In the second two edits, the scientists used Crispr to cripple genes that code for natural T cell receptors—deleting them from the cell’s surface and creating a blank slate. Then, after a few days’ rest, the researchers inserted a new gene into the cells, this one containing the code for their designer receptor. That step armed each cell with a kind of cancer homing device. Scientists next moved the cells into a collection of large bags, each holding several liters of liquid sugars, salts, and other things cells need to grow. For weeks, the bags rocked gently inside incubators, until the cells had multiplied into the many millions, before being cryopreserved and shipped off for infusion into each patient.

The biggest question going into the trial was what would happen when those 100 million cells were plugged into patients’ bodies. Would they settle in? Would they find their way to the cancer? Would they even survive? Or worse, would residual Crispr proteins trigger massive immune reactions?

There wasn’t much international research they could rely on for precedent. Scientists in China were the first to use Crispr to try to treat cancer in humans in 2016. They have since initiated a number of clinical trials, but released very little data about them.

In case the stakes weren’t plain enough, it might help to recall that the University of Pennsylvania is the same place where an 18-year-old named Jessie Gelsinger died from a catastrophic immune reaction to an experimental gene therapy in 1999, setting back the whole field for decades. A similar disaster could sink the efforts of the dozens of companies chasing the engineered T cell idea, and the research they support. June holds a number of patents on T cell technology and is a cofounder of Tmunity, an engineered T cell company that provided funding for the trial. Many of his coauthors have received funding or consulting fees from other cell therapy companies with T cell products in the pipeline including Novartis, Gilead, and Arsenal Biosciences. Proving to the public that these cells are safe for people is more than just an academic exercise. Billions of dollars are on the line.

This time around things went much better. The patients’ health either improved or held steady. They tolerated the engineered T cells with only mild adverse effects and no immune response. And when Fraietta’s team sampled their blood every few months, the researchers kept finding cells with the edits they had made. That’s a good sign, because it means the cells weren’t dying, and appeared to be just as fit as the patient’s natural cells. Moreover, when the researchers biopsied bone marrow from the patients, they found the edited T cells there too, at the sites of the cancer, indicating the new cells had migrated to the right spots.

But though the three patients experienced some stabilization of their disease during treatment, and one saw tumor size reduction, the T cells were far from a total fix. One of the patients, a woman with multiple myeloma, died in December, seven months after receiving the treatment. The other two—another woman with multiple myeloma and a man with sarcoma (the one who’s tumor shrank)—have since had their cancer worsen and are now receiving other treatments.

“It’s really hard for us to make any conclusion about the effectiveness of the therapy except to say it’s not 100 percent effective,” says Stadtmauer. “You really need to treat many more patients to get at that question.”\

Originally, the UPenn team’s plan was to move this Crispr technique into a larger trial involving 18 participants, which could start to answer that question. But so far, they have not treated any additional patients. The reason, says Stadtmauer, is that the gene editing field is moving so quickly they’re not sure they want to push forward with what is now considered to be outdated tech. Today, a Crispr system developed in 2015 looks positively prehistoric. In the years since the trial was approved, a suite of new gene-editing tools that promise greater accuracy and more design flexibility have since been developed. “I see this study as the first stepping stone that leads to many more investigations of this approach,” says Stadtmauer.

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