One of the hottest topics in Cancer Research is using the body’s immune system to fight cancer. This report discusses the promise of Chimeric Antigen Receptor (CAR) T Cell Therapy.

It was previously broadcast on the Sound Medicine Radio Hour on March 22, 2015.

Dr Stephan Grupp presents data at ASH 2014 media briefing moderated by Dr Catherine Bollard

Dr Stephan Grupp presents data at ASH 2014 media briefing moderated by Dr Catherine Bollard

In it you will hear an interview with Dr Stephan Grupp (The Children’s Hospital of Philadelphia) who talks about the clinical trial results seen with CTL019, a new CAR T Cell therapy in development by Novartis & The University of Pennsylvania.

This audio story was done in support of the Ken Burns/Barak Goodman “The Emperor of All Maladies” cancer film broadcast recently on PBS.

CAR T Cell Therapy is mentioned in the documentary – it features one of the first children with acute lymphoblastic leukemia (ALL) who received this treatment at The Children’s Hospital in Philadelphia (CHOP), Emily Whitehead.

Show Notes:

Immunotherapy works by helping the body’s own immune system target and kill cancer cells. It has the potential to target only cancer cells, says Dr. Catherine Bollard, a pediatric oncologist who leads a program researching these therapies at Children’s National Medical Center in Washington, DC.

“Ultimately our goal is to overcome the use of chemotherapy [and] radiation which blast everything healthy and malignant cells,” says Bollard. “It’s extremely exciting to target the tumor cells themselves by using our own immune system to attack the cancers.”

Your Cells, But Smarter

Every day, our immune system recognizes foreign invaders and destroys them. The problem for cancer patients is that the immune system has trouble identifying and targeting cancer cells because they often resemble normal healthy cells. Immunotherapy works by helping the body do a better job of detection.

However, the other exciting area in cancer immunotherapy is reprogramming the body’s T cells. These are a type of white blood cell that seeks out and destroys foreign invaders.

You can think of it like giving the immune system a software upgrade. Scientists remove T cells from a patient’s blood then genetically modify them in the laboratory. Gene therapy is used to express chimeric antigen receptors (CARs) onto their surface, resulting in T cells that are redirected to target tumor cells.

These modified T cells are then allowed to multiply until there are hundreds of millions, a process that can take a few weeks. They are then transfused back into the patient. These modified T cells can identify a specific protein or antigen on the surface of cancer cells, and kill those cells.

The reprogrammed T-cells are commonly referred to as CAR-T cells. CAR stands for Chimeric Antigen Receptor. That’s the engineered protein that enables them to attack cancer cells that have a specific marker on their surface.

Clinical trials with CAR T-cell therapies are currently underway.  Several companies and academic institutions are working to bring these new CAR T-cell therapies to market. However, none is yet approved by the US Food and Drug Administration (FDA), so they remain experimental and you have to be enrolled in a clinical trial at a specialist center.

The most promising results seen to date have been in the treatment of blood cancers, in particular a type of leukemia called acute lymphoblastic leukemia, or, ALL, for short.

Dr Stephan Grupp a pediatric oncologist, at The Children’s Hospital in Philadelphia (CHOP) led a clinical trial with CTL019 (a CAR-T cell therapy from Novartis/University of Pennsylvania) in pediatric ALL.The results have been stunning!

Data was reported last year in the New England Journal of Medicine, Chimeric Antigen Receptor T Cells for Sustained Remissions in Leukemia.

This November 2013 video highlights what this new therapy has meant to parents of children treated at CHOP.

CTL019 CAR-T cell therapy was given to 39 children at CHOP who were extremely sick with acute lymphoblastic leukemia (ALL). All of the children in the study had either failed previous treatments, or were no longer responding to them.

After one month of CAR T-cell therapy, 92 percent of patients went into a complete remission – there was no sign of their cancer. Six months later, three-quarters of the patients were still in remission. Dr Grupp says, without this treatment, many of these children would have died.

“To have 92 percent of those patients in a complete response and to have that maintained in a large fraction of the patients is nearly unprecedented,” says Grupp. “[It’s] very exciting for our group, for this group of patients and for the possibility that engineered T cells might be a very powerful treatment for cancer.”

Dr Grupp says that in addition to the results seen, what makes the treatment so exciting is it’s flexibility:

“Not only do we have an army of T cells that we can put into the patient to fight, but that army will expand as needed.” In other words, if the cancer is spread throughout the body, the T cells will replicate as much as necessary to kill it.

That’s not to say that CAR-T cell therapy doesn’t come without risks.

“The caveat is that when you really rev up the immune response there is some toxicity associated with that,” explains Bollard. Think of it like over-revving the engine of your car.

CAR T-cell therapy does come 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 circulation as a result of T cell stimulation that results in range of bodily symptoms such as fever, nausea, headache, low blood pressure and raised heart rate).

That’s why CAR-T cell therapy is now only given in a specialized center at a hospital where patients can be monitored and any side effects quickly treated.

Dr Grupp and others have done a lot of work to be able to predict which patients may be at greater risk of complications such as cytokine release syndrome, and have developed effective ways to manage this.

The standard of care for many blood cancers is a bone marrow transplant that carries the significant risk of death and long-term complications. Dr Grupp says CAR-T cell therapy has much fewer side effects.

“My fondest hope is that we may able to substitute CAR-T cell therapy for bone marrow transplant, at least for patients with this particular kind of leukemia,” says Grupp.

Beyond Blood Cancers

CAR-T cell therapy could be effective in many cancers, not just blood cancers such as ALL, if researchers can find the right marker or antigens on the surface of cancer cells to target, explains Dr. Renier Brentjens, an oncologist at Memorial Sloan Kettering Cancer Center in New York.

He’s one of the scientific founders of a biotech company, Juno Therapeutics, seeking to bring CAR-T cell therapies to market. It’s one of several companies and academic institutions with cell therapies in development.

“The current iteration of CAR-T cell therapy is a little bit like a Model A Ford, and ultimately, we are looking for a Ferrari,” he says. “The proof of principle is in there, but there is a lot of room to make these cells better so they won’t just be able to eradicate ALL, but they’ll be able to eradicate lung cancers, colon cancers etc, as long as we can identify appropriate target antigens.”

Grupp says this could be game changing and a revolution in cancer treatment. “If we can replicate the success that we have seen in leukemia, in other kinds of cancers, that would completely change the face of cancer therapy.”

The Future: Off the Shelf CAR T-Cells
At the moment CAR-T cell therapy is a personalized medicine: You take the T cells from a patient, modify them, then give them back.

But the next step might be to make CAR-T more readily accessible, so that a doctor could simply take a package of T cells out of a freezer, defrost them and give them to any patient.

Dr. Julianne Smith, is a vice president at Paris-based Cellectis, a biopharmaceutical company working on this approach.

Dr Julianne Smith at ASH 2014 annual meeting.

Dr Julianne Smith at ASH 2014 annual meeting.

She says that this might make the therapy a lot more efficient: “We think that if you want to get the product out to a large number of people, it may be the best way to go in the sense that we can produce enough patient doses from one healthy donor to treat hundreds of patients instead of taking the cells from the patient, modifying them and having one patient dose at the end of this prolonged process.”

These T-cells would be also taken from healthy donors, instead of cancer patients, something that may make them more robust to begin with.

In the future multiple CAR-T cell therapies may be available, so how will doctors choose one over the other?

P1270820Dr. Krishna Komanduri, (@DrKomanduri) Director of the Adult Stem Cell Transplant Program at the University of Miami Sylvester Cancer Center says he expects this will require balancing several factors.

“Obviously, as a physician and scientist, I want to see the best possible therapies reach my patients,” he says. “But in the real world, I think a constellation of factors between efficacy, toxicity, and then, of course, cost and value, will ultimately determine who the winners are in this field.”

Dr Komanduri will be an investigator in clinical trials with CAR T cell therapies from Kite Pharma and Juno Therapeutics.

It’s exciting times as researchers and doctors seek to maximize the promise and potential of cancer immunotherapy to revolutionize how we treat cancer in the future.

Additional Information:

Several of the interview quotes in the above audio story were first published on Biotech Strategy Blog (subscription required). They are used with permission.

Quote from Dr Brentjens: “Juno Therapeutics takes on Novartis and seeks to revolutionize the treatment of blood cancers – an interview with Dr Renier Brentjens.

Quote from Dr Smith: “Cellectis ramps up CAR-T Development in 2015

Quote from Dr Komanduri: “CAR T and Gene Therapy Excite BMT Tandem Meeting.

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