The (unsung) best of Ash 2018

At any medical conference it is easy to become caught up with the results of huge clinical trials and the ups and down of biotech stocks. The 2018 edition of Ash was no different, especially as the sector faces an uncertain future in terms of market sentiment.

But away from the limelight the meeting saw plenty of early-stage research. Here are, in reverse order, Vantage’s top three adoptive cell therapy presentations that might have sailed under the radar on account of being early-stage, but which could nevertheless hold huge future promise.

3. Let’s move on from BCMA

At a meeting that some called a BCMA-palooza one abstract showed that academics are not letting the grass grow under their feet. Memorial Sloan Kettering’s Dr Eric Smith presented preclinical work on MCARH109, a CAR-T project targeting the novel antigen GPRC5D.

This protein, G protein-coupled receptor class C group 5 member D in full, is present on plasma cells, but what makes it really interesting is that its expression is independent of BCMA. This means that it could be a target for treating multiple myeloma in patients who have relapsed on anti-BCMA therapy.

In a mouse model of multiple myeloma with BCMA knocked out, the anti-GPRC5D CAR cleared malignant cells. A first clinical trial – including patients who progressed after BCMA therapy – begins in the first quarter.

2. Human league

It has been known for some time that the use of murine binding domains in CAR-T therapy could lead to rejection and low persistence of the cells. Several institutions are therefore developing fully human binders.

But direct comparisons of the two are few and far between – a situation the NCI’s Dr James Kochenderfer remedied at Ash. His comparison of two trials showed similar remission rates in lymphoma patients treated with the NCI’s fully human construct to that seen with a murine CAR: 70% versus 73%.

But what set the pulses racing was a staggering reduction in toxicity: only 5% of subjects treated with the human construct experienced serious neurotoxicity, versus the more usual 55% treated with the mouse CAR. The only remaining question is why so many companies and institutions still focus on CARs with murine binders.

1. The next generation

And the winner is... a next-generation CAR construct with a completely separate co-stimulatory domain, whose concept has been expounded for some years by Sloan Kettering’s Dr Michel Sadelain. This comprises a membrane-bound 4-1BBL (the ligand, as opposed to 4-1BB itself), and is designed to cause additional stimulation of bystander T cells to result in potent tumour killing.

Ash saw Dr Jae Park present the first clinical data from this so-called third-generation “armoured CAR”. Remarkably, in just a few months this trial has managed to yield 28 evaluable haematological cancer patients, giving an impressive 82% overall response rate, with 15 complete remissions.

But again it was safety that truly amazed, with just three grade 3 neurotoxicities and zero incidence of serious cytokine release – a virtually unheard of finding in this patient population.

Investors and biotechs alike will note the lack of active industry involvement in any of the above assets. Congratulations to all involved.