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Patients taking part in early clinical trials of the riskiest new cancer drugs are often in the final stages of the disease. When other medicines have failed, little is to be lost from a last throw of the dice on an experimental therapy.
This helps explain the excitement over a high-tech treatment which has led to the disappearance of cancer from scores of patients — in contrast to the few extra months of life which is usually the best that can be hoped for.
A growing body of evidence shows that use of adoptive T-cell therapy — involving the modification of immune cells to help them attack cancer — can transform the prospects of patients with advanced forms of blood cancer.
In one study published last month, 27 of 29 patients with acute lymphocytic leukaemia experienced sustained remissions after having their T-cells re-engineered. “You don’t expect results like these from early-phase trials,” says David Maloney, of the Fred Hutchinson Cancer Research Center in Seattle, which led the study. “That’s why these response rates are so extraordinary.”
The trial involved a Seattle-based company called Juno Therapeutics, whose early backers included Jeff Bezos, founder of Amazon. Other companies, including Kite Pharma of California and Novartis of Switzerland, have reported similar results.
Their treatments involve extracting disease-fighting T-cells from a patient’s body and modifying them in a laboratory with chimeric antigen receptors (CAR). This equips the cells to overcome defences used by cancer to avoid attack. Once reinfused into the blood, these “designer” CAR-T cells swarm the body, hunting out cancer cells to destroy.
The first of these products is on course to be filed with US regulators for approval next year. Several questions remain to be answered before CAR-T can be declared a success. The most important involves safety. The effectiveness of the treatments reflects their great potency but this also creates risks if the CAR-T cells kill too many healthy cells as well as cancerous ones.
Fatal side-effects have been reported in some CAR-T trials and Cai Xuan, oncology analyst at GlobalData, a research company, predicts these risks will limit usage. “The aggressive nature of T-cell therapy’s side effects means it is highly unlikely to replace current frontline therapy options,” she says.
The treatments have so far been limited mainly to blood cancers. It remains unclear whether it will be possible to safely extend the approach to solid tumours — a much larger market.
There are also big commercial problems relating to the exceptional cost of a treatment which must be individually tailored for each patient. The price has been estimated at between $300,000 and $500,000 per treatment. Dr Xuan says this can only be justified by a lasting cure, something that must be proven with longer-term clinical studies. “To date, only a handful [of trials] have gone ahead, in a limited number of patients, due to the high cost, as well as the long and difficult manufacturing processes.”
The one company to have reached market with a similar therapy — Dendreon of the US — filed for bankruptcy in 2014, much due to high production costs. Cell therapy advocates point out that Dendreon’s Provenge treatment for prostate cancer was less effective than CAR-T therapies and say lessons have been learned from Dendreon’s failure.
“The process used [by Dendreon] in early clinical trials was never really developed as the product was commercialised,” says Clive Glover, product leader for cell therapy technologies at GE Healthcare, which is working with Kite and others on manufacturing infrastructure. “The lesson is that you need to think about your manufacturing very early in the development process.”
The logistical and economic problems of CAR-T have led some researchers to an alternative approach. Cellectis, a French biotech company, is the leader among those pursuing so-called allogeneic cell therapies, which are made from donor cells and can be used by any patient. If proven safe and effective, this “off-the-shelf” method could provide a big cost advantage over “autologous” therapies. It would also overcome the difficulty of extracting enough cells from very ill patients whose immune systems are often severely depleted.
The Cellectis treatment has so far been used successfully on a compassionate basis on two British infants at Great Ormond Street hospital in London. The first formal clinical trials are due to get under way this year, backed by Pfizer, which has US rights to the therapy and a stake in Cellectis.
“It is early days,” says Chris Boshoff, who directs early development of cancer immunotherapies at Pfizer. “We still need to do well-controlled, formal studies to demonstrate the potential of the allogeneic approach but the data we have so far suggest this is an approach worth pursuing.”