the center to advance further in clinical trials to gather more evidence on whether its treatments really work consistently or not.
So, what was it about the state of the art in the science that convinced the Bezos family to open up their checkbook? Appelbaum was a lot more talkative about this. He pointed to four important discoveries that have been made at the Hutch. (Warning: I’ve tried to distill this science into something reader-friendly for non-biologists, but it’s still technical.)
—Research by Cassian Yee that showed a long-term complete remission in a patient who got an immunotherapy after relapsing on prior treatment for melanoma that had spread through the body. Yee’s team drew some blood from the patient, and found a new way to grow up billions of additional “helper” T cells in the lab that were made to recognize a hallmark on cancer cells. The helpers are supposed to marshal growth factors to the so-called “killer” T cells that fight tumors. When the expanded number of “helper” T cells were re-infused into the patient, without any additional drugs, the tumors disappeared and the patient went into remission, according to this paper in the New England Journal of Medicine.
By provided added helper T cells, that enables the patient’s killer T cells to recognize a more diversified array of markers on cancer cells, Appelbaum says.
—Work by Stanley Riddell into how to make immunotherapies last longer. Scientists have long tried to separate out killer T cells of the immune system in the lab, grow them up in greater numbers, and re-infuse them, Appelbaum says. This can sometimes produce tumor shrinkage, but it usually doesn’t last very long, he says.
Riddell’s insight was to show how certain immune system cells have different kinds of “memory” to attack certain invaders. Most T cells “fight a battle that’s short-lived” against certain pathogens like flu, and then die off when the job is done. Yet some T cells, like those programmed by a measles vaccine, can remember the signature of that kind of invader and leap to the body’s defense for many years, Appelbaum says. Riddell’s work—which has been done in mice, not people—has shown that he can stimulate this longer-lasting immune memory against a cancer cell for a year, Appelbaum says.
—Philip Greenberg‘s lab has done experiments that take an up-close look at how T cells actually bind with the protein receptors on cancer cells, Appelbaum says. Usually these bonds are “loose,” or what scientists call low-affinity. By swapping out certain genes, Greenberg’s idea is to grow up T cells outside the body, and filter them so that patients get re-infused with the best type of cells that can form 100 to 1,000-fold tighter, stronger bonds to the receptor that scientists want to hit, Appelbaum says.
—Lastly, experiments by Thomas Spies have identified a molecule secreted by cancer cells that serves as a decoy, so that T cells get thrown off track before they can gang up on the tumors. The idea is to develop a targeted antibody that eliminates these decoys. That drug would be given before the patient has their revved-up T-cells re-infused, Appelbaum says.
Add it all together, and Appelbaum says this is why he wants to accelerate the research. “You can give people helper T cells to get a broader response, you can provide memory to make them last longer, and you can engineer them to have higher affinity for the target,” he says.
It’s too early to say there’s much in the way of medical proof that these ideas will work on a large scale, however. The Hutch may need help from biotech or pharmaceutical partners to commercialize the work. Immunotherapy has long been plagued by promising anecdotal responses that weren’t reproduced in the rigorous setting of randomized clinical trials. But Appelbaum insists that he’s optimistic about the chances of this new approach for melanoma, kidney cancer, breast cancer, sarcomas, gastrointestinal tumors, and other malignancies.
“It’s an educated bet,” he says. But, he added, he’d be “very disappointed” if it fails.
