Can we use our own cells to fight cancer? CAR T cells are designed to do just that. They are engineered T cells that can be "programmed" to target certain proteins or other identifiers that cancer cells might have. The scFv (single chain variable fragment) of the T cell is what is modified to make that T cell target certain cells.
The idea of using a patient's own immune system to fight their cancer sounds like a great idea, a "use what you have," approach.
But, the problem with immunotheraphy is the same problem with all cancers. Cancer cells are your cells. They start with the same DNA, protein makeup, etc. as your non-cancerous cells. So, the problem is what about cancer cells is identifiable (and different) than normal cells, i.e. what can you target? The ideal targets in solid tumors are proteins ErbB2 and EGFR, which have high levels in cancer cells. BUT, these proteins also exist in normal cells. So, when you make a CAR T cell that targets these proteins, normal cells will inevitably be targeted also.
But, now, scientists have been able to make the scFv so specific that the target does not include normal cells. In their experiment, they tested the ability of CAR T cells with different affinities to protein ErbB2 to target cancer cells but not normal cells. What they found was that high affinity CAR T cells targeted any cells that had ErbB2, including normal cells. However, the targets of CAR T cells with low affinities of ErbB2 targeted only those cells with high ErbB2 levels (cancer cells). This same experiment with low affinity CAR T cells was also done with the other protein that is expressed in high levels in cancer cells - EGFFR, with similar results.
This is a huge step in the use of immunotherapy to fight cancers that do not respond to chemotherapy, or that are classified as "inoperable."
These scientists also showed the importance of open-mindedness when approaching problems. If they had stuck with the high affinity-high efficacy expectation, this advancement would not have been made.
TL;DR, kids, if you think outside the box, you just might come up with a (potential) cure for cancer.
Thanks for sharing this! I think CAR T cells are amazing. When I was working at the cancer center, our doctors were particularly interested in CAR T cells for advanced lymphoma patients.
ReplyDeleteI know CAR T cells are known as particularly potent to cancer cells compared to other modalities (i.e. chemotherapy). My question is what are the risks of tumor lysis syndrome when patients are undergoing CAR T cell therapy? I know it is currently undergoing clinical trials and the risks for TLS and the appropriate dose is yet to be determined, but for such a potent therapy, I wonder if even a small dose can lead to a buildup of cytokines, ions, and other byproducts in the bloodstream. This is especially of concern since CAR T cells seem to be for cancers that are not responsive to other treatments such as chemotherapy. Since the cancer will be advanced, I think concern for TLS would be increased (more cancer cells= more cancer cells dying by CAR T cell targeting). I wonder if patients receiving this treatment will get more aggressive TLS preventative measures during treatment (more than current preventative measures like Allopurinol, Rasburicase, continued hydration), and what that would look like.
Was this done in vitro with cell lines? I'm curious if the lack of effect on normal cells from the low affinity CAR T cells will stay true once it is done in actual patients. It seems like on a small scale that it would make sense that they don't have an effect on normal cells compared to tumor cells but actually introducing them into a patients body could create a very different environment where they will have a negative effect on normal cells. It may be negligible in vitro but then in vivo they could accumulate in a specific tissue or organ and cause more harm than estimated. Also, what is the process like for the termination of the therapy? Can they effectively stop the CAR T cell increase once the cancer has been eliminated? I imagine even a low affinity CAR T cell would have some effect when in the presence of only healthy cells.
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