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News in brief

Novartis revs the CAR immunotherapies

Credit: Artville

Novartis has licensed rights to the University of Pennsylvania's chimeric antigen receptor (CAR) immunotherapies, a new anticancer therapeutic modality.

The lowdown: CAR immunotherapies are akin to a hybrid of T-cell-stimulating therapy, gene therapy and antibody therapy: T cells are harvested from patients, transduced with a vector encoding a chimeric protein that consists of an antibody-binding domain coupled to an immunostimulatory domain, and then re-infused into the body to induce tumour cell killing. Researchers can modify the antibody-binding domain to specifically target different tumour types or the immunostimulatory domain to increase anticancer activity. Unlike some other immunotherapies that act by broadly boosting immune surveillance, one advantage of the CAR therapies is that they can be targeted against tumour cells, thereby potentially minimizing off-target effects and autoimmunity complications.

In a proof-of-principle study of the technology in humans, researchers reported last year that one patient with chronic lymphocytic leukaemia (CLL) went into remission after treatment with CART-19 — in which T cells are engineered to express CD19-targeting CARs (N. Engl. J. Med. 365, 725–733; 2011). So far, three CLL patients have now been treated with CART-19: two remain in complete remission more than a year since treatment, and the third maintained partial remission for more than 7 months. CART-19 was also well tolerated, says Novartis. The engineered cells have been shown to persist in patients for months after infusion, suggesting that one dose may be sufficient for treatment. Novartis plans to initiate a Phase II trial of CART-19 before the end of the year.

Novartis has also licensed the underlying platform technology, and so will work with the University of Pennsylvania, USA, to develop the CAR technology against other antigens and for other cancer indications. To this end, it will provide US$20 million to establish a Center for Advanced Cellular Therapies at the University of Pennsylvania.

New hope for anti-inflammatory p38 inhibitors?

Array's ARRY-797 met its primary efficacy end point in a Phase II osteoarthritis trial, potentially renewing interest in a troubled drug class.

The lowdown: p38 mitogen-activated protein kinase inhibitors have been proposed as possible anti-inflammatory agents because of the kinase's role in mediating the production of the inflammatory cytokines tumour necrosis factor (TNF) and interleukin-1, and the pain mediator prostaglandin E2. Clinical candidates, however, have yielded disappointing results. Vertex and Boehringer Ingelheim have both previously abandoned Phase II candidates, for example, owing to liver, skin and central nervous system toxicity signals. “The general concern is that some of the side effects of p38 inhibitors are not off-target, but are on-target effects,” warns Matthias Gaestel, a professor of biochemistry at the Hannover Medical School in Hannover, Germany.

New trial results suggest that there may still nevertheless be hope for the class. Array treated 157 patients with osteoarthritis who were suffering with severe knee pain with their p38 inhibitor ARRY-797 or with oxycodone ER as an active control. The trial met its primary end point of reduction in pain at 28 days as assessed by the Western Ontario and McMaster Universities Arthritis Index. The drug was reportedly well-tolerated, although it was associated with transient increases in creatine kinase and aspartate aminotransferase levels, as well as mild prolongations of the QTc interval and sustained decreases in systolic and diastolic blood pressure.

The results are “very good news for the field”, says Gaestel. Outstanding questions include whether the increases in aspartate aminotransferase levels relate to liver injury, and whether c-Jun N-terminal kinase activity is affected in select tissues. An ongoing dosing study in healthy volunteers may also provide further clarity on the drug's safety profile.

According to BioMedTracker, the only other p38 inhibitor in active clinical development for osteoarthritis indications is Flexion Therapeutics's Phase II candidate FX005. Several are also in development for chronic obstructive pulmonary disease. Gaestel notes that much of the interest in the space has shifted to MK2/3 inhibitors, which act downstream of p38 activity and may therefore have better safety profiles.

Sepsis field set back again

AstraZeneca and BTG have stopped developing their Phase II sepsis candidate, leaving few drugs in the sepsis pipeline.

The lowdown: Effective sepsis drugs have long eluded drug developers. Most of the trials that have been conducted over the past decade or so have failed to yield positive results, and one of the only novel therapies approved in this time — Eli Lilly's drotrecogin alfa — was withdrawn late last year owing to a lack of evidence of efficacy in follow-up studies.

AstraZeneca and BTG are now the latest to suffer a setback, after their CytoFab did not improve ventilator-free days or mortality in a Phase IIb trial in patients with severe sepsis and/or septic shock. CytoFab was a polyclonal antibody fragment against TNF, and is not the first candidate from this class to fail in sepsis. As far back as 1996, groups were reporting that anti-TNF drugs were ineffective (N. Engl. J. Med. 334, 1697–1702; 1996). Past failures have been attributed to insufficient potency, clinically heterogeneous patient populations and the possibility that anti-TNF therapies need to be administered within narrow time frames.

As a result of the continued failures and subsequent disinvestment, the sepsis pipeline is practically dry. Earlier this year, Agennix halted a trial of its candidate talactoferrin alfa, a targeted dendritic cell recruiter and activator, after preliminary results suggested that it would not improve all-cause mortality versus placebo in a Phase II/III trial in patients with severe sepsis. Agennix says it is continuing to consider its options for the drug, which also failed a Phase III trial in non-small cell lung cancer last month. Eisai reported in early 2011 that its toll-like receptor 4 antagonist eritoran did not reduce all-cause mortality in a Phase III severe sepsis trial.

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News in brief. Nat Rev Drug Discov 11, 663 (2012). https://doi.org/10.1038/nrd3840

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