The next CAR-T target generates promise and caution

In the search for amenable CAR-T antigens beyond CD19 two targets are fast emerging as ones to watch: BCMA in multiple myeloma, and CD22 in B-cell malignancies.

And as clinical data are starting to emerge the latter is looking particularly interesting, putting Juno in pole position after its 2014 licence of the anti-CD22 CAR-T project JCAR018 from Opus Bio. However, results unveiled at last week’s AACR meeting show both the potential and the limits of this approach, as the doctor leading the study detailed a new mechanism of resistance to treatment.

The highlight of Dr Terry Fry’s presentation came from three young adult ALL patients who had been given a higher dose of cells: all three had complete responses that were ongoing at three to six months. One of six earlier lower-dose patients had also had a complete response, but relapsed after three months.

This appears to be the first sign of real efficacy with a CD22 CAR, and another key finding concerned the two most important side effects of adoptive cell therapy: while cytokine release was seen, there was no neurotoxicity, said Dr Fry, who is running the study at the NCI.

Magnum Opus

Juno bought rights to this asset from Opus Bio for around $84m, and paid out a $15m milestone after Dr Fry unveiled data in an initial seven patients at last year’s ASH meeting.

Juno is paying for elements of Dr Fry’s study while remaining slightly at arm’s length, its chief scientific officer, Hy Levitsky, told EP Vantage, adding: “We will of course be running our own studies [of JCAR018], under our own INDs. Our plans are very much aligned.”

He called the three new complete responses a “very nice signal”, and said the lack of neurotoxicity was intriguing, but cautioned that these were still very small patient numbers. Still, it is well worth noting that one of the three patients responded after a CD19-negative relapse to an anti-CD19 CAR. For the other two it was their first CAR-T treatment.

These early data therefore support use for an anti-CD22 CAR-T therapy in both relapsed and anti-CD19 CAR-T-naive patients; at a time when CD19-directed therapies abound, Juno’s JCAR018 is unique as the only CD22-directed CAR in the clinic (Therapy focus – How do you solve a problem like CAR-T relapse?, December 22, 2015).

What is still not known is whether patients can suffer loss of the CD22 antigen as response to treatment. With CD19 therapies this type of antigen escape has been seen in up to 30% of relapsing patients, and often involves part of the CD19 epitope being spliced out.

Dr Fry went as far as suggesting that treating patients with an anti-CD22 CAR could prevent relapses by CD19 antigen loss.

Lineage switching?

However, he outlined another escape mechanism seen in preclinical trials, whereby a B-cell malignancy treated with a CD19 CAR switches lineage, so the cells phenotypically stop being B cells, and become myeloid cells.

Not only would any such patients no longer be candidates for either a CD19 or a CD22-directed therapy, they would now have a mixed-lineage leukaemia for doctors to deal with – a potentially serious development.

Mr Levitsky, however, was sanguine. “The outgrowth of the myeloid phenotype is concerning, but we’ve not yet seen it in adults,” he stated. “Paediatric and adult ALL are very different diseases, and paediatric ALL has been curable with chemotherapy for decades now.”

He also expressed confidence in the anti-CD22 construct that Dr Fry had developed, confirming that it was the one Juno would take forward. This had undergone several alterations, including the addition of a spacer to move the binding site away from the cell membrane, and changing the co-stimulatory domain from CD28 to 4-1BB to improve persistence.

Such considerations are vital given that the Fred Hutchinson Cancer Center's Dr Stanley Riddell, a scientific co-founder of Juno, has some doubts about current anti-CD19 constructs, telling the AACR meeting: “They might still not be optimal as regards signalling.”

Study Trial ID
Phase I, 57 patients with B-cell malignancies NCT02315612

This story has been amended to correct Dr Riddell's affiliation and the initial value of the Opus Bio deal.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter

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