/ 26 January 2015

Experimental cancer drugs effective – but with drawbacks

In some trials two new approaches have eliminated all traces of blood cancers in 40% to 90% of patients who had no remaining options.
In some trials two new approaches have eliminated all traces of blood cancers in 40% to 90% of patients who had no remaining options.

A new wave of experimental cancer drugs that directly recruit the immune system’s powerful T cells are proving to be immensely effective weapons against tumours, potentially transforming the $100-billion global market for drugs that fight the disease.

But top oncology researchers are concerned about the two emerging technologies, citing dangers seen repeatedly in clinical trials including the potentially fatal buildup of toxic debris from killed tumour cells and damage to healthy tissue. Such side effects could block regulatory approval if they aren’t controlled, say researchers and drug company executives.

In some trials, the two new approaches, known as CAR T cells and bispecific antibodies, have eliminated all traces of blood cancers in 40% to 90% of patients who had no remaining options. 

The drugs could reap annual sales in the tens of billions of dollars for their manufacturers, especially if they can also eliminate solid tumours in such terminally ill patients.

CAR T cells, or chimeric antigen receptor T cells, are T cells that have been removed from the body and attached through genetic engineering to an antibody fragment that recognises a specific tumour protein. 

T cells are an especially powerful disease-fighting kind of white blood cell. The result is a drug with the killing power of a greatly enhanced T cell, combined with the tumour-spotting ability of an antibody.

Bispecific antibodies are a twist on conventional antibodies, Y-shaped proteins whose two arms grasp for the same protein target found on cancer cells.

With bispecifics, one arm of the antibody typically grasps a cancer cell while the other arm takes hold of T cells, bringing the mortal enemies into contact. The T cell punches holes into the adjacent tumour cell and injects deadly enzymes. Conventional antibodies, by contrast, don’t directly recruit T cells.

‘Unleashing the killing power’
“Unleashing the killing power of the T cell directly on the tumour cells allows a large increase in potency of these antibodies,” said Dr David Scheinberg, chairman of molecular pharmacology at Memorial Sloan Kettering Cancer Centre.

Investor excitement over these therapies have helped boost interest from companies including Amgen Inc and Roche, and have fueled a jump in share prices of smaller firms such as Kite Pharma, Juno Therapeutics and Bluebird Bio.

“We take patients that have failed every treatment, every chemo combination, that have just two to six months to live. You give them a CAR, and within three to four weeks you can see massive tumours melting away,” said Arie Belldegrun, chief executive of Kite. The company went public in June and announced a partnership with Amgen earlier this month.

CAR T cells could cost $300 000 to $500 000 per patient, if approved, making them among the world’s most expensive drugs and testing the ability of insurers to pay for them, said Les Funtleyder of E Squared Asset Management. The hedge fund owns shares of Kite Pharma. Bispecific antibodies could command prices of $200 000 or higher, he said.

The potency of the experimental drugs comes with some dangerous potential side effects. In the killing process, inflammatory chemicals from the medicines and the tumour cells, called cytokines, are released into the bloodstream and can cause fever, low blood pressure and rapid heartbeat that can be life-threatening.

The drugs, because of their unique structure and how they work, make it harder to predict whether they will go astray, said Dr Bindu George, team leader of the US Food and Drug Administration’s Office of Cellular, Tissue and Gene Therapies, who called CAR T drugs perhaps the most interesting new technology.

Most CAR T cells and bispecific antibodies in development identify blood cancer cells by a specific protein, CD19, found on the surfaces of lymphomas and leukemias. Because the same protein can also be found on non-cancerous cells, the drugs can go off track and attack healthy tissues.

“Our biggest concern would be an off-target toxicity that wasn’t expected and we didn’t know the cause of it,” George said. In that case, “we might have to ask [the drug manufacturer] for additional information, how the toxicity happened, what organ it was, and literally go back to the drawing board”.

Taming a powerful drug
Researchers have used anti-inflammation medications to tame some of the adverse reactions, not always successfully. A study of CAR T cell treatment sponsored by Juno for patients with aggressive non-Hodgkin’s lymphoma was briefly put on hold after two people died.

Unlike antibodies, which are excreted from the body within days or weeks, engineered CAR T cells are expected to circulate for years or even a lifetime in the bloodstream, potentially providing lasting benefits, but also risks.

“You can start to reject normal tissues; it can kill organs or cause autoimmune disease, and you don’t want that,” said Zelig Eshhar, a professor emeritus of the Weizmann Institute in Israel who pioneered the CAR approach.

To reduce that danger, researchers are attempting to build “suicide switches” into CAR T cells to turn them off after they have wiped out all signs of cancer.

At least 30 bispecific antibodies are believed to be in development, including ones from Roche, Johnson & Johnson, AbbVie and Eli Lilly.

A growing number of drug manufacturers are also racing to develop the first CAR T therapies, including Kite, Novartis, Juno, Cellectis and its partner Pfizer, and Bluebird, in partnership with Celgene.

An expensive option
The United States Food and Drug Administration (FDA) in December approved the first bispecific, Amgen’s $178 000 Blincyto for acute lymphoblastic leukemia (ALL) that did not respond to previous treatment.

One third of patients in the Amgen study had no detectable cancer for nearly seven months after receiving the drug through a month-long infusion.

A main hope for Blincyto is that it will keep patients alive until they can receive stem cell transplants, their best chance of a possible cure.

CAR technology may also come to the rescue where few options remain.

“If doctors and specialists learn how to control this very powerful gun, CAR T cells could save hundreds of thousands of people in the United States,” said Ori Hershkowitz, a Tel Aviv-based fund manager with Sphera Funds, which owns shares of Kite and rival CARs developer Novartis.

A Novartis trial showed 27 of 30 children and adults with ALL had no signs of the disease after being treated with its CAR T drug. Some 78% of patients were still alive six months after treatment, while some sustained remission for up to two years.

But everyone in the study developed cytokine release syndrome, including a severe form of it in 27% of patients.

“It certainly needs to be watched and evaluated,” said Usman Azam, global head of cell therapies for Novartis. He still believes the drug’s benefits provide “compelling hope that you can potentially cure patients”.

Roche’s Genentech unit is conducting a mid-stage trial of a bispecific antibody to treat head and neck cancer and colorectal cancer. It is studying a dozen others in preclinical trials against cancer, Alzheimer’s disease and inflammatory diseases.

Paul Carter, a Genentech executive, was cautious about the prospects.

“It’s too early to say whether this will be a home run, although there’s optimism it will be at least a base hit that will help us figure out how to go further.” – Reuters