Drug Development

Stung by patient deaths, a small Juno study points to a Goldilocks formula for CAR-T

For Juno, the hunt to find just the right mixture of T cells along with an effective regimen to prep patients for their CAR-T therapy has had a lethal history, tangling up development timelines in a way that has ceded the lead in the field to rival Kite.

Stanley Riddell

Stanley Riddell

But in a new, small study involving one of their most advanced CAR-Ts, an investigative team feels that they came up with just the right recipe. And that could have big implications for another CAR-T program in which Juno holds high hopes for a comeback.

The drug involved in the study is called JCAR014, and the investigators say that they came up with a one-on-one mix of CD4+ helper cells with CD8+ killer cells that showed a remarkable ability to wipe out cancer cells that express CD19, which has been the big initial target for all the players in the vanguard of CAR-T work.

Significantly, the investigators also concluded that adding fludarabine to cyclophosphamide (Cy/Flu) in a cocktail to prep patients creates the right environment for the T cells to grow in the body. Half of the 18 patients with non-Hodgkin lymphoma who got the Cy/Flu combo had a complete response to the therapy, compared to only 8% of the group who received only cyclophosphamide.

The team pointed out that these results could indicate similar outcomes for JCAR017, which is now in early studies. Juno has tapped JCAR017 as a potential “best-in-class” treatment for blood cancers.

The message helped buoy the company’s stock today, sending shares up about 3%.

“With the defined composition treatment, we are able to get more reproducible data about the effects of the cells — both the beneficial impact against the cancer and any side effects to the patient,” said Fred Hutch clinical researcher Stan Riddell, one of the senior authors of the paper, along with Dr. David Maloney. “We are then able to adjust the dose to improve what we call the therapeutic index — impact against the tumor, with lower toxicity to the patient.”

The addition of fludarabine to Juno’s lead CAR-T, JCAR015, was fingered for killing four patients, a setback for the biotech which triggered a brief but damaging clinical hold by the FDA. The hold lasted only days, ending with the FDA signing off on the biotech’s decision to drop fludarabine. But the hold ended up forcing Juno to delay its expected move to file for their first approval back to 2018. Kite, meanwhile, which is using its own mix of T cells and Cy/Flu, has said it expects to take the first batch of data from its leading study to the FDA after an initial review that comes in just a matter of weeks.

This new study from Juno also raises questions about its lead drug, JCAR015. If patient outcomes are significantly lowered by the absence of fludarabine, Juno’s first attempt at a commercial entry against the competition could be severely affected.

CAR-Ts became a hot field a couple of years ago, attracting hundreds of millions in new investments as the front runners raced to advance new remedies for cancer by adding a chimeric antigen receptor to a patient’s T cells and then infusing them back into the patient. But with Juno’s derailment and a recent decision by Novartis to dissolve its cell and gene therapy unit and reabsorb it into their big oncology division, all eyes are on Kite now to see if it can claim the first approval and market entry.

The stakes are high.

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