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Injected antibody melted mouse tumors
An accidental cancer project
Nobody in the lab was trying to cure cancer. The thesis project began with curiosity about some molecules on T cells, and AIDS had already shown that T cells mattered. The student had shown that blocking one of those molecules made T cells more activated.
A series of mouse experiments across all kinds of diseases kept turning the T cells up. The lab had some tumors in the fridge, so they set up that experiment. The student injected the antibody, and the tumors melted.
What it unlocked
Once the effect showed up, the immune system became something to dial up. In mice, vaccination got better, multiple sclerosis got worse, and cancer could be affected for the first time.
That student is Max Krummel, now a professor of immunology and cancer biology at the University of California, San Francisco. His advisor won the Nobel Prize for it.
How does blocking a molecule on T cells shrink tumors?
The molecule in this work was CTLA-4, which acts as a brake on T cells. James Allison's lab showed that an antibody covering CTLA-4 takes the brake off, so T cells that were already near the tumor turn on and attack it. The 1996 Science paper from Allison's group, with Dana Leach and Matthew Krummel, reported tumors rejected in mice. In 2018, Allison shared the Nobel Prize in Physiology or Medicine with Tasuku Honjo, who found a second brake called PD-1.
Why do tumors escape T cells in the first place?
Cancer cells are made from the body's own cells, so most of their proteins look normal to T cells. Some tumors also switch on brake signals, such as PD-L1, that press on the PD-1 receptor and tire out T cells. Tumors can also fill their surroundings with cells that suppress immune attack. Together these effects explain why a tumor can sit among T cells without being cleared.
How did the antibody become a human drug?
An antibody against CTLA-4 called ipilimumab was tested in people with advanced melanoma. In 2011, the US Food and Drug Administration approved it, making it the first checkpoint inhibitor on the market. Because the drug releases a brake on T cells in the whole body, it can also cause inflammation in organs such as the gut and skin. PD-1 antibodies followed in 2014.
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