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Biology resists one-button drugs
No cure-all pill
A pill that cures everything forever is a youthful hope, and a few drugs have come close. Checkpoint blockade is one of them: in 50 percent of melanomas, the tumor goes away.
Wired in layers
Most things are wired in complicated ways, and bodies are remarkably resilient. People can go from minus 20 degrees to 110 degrees and can go a long time without eating without falling apart. In cancer, moving the immune state from low reactivity to high may not be a straight push along one dial. Some cells have to be pushed through new states, creating an environment that looks like development.
Sequence matters
The order matters. To get a tumor eaten, the first step is to stop it from looking like a healing wound, which would hand it the immune system's positive power, and to take apart some of its defenses. Only then does it make sense to teach the immune system to kill it. Drugs may work best given in the right sequence and the time and the place, and a series of nudges can add up until the last one carries the system across the border.
How does combining checkpoint drugs change outcomes?
Two checkpoint antibodies, one against CTLA-4 and one against PD-1, release different brakes on T cells. The CheckMate 067 trial in advanced melanoma compared them alone and together. At five years, it reported survival of 52 percent with the combination, versus 26 percent with the anti-CTLA-4 antibody alone. The combination also caused more immune-related side effects.
How do bodies cope with such extreme temperature swings?
In 1926, Walter Cannon coined the term homeostasis for the body's ability to keep its internal conditions steady. Feedback loops do the work: sweating and widened skin vessels shed heat, while shivering and narrowed vessels hold it in. Many of these loops overlap, so if one fails another can partly cover for it. Core body temperature stays near 37 degrees Celsius across a wide range of outside temperatures.
How do viruses exploit a single weak point?
HIV makes a protein called Nef that pulls MHC class I molecules off the surface of infected cells. With fewer MHC molecules on display, T cells have less to read and recognize. Cytomegalovirus carries several genes that block the same display pathway at different steps. Each virus has found a way to interfere with the one system T cells depend on.