Juno Therapeutics has built remarkable momentum—including last week’s much-dissected $1 billion deal with Celgene—upon early success treating leukemia and lymphoma patients with a first generation of experimental T cell therapies developed by its academic partners.
Now, with one of those partners, Seattle-based Juno (NASDAQ: JUNO) is about to start another landmark trial: The first test in humans of engineered T cells with added firepower and sophistication, which some call “armored CARs.”
The basic idea behind T cell immunotherapy is to use a patient’s own immune cells as the medicine. They are extracted from the body, engineered to become better cancer killers, and re-inserted into the patient. CAR stands for chimeric antigen receptor, which is the piece of the T cell modified to zero in on proteins on the surface of cancer cells.
Funded by Juno, an upcoming Phase 1 trial will treat patients with relapsed ovarian cancer, one of many solid-tissue tumors that are expected to be a much higher hurdle for the field of cell-based immunotherapy. Though T cells still have much left to prove in blood-borne cancers, which are relatively rare, scientists want to use the technology to target a cancer like ovarian, which will kill an estimated 14,000 women in the U.S. this year.
“The big question is, ‘Can you cross over to solid tumors?'” says Renier Brentjens, the director of cellular therapeutics at Memorial Sloan Kettering Cancer Center in New York and a Juno scientific founder.
Brentjens will begin to answer his own question soon. He tells Xconomy that in August or September he will begin treating ovarian cancer patients with armored CAR-T cells, engineered to send out a chemical signal that recruits the patients’ non-engineered T cells to come join the attack. “We’re going full force forward,” says Brentjens.
That extra boost is one of three main modifications. The cells will also zero in on a tumor cell target called MUC16, and they will carry a self-destruction switch that clinicians can trigger in case the cells get too aggressive, hit unintended targets, or cause an immune overreaction.
Those modifications are meant to overcome some of the challenges solid tumors present, although Brentjens cautions not to expect the same results that CAR-T cells have shown so far in leukemia and lymphoma—remission rates well above 50 percent.
Just as it did with some of the blood-cancer programs now under Juno’s roof, Sloan Kettering will run the trial. Juno has license to the technology, says Juno chief financial officer Steve Harr.
The trial is important on two fronts. To date, T cell therapies have treated relatively rare blood-borne cancers. If that’s the extent of the treatment’s reach, it would still be a medical breakthrough. But researchers, doctors, and patients dream of the cells attacking solid tumors, which account for about 90 percent of all cancers.
The American Cancer Society estimates that ovarian cancer is the fifth-deadliest in the U.S. “The animal data have been compelling, and we want to get this into patients,” says Harr.
The Sloan Kettering trial won’t be the first test of engineered T cells in solid tumors. In a tiny, six-person study reported in April, CAR-T cells from the University of Pennsylvania appeared to be safe. But the university, which has an exclusive partnership with Novartis (NYSE: NVS), reported the cells showed no effect on the tumors. And Juno’s partner, Seattle Children’s Hospital, has just started a Phase 1 CAR-T trial for children with neuroblastoma, a cancer that develops from immature nerve cells.
In the case of Brentjens’s cells, the protein that signals to other T cells to help with the attack, could be the difference. His cells use interleukin-12, or IL-12, a so-called cytokine that has powerful immune stimulation properties.
“If we can safely deliver the cytokine and help turn on the rest of the immune system, and do that locally instead of systemically, it would be a major advance,” says Harr.
Brentjens says by restricting the secretion of IL-12 to the area right around the tumor, the armored CAR-T cells become a “micro-pharmacy.”
Keeping tight control of that secretion is important. Cytokines are a double-edged sword; if the body produces too many of them, they set off a dangerous immune over-reaction, sometimes called a “cytokine storm.” (In an earlier CAR-T trial at Sloan Kettering, to treat non-Hodgkin’s lymphoma, two patients suffered a cytokine storm and died, halting the trial for a few weeks but not derailing the program.)
Researchers are slowly learning which patients might be more susceptible to the overreaction. For example, people with a lot of tumor mass in their bodies might need to be monitored more closely. Overall, however, Brentjens cautions that no one can yet predict which patients might respond favorably to T cell therapy. Researchers at the University of California, Los Angeles published work late last year that showed why certain patients responded well to a different kind of cancer immunotherapy—an antibody called pembrolizumab (Keytruda). But that was looking back, not looking forward.
For extra safety, Juno, Sloan Kettering, and others working in the field are also building “kill switches” into their cells. With the upcoming ovarian cancer trial, Brentjens’s cells will have an extra protein—a truncated form of epidermal growth factor receptor, or EGFRt—engineered into them. If something goes wrong, the clinical team can inject patients with an antibody that attaches to the EGFRt and causes the cell to die. “We want to eliminate the T cells in rapid fashion if we see unforeseen toxicity,” says Brentjens.
The EGFRt tag has been incorporated into other Juno CAR-T programs, but there hasn’t yet been the need to activate the kill switch, says Michael Jensen, another of Juno’s scientific founders. Jensen invented EGFRt when he was at City of Hope, a top cancer center near Los Angeles. Now at Seattle Children’s, Jensen says the CAR-T cells in the neuroblastoma trial there have an EGFRt kill switch, as well. They are not armored with cytokines.
It’s all uncharted territory—the latest in a series of frontiers in cancer immunotherapy that researchers, doctors, and patients will continue to push toward as long as the field shows promising results.
Brentjens can’t help but look back at the field’s early days. “Seventeen years ago, ASH”—the American Society of Hematology, which holds a big medical conference every year—“let us present our posters because they felt sorry for us,” he says. “Now here we are, sitting on the edge of our seats for this trial.”
Photo of an armored Czechoslovak Škoda courtesy of Phil DeFer via Creative Commons.