Unanimous recommendation for CTL019 ahead of October decision builds confidence in T-cell genetic reprogramming

The first cancer therapy based on the revolutionary CAR-T approach, which genetically reprograms patients’ own white blood cells, looks set for approval in early October. On 12 July, a 10-person US Food and Drug Administration (FDA) committee unanimously recommended Swiss pharma giant Novartis’ CTL019 (tisagenlecleucel) for approval.

The resounding response adds confidence that several chimeric antigen receptor T-cell (CAR-T) blood cancer treatments from Novartis and other companies will progress in the near future. That’s especially welcome following setbacks the technology suffered in 2016 when patients died during a clinical trial for a CAR-T treatment from US-based Juno Therapeutics.

Novartis’ trials, in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukaemia (ALL), saw severe cytokine release syndrome (CRS) side-effects, but no deaths. This population has very short life expectancy and no other treatment option, explains Rachel Webster, senior director, oncology, at Decision Resources Group in London, UK. ‘The efficacy data are very strong and justify the potential risk,’ she adds.

This FDA committee looked mainly at one of three Phase II trials that Novartis is conducting on CTL019, called ELIANA, in which 57 of 68 patients responded by 28 days after treatment, with 41 in complete remission. This compares to expectations that fewer than 13 would respond if the drug had no effect. 11 patients in the trial have died from their leukaemia since treatment. However, a Novartis spokesperson tells Chemistry World that some others’ responses have lasted five years so far.

Novartis is preparing to scale up production ahead of commercial launch later this year, signing a deal for viral vectors with the UK’s Oxford BioMedica. The company will receive $10 million (£7.7 million) initially, and could be paid over $100 million over the next three years.

Calming the storm

CTL019 is manufactured for each individual patient using samples of their own white blood cells. Viruses are introduced to the cells to insert a gene for a chimeric antigen receptor. The CTL019 CAR-T cells then express the receptor protein, enabling them to target cancer B-cells, and are reintroduced to the patient. But the CAR-T cells also kill normal cells, leading to the life-threatening CRS experienced by 43 of the 68 patients in the ELIANA trial. Principally this causes symptoms such as high fevers and aches, with a median duration of eight days. To address the potential of fatal side-effects, Novartis offered supportive care and administered the drugs tocilizumab and siltuximab, which target cytokine immune signalling molecules.

Novartis now plans additional filings for CTL019 in the US and EU markets later this year for ALL and a different blood cancer, diffuse large B cell lymphoma (DLBCL). It is also continuing its research collaboration with the University of Pennsylvania team that it has licensed its CAR-T technology from. As well as exploring other blood cancers, the researchers are now looking at solid tumours, recently publishing results from a phase I trial in glioblastoma brain cancer.1 However, Webster warns that it’s too soon to talk about the potential or prospects of CAR-T in solid cancers.

Meanwhile, the FDA is also reviewing a CAR-T treatment from US-headquartered Kite Pharma called KTE-C19 (Axi-cel) in non-Hodgkin’s lymphoma, with a decision due on 29 November. And even Juno’s CRS woes ‘are beginning to feel like a distant memory’ according to Webster. Its current lead treatment, JCAR017 is providing high rates of durable response in non-Hodgkin’s lymphoma trials, with just 2% of patients suffering from CRS.