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to infection. It remains to be seen how much risk the immunosuppression will add to the procedure.
So far, Cellectis and its partners have reported manageable immune reactions in the two infants and the first four people from two UCART19 European trials that began last year. Some of them were transient skin rashes, according to information presented to the NIH advisory committee in December.
More data should arrive this year or in early 2018. Pfizer is expanding the Phase 1 UCART19 program to the U.S., and Cellectis is starting a Phase 1 U.S. study of a different CAR-T, UCART123, to treat acute myeloid leukemia and blastic plasmacytoid dendritic cell neoplasm, an often misdiagnosed blood cancer.
If it works, allogeneic CAR-T will almost certainly be cheaper than autologous. One donor could supply enough blood to provide up to 4,000 doses, says Choulika. Choulika says one vial of UCART123 cells necessary for a treatment at this stage costs $4,000, and with behind-the-scenes improvements, the price should keep coming down. (The cells themselves will be only one part of the overall eventual cost, of course—and it’s too early to make predictions.)
Various estimates peg autologous production in the tens of thousands of dollars per patient. Autologous developers feel the pressure to be faster and cut costs. In Juno’s manufacturing site near Seattle, employees point out a contraption, a bit bigger than a vintage Japanese pachinko machine, that’s meant to do the work currently spread across many machines and rooms.
It’s a prototype called “the excellence machine,” either a spasm of self-improvement jargon or an impish nod to Bill and Ted of teen movie fame. It’s at least a few years away, says CFO Harr, but could be a “radically” different way of manufacturing cells. In the interim, Juno needs to speed things up, like the safety checks on a cell product before it’s released to the patient. “You have to automate quality,” says Harr. “It’s still more manual than we’d like.”
Usman “Oz” Azam, who is developing T cell medicines as CEO of Tmunity Therapeutics in Philadelphia, says that “bringing down the cost of goods” is a “big battle in the space right now.”
“I was heavily involved in that in my former role,” says Azam, who until last year ran Novartis’s cell and gene therapy group. (It was disbanded last year, with 120 jobs cut, but Novartis pledged to continue development of its lead experimental CAR-T products.)
For autologous CAR-T, analysts have floated possible prices in the hundreds of thousands of dollars, the same range as the most expensive rare disease treatments. In late 2015, a British academic group mocked up theoretical U.K. pricing models. CAR-T used as a bridge to prepare patients for a bone-marrow transplant was considered less valuable than CAR-T that could stand alone as a potential cure. (With many caveats, the group estimated rough costs of each north of a half-million dollars per patient.)
Others in the field are watching. Bristol-Myers Squibb (NYSE: BMY), one leader in another kind of cancer immunotherapy, hasn’t taken a shine to CAR-T. Allogeneic success could change that, its top deal maker told Xconomy recently. “We would love to see a technology like that be more ‘off the shelf,’ because I think it fits our business model well,” said Paul Biondi, Bristol’s senior vice president in charge of business development. “Also I think you’ll see the opportunity for [CAR-T] to expand beyond just a limited numbers of hematologic tumors.”
THE SOLID TUMOR CHALLENGE
CAR-T has made progress against leukemia and lymphomas because, in part, the collateral damage is manageable. Those cancers carry a protein called CD19 that CAR-T cells are programmed to recognize. But they also attack healthy immune “B” cells that also carry CD19; fortunately people can live without their B cells with anemia treatments. There are other reasons CD19 is “in many ways the perfect target,” says Stanley Riddell, a top T cell researcher at the Fred Hutchinson Cancer Research Center in Seattle. (He is a Juno co-founder and holds a stake in the company.) “It’s highly expressed on the tumor, and there’s a lot of tumor [so] the CAR-T cells get very activated.”
This year, we should see what happens when CAR-T programs go after less-than-perfect targets. The first treatments for multiple myeloma, the third most common blood cancer in the country after lymphoma and leukemia, have reached the clinic and more are coming.
But the biggest step for CAR-T therapy would be success in solid tumors, such as lung, breast, and colon cancers, which are far more prevalent than blood-borne cancers. “It’s the holy grail we’re looking for,” says Aya Jakobovits, the former president and CEO of Kite Pharma who now runs Adicet Bio, a developer of allogeneic cell therapies.