With the start of a new year, I like to take a moment to think about what things in cancer research got me really excited the previous year. Beyond a doubt, that thing for me in 2017 was the first (and second!) FDA approval of a CAR T-cell (chimeric antigen receptor T-cell) therapy as a treatment option for certain cancers.
I am particularly excited about these leaps forward for cancer treatment options, as I used to work in a cancer immunotherapy lab on projects involving CAR T-cells for breast, colon and skin cancers. My work was in no way related to the FDA approvals, so I have no disclosures to report… but I kind of feel like someone who was a friend of someone’s sibling who’s now famous, going ‘OMG, I know them!’ every time it comes up.
The two newly approved CAR T-cell therapies, Kymriah™ (Novartis) and Yescarta™ (Kite Pharma), are for use in specific patients with B-cell acute lymphoblastic leukemia (ALL) and large B-cell lymphoma, respectively. Signals’ editor Stacey Johnson covered the announcements in this Right Turn post that also explained gene therapies. You can check out the table for a quick guide to the two therapies.
I’m definitely not the only one at Signals who has been excited by, and following, CAR T-cells – we’ve been writing about this promising therapy for a few years now. To learn more, blogger Mark Curtis is your best bet for consistent coverage. Read his Updates from the Clinic and Cell Therapy Deal Reviews.
While this is all well and good, what are these CAR T-cell therapies, how do they work, and how are they made?
The first step to understanding CAR T-cell therapy is to take a quick look at the immune system.
The immune system is a powerful tool that automatically targets and destroys pathogens (e.g. bacteria, viruses). While the immune system is a complex network of cells and signalling proteins (I’m not even going to pretend to understand it all), a key component are lymphocytes (white blood cells), specifically a subtype of lymphocytes called T-cells. The external surfaces of T-cells are covered in receptors that recognize surface markers (antigens) on pathogens. When these antigens bind the external part of the T-cell receptor, the internal portion initiates a signalling cascade that unleashes cytotoxic proteins directed towards the pathogen, and recruits even more immune cells to help finish the job.
The idea behind CAR T-cells is to harness that innate T-cell destructive power and focus it on cancer cells, which are notoriously good at evading the immune system. This is done by engineering a patient’s T-cells to target a specific marker on the cancer cells. Essentially, this is done by swapping the external part of the T-cell receptor for something specific to cancer cells – this is the ‘chimeric’ part of chimeric antigen receptor T-cell (sorry, no Greek mythological fire-breathing creature) – while leaving the internal parts of the receptor intact. So now instead of that cytotoxic cascade being released in response to a pathogen (e.g. bacteria), it is now re-programmed to activate in response to binding antigens on the cancer cells.
The Associated Press has a nice video on CAR T-cells that you can watch here.
In the case of Kymriah™ and Yescarta™, the patient’s T-cells have been engineered to recognize the B-cell surface marker CD19, common to the culprit B-cells in ALL and large B-cell lymphoma. (A quick aside: B-cells are actually a normal part of the immune system. They help govern its “memory” to pathogens it has seen before, so the next time around it can respond even faster. But as is the case of many cancers, the B-cells in ALL and lymphoma are normal cells that have “gone bad.”)
In terms of how this is actually done, blood is taken from the patient and is sent to a manufacturing centre. There, the T cells are isolated from the blood and genetically modified so that the DNA for the T-cell receptor now codes for the chimeric antigen receptor (CAR); this step is usually done with the help of a virus capable of inserting new (i.e. the CAR) DNA into the cells’ DNA. To get the number of cells needed for therapy, an expansion process occurs, using cell culture techniques to help the CAR T-cells grow. Once ready, the CAR T-cells are sent back to treatment centres, where they are transfused back into the patient. If all has gone according to plan, the CAR T-cells should begin attacking the cancer cells with the CD19 surface marker, hopefully leading to reduction in disease burden and eventual cure.
But – yes there is a “but” – like any sort of drug or therapy, there are downsides. One of them is the logistics behind preparing the CAR T-cells. The uptake of the CAR DNA is far from 100 percent – it can be a very inefficient process – which can cause problems when you need 2 million CAR positive T-cells (patient T-cells that are successfully expressing the anti-CD19 CAR) per kilogram of body weight. Other problems include the potential side effects, two common ones being very serious: (1) cytokine release syndrome, where the CAR T-cells over-stimulate the immune system, potentially leading to some serious autoimmune complications; and (2), making the patients more susceptible to infection, as the CAR T-cells will also kill healthy B-cells, reducing the immune system’s ability to respond to infectious pathogens. Both of these side effects can lead to serious illness, or death in extreme cases.
Despite all that, I’m still super excited to see where this cellular-based immunotherapy goes in 2018. Not only are the current approved therapies giving previously incurable B-cell ALL and B-cell lymphoma patients a great chance of cure and survival, but there are so many opportunities that will hopefully come from this.
As I alluded to earlier, there are researchers around the world looking at cellular-based immunotherapies in other cancers, such as those of the breast, colon and melanoma. There are others looking at ways to make CAR T-cells even better, such as: exploring different constructs of the CAR to make them more efficient; increasing the specificity of the CAR T-cells by making them recognize two tumour antigens (tandem or dual-antigen CARs); or by trying to imbed them with an “on/off switch” to a small molecule, in efforts to control their response. There are even more studies looking at how CAR T-cells work with existing immuno- and chemotherapies. A quick search on ClinicalTrials.gov for “chimeric antigen receptor T-cell” offers over 100 clinical trials. I think we’re on to something here!
We’re in an exciting era of cancer research where our knowledge of the immune system and rapidly expanding repertoire of genetic engineering tools are coming together, and giving new hope to those previously without.