What triggered me yesterday to ponder my lack of scientific curiosity was a pair of papers published in the magazine Science two weeks ago. I subscribe to Science and scan the contents every week. Nevertheless, these two papers eluded me. The only reason I noticed them is that they popped up in my regular search of recent high-profile publications containing protein structures solved with the detectors I sell.
Both Antitumor activity of a systemic STING-activating non-nucleotide cGAMP mimetic and An orally available non-nucleotide STING agonist with antitumor activity talk about orally available activators of a particular immune pathway that might help the body better fight cancer. If this sounds like drugs, it's not, though one of the papers was authored by researchers at Merck, with a patent application mentioned. The experiments were done in mice, and mice are not humans. But the science behind the titles is quite intriguing.
Helping the immune system fight cancer is not a new idea, but it's one that's been gaining traction over the past ten years or so. Immunotherapy should be the most normal thing in the world. The immune system is designed to protect the body from all sorts of assaults – bacteria, viruses, liver transplants. Cancer cells are just another aspect. Since cancer cells are derived and don't differ much from endogenous cells, they are hard to recognize. In addition, they've developed all sorts of mechanisms to evade or suppress the immune response. The immune system is thus often struggling to contain cancers1.
Still, immunotherapies exist. Rather experimental at this point is adoptive T cell therapy. The idea is to engineer a particular type of immune cells called T cells to kill cancer cells. In CRISPR-engineered T cells in patients with refractory cancer, the authors extracted T cells from three patients. They then genetically modified these cells to achieve two goals. They blocked the production of a few proteins thought to inhibit the cells' ability to target tumours. They also gave the cells the ability to recognize a protein produced by cancer cells. Reintroduced into the original patients, the T cells remained detectable for nine months. There were no side effects, but there didn't seem to be a beneficial effect either. Research continues.
Already established are therapies based on antibodies that recognize and neutralize proteins that block the immune response. Six antibodies with such function (nivolumab, pembrolizumab, cemiplimab, atezolizumab, avelumab, and durvalumab – the ab at the end of their names marking them as antibodies) have been approved for various cancers at various stages by the Food and Drug Administration in the US and possibly in Europe and Switzerland as well. One of them, pembrolizumab, might apply in my case as a treatment of last resort when two or more lines of therapy based on fluorouracil and platinum-based drugs have failed.
The antibodies that I have received might technically also be considered immunotherapy. Both of them were targeted against a growth factor that promotes the creation of new blood vessels (angiogenesis), which tumors need to sustain their growth. This is not what I'm talking about here. This post is about helping the immune system directly attack (and, optimally, beat) the cancer, not co-opting parts of it to make the cancer's life harder.
What is it about these STING activators mentioned at the very top? STING is a protein at the heart of a complicated cellular pathway that leads to a T cell response. It all starts with the recognition of the genetic material of cancer cells. This recognition triggers a biochemical cascade that leads to the activation of STING. The signalling cascade continues until T cells are recruited and primed to go after cancer cells.
The molecules identified in the two papers ensure that STING is active. The details of these drug candidates are of little interest to me. They're unlikely to become drugs within the next few years. But the biology behind them is interesting. I've learned that many cancer patients do not show sufficiently active T cells. They would benefit from STING stimulation. Am I among them? Are my T cells not doing their job? Has this ever been tested? I'll certainly have something to talk about with my new oncologist on Tuesday.
(1) This statement might not be giving enough credit to the immune system. It would probably be fairer to write that cancers form when the immune system fails to eliminate cells that turn cancerous. These are rare, unfortunate events. Most of the time, the immune system does its job.
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