A Revolution is Taking Place in the Treatment of Blood Cancers

12/16/13Follow @3nt

I try to avoid sensationalizing early clinical trial results presented at medical conferences, what’s commonly known as “hype over hope.” But at this year’s annual meeting of the American Society of Hematology (ASH) in New Orleans I was struck by the thought that I was a witness to the beginning of a revolution in the treatment of blood cancers.

Switzerland-based Novartis and Seattle-based Juno Therapeutics are blazing the trail to bring novel therapies to market based on modifying a patient’s own white blood cells known as T lymphocytes, central to the immune process and fighting cancer.

After harvesting T cells from a patient, gene therapy is used to express chimeric antigen receptors (CARs) onto their surface, resulting in T cells that are redirected to target tumor cells.

Dramatic results have been seen in acute lymphoblastic leukemia (ALL).

Stephan Grupp, the director of translational research for the center for childhood cancer research at The Children’s Hospital of Philadelphia (CHOP) presented data at ASH that showed complete remissions for 19 out of 22 children with relapsed, treatment-resistant forms of ALL who got the new form of therapy. All five adults treated with the Novartis CTL019 chimeric antigen receptor (CAR) modified T cells also achieved a complete remission. This data, although still preliminary, was worthy of being presented in the plenary session of the ASH meeting.

Renier Brentjens, director of cell therapeutics at Memorial Sloan-Kettering Cancer Center in New York, and one of the scientific founders of Juno Therapeutics put this data in context:

“I see a therapy that now offers life-saving treatment to patients with e.g. relapsed B-cell ALL,” Brentjens said. “It really is a heart-warming story and it’s an incredible experience to have one of your own patient’s that was basically doomed to die, make it to transplant, then run into them in the hallways two years later. It’s fantastic! “

Significant challenges remain with CAR modified T cell therapy.

“I think the current iteration of CAR T cell therapy is a little bit like the model A Ford and ultimately we are looking for a Ferrari,” Brentjens said.

Researchers are already on the third generation of chimeric antigen receptors and a fourth generation is in development.

There’s still a lot we don’t understand, such as the optimal dose of T cells or why some patients respond or relapse and others don’t. Since this is a new technology, the follow-up of patients who have received this new therapy in ALL is quite short (2-18 months). We still need to know that the responses are long lasting.

The treatment also comes with the risk of quite serious and potentially life-threatening side effects that need to be carefully managed. These include cytokine release syndrome (a massive release of cytokines into the bloodstream that results in a range of bodily symptoms such as fever, nausea, headache, low blood pressure and raised heart rate). Researchers also have to keep an eye on delayed tumor lysis syndrome, which occurs when cancer cells are killed rapidly and such a large volume of metabolites are released into the bloodstream that the liver and kidneys can’t get rid of the excess potassium and other elements fast enough).

Some patients receiving CAR modified T cell therapy have needed hospitalization and intensive care, so in the immediate future this is not a therapy that is likely to be administered outside of a specialist hospital setting.

What does the future hold with CAR modified T cell therapy? Brentjens said he sees the potential to target not only blood cancers, but also solid tumors. Collaborations between industry and academia are central to this:

“The proof of principle is in there but there is a lot of room to make these cells better and that is again why Juno is so important. It allows us as investigators, as basic scientists in academia, to continue to devise creative ways to make these cells more potent so they won’t just be able to eradicate ALL and CLL in some cases, but they will be able to eradicate lung cancers and colon cancers etc as long as we can identify target antigens.”

Both Novartis and Juno Therapeutics will have to undertake multi-center clinical trials in order to convince the Food and Drug Administration (FDA) and other regulatory agencies that their CAR modified T cell therapies are safe and effective. We have a long way to go, but the promise is clearly there.

It is an exciting time in hematology, and from what I heard at the ASH annual meeting, I think we are on the cusp of a paradigm shift and a revolution in the treatment of blood cancers such as ALL.

Excerpts of the interview with Renier Brentjens were previously published on Biotech Strategy Blog, and are reproduced with permission.

Pieter Droppert is a management consultant, lawyer, science writer and editor of the Biotech Strategy Blog (http://biotechstrategyblog.com) on science, innovation and new product development in the pharma & biotech industries. Follow @3nt

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