy-tar…).
Among T-cell transfer therapies, the most recent – and potentially promising – is CAR T-cell therapy. CAR T-cells are made by collecting T-cells from the patient and engineering them in the lab so that they produce proteins on their surface that recognise and bind to specific proteins, or antigens, present on the surface of cancer cells.
CAR T-cell therapy consists in reinjecting these engineered cells back into the patient after they have been cloned to become millions. Then, when these T-cells come in contact with their target antigen on a cancer cell's surface, they will bind to it and become activated, proliferate and become cytotoxic, able to destroy the cancer cells.
The acronym CAR is for “chimeric antigen receptor”. A CAR is in fact an artificial molecule (a fusion of several molecules that does not exist in nature – in short, a “chimera”) that sits across the T-cell membrane. It includes a fragment, jutting out of the T-cell membrane, and derived from an antibody specifically directed to a cancer cell receptor (the antigen, as we already mentioned), as well as a signaling fragment, inside the T-cell itself, which will signal to the T-cell to do its work once the target antigen has been bound by the external part of the CAR. The CAR is introduced into the T-cells aboard a virus vector.
In the last few years, several CAR T-cell therapies have been approved by the Food and Drug Administration (FDA). They are all for the treatment of blood cancers, including lymphomas, some forms of leukemia, and multiple myeloma. Let it be said here that these are very expensive treatments, and that their success rates vary substantially. Also, they have not been efficient, so far, at treating solid tumours.
As all cancer treatments, CAR T-cell therapies can cause severe side effects. One of the most frequent and serious ones is the so-called cytokine release syndrome (CRS). This happens when, as part of their immune response, the CAR T-cells induce the release of excessive amounts of mediator molecules called cytokines. Although cytokines are supposed to positively stimulate the immune response, such a “cytokine storm” can wreak havoc in the patient’s body (by the way, the expression “cytokine storm” has become familiar in relation to COVID). The symptoms of CRS include very high fevers and acute drops in blood pressure, and can be fatal in its most severe form.
The other most worrisome side effects with CAR T-cell therapies are neurologic symptoms, including severe confusion, seizure-like manifestations and impaired speech. The precise cause of these neurologic side effects is still unclear.
As already mentioned, the use of CAR T-cells to treat solid tumours, such as brain, breast, prostate cancers and so on has not been successful. The problem here is to develop a treatment that doesn’t also kill neighbouring healthy cells, due to lack of target specificity, and that can be delivered to the tumour across its so-called “microenvironment”, which actively contributes to reducing the efficiency and survival of the CAR T-cells.
A lot of research effort is currently ongoing to make CAR T-cells more specific and efficient, and to better control the cells’ response so as to minimise the treatment’s dangerous side effects.
Sources:
https://www.cancerresearchuk.org/
https://www.cancer.gov/
https://www.proteogenix.science/
