By Tom Ulrich
One of the immune system’s basic jobs is to tell “self” from “non-self.” Our cells carry markers that the immune system uses to recognize them as being part of us. Cells that don’t carry those markers – like bacteria and other pathogens – therefore don’t belong.
Cancer cells, however, fall into a gray area. They’re non-self, yet they also bear markers that connote self-ness – one of the reasons the immune system has a hard time “seeing” and reacting to cancer.
Can we focus the immune system’s spotlight on cancer cells? The provisional answer is yes. Research on cancer immunotherapy – treatments that spur an immune response against cancer cells – has boomed in recent years. (The journal Science recognized cancer immunotherapy as its Breakthrough of the Year in 2013.)
And one of the more recent methods – called chimeric antigen receptor (CAR) T-cell therapy – is now in a clinical trial for relapsed or treatment-resistant B-cell acute lymphoblastic leukemia (ALL) at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.
ALL is the most common childhood cancer. While 95 percent or more of newly diagnosed children get into remission with standard therapy, between 10 and 15 percent of those children ultimately relapse within five years of being diagnosed. Salvage therapies for children with relapsed ALL are highly toxic and only work in about 50 percent of relapsed patients.
For these patients, immunotherapies – such as cancer vaccines, monoclonal antibodies and cytokine therapies – hold a lot of promise. The problem has been translating that promise into clinical success.
“There has been evidence for many years that the immune system can be used to help control leukemia,” says Lewis Silverman, MD, clinical director of the Hematologic Malignancy Center at Dana-Farber/Boston Children’s and the trial’s site lead. “But we have yet to find the best way to harness the immune system to treat disease.”
The CAR T-cell approach may be one way. It starts with the patient’s own T-cells, and uses genetic engineering to make them more active than usual and better at targeting tumors.
“We’re educating and energizing T-cells to go after leukemia cells,” says David Williams, MD, a gene therapy specialist, chief of hematology/oncology and director of clinical and translational research at Boston Children’s Hospital and associate chair of pediatric oncology at Dana-Farber Cancer Institute. “It’s a very focused approach.”
Putting T-cells’ pedal to the metal
In a laboratory, patients’ T-cells are first exposed to a viral vector holding the genetic instructions for building a CAR. The CAR has two parts:
- A receptor portion that sits on the T-cell’s surface. To target B-cell ALL, CAR T-cell trials typically use receptors for CD19, an ALL marker that is almost always expressed on B-lymphoblasts (the malignant cells in B-cell ALL).
- A signaling portion that stays within the T-cell. When the receptor detects an ALL cell, the signaling portion, revs the T-cell up, prompting an aggressive and rapid attack.
The vector plugs the CAR instructions into the T-cells’ genomes. Once the T-cells grow and start producing CARs on their surface, they’re infused back into the patient.
Promising, but not perfect
One downside of CAR T-cell therapy is a phenomenon called cytokine release syndrome (CRS). As the engineered T-cells mount their attack, they release a rush of immune signaling molecules called cytokines. This overabundance of cytokines can have severe effects, including drops in blood pressure, fever spikes and neurological complications.
As a result, it’s standard practice to admit patients in CAR T-cell trials to the intensive care unit for a few days, so doctors can monitor for and quickly address CRS.
Another concern is that ALL cells aren’t the only cells that carry CD19; healthy B-cells also display the marker on their surface. The CAR-bearing T-cells will therefore attack them as well, but it is not clear how long this effect will last.
“It depends on how long the engineered T-cells persist in the body,” Silverman explains. “Right now, no one knows. That’s one thing we’re measuring as a secondary outcome in the trial.”
Even with those concerns, though, CAR T-cells are garnering lots of attention for relapsed ALL. Other pediatric and adult trials of CD19 CARs at Memorial Sloan Kettering Cancer Center (where the Dana-Farber/Boston Children’s trial was initially launched), the Children’s Hospital of Philadelphia and the National Cancer Institute have resulted in response rates of around 90 percent. Silverman hopes to see similar results at Dana-Farber/Boston Children’s.
“The whole field is still figuring out how best to do this: the best receptor, the best vector, the best co-stimulatory molecule,” Silverman says. “But this could be a way of establishing a long-lasting immune response against relapsed ALL without the toxicity that comes with stem cell transplantation.”
To learn more about this trial, including eligibility requirements, visit the clinical trial’s listing at Dana-Farber/Boston Children’s, or email Colleen Dansereau, RN.