Immune therapies pose dilemma: How much is enough?
When experimental medicines aiming for approval are tested in humans, the first step is finding a safe dose range in a small group of patients. Then the focus shifts to showing effectiveness in larger groups.
But what if the "drug" is genetically engineered using the patient's own immune cells -- and those cells don't follow the usual dose-effect patterns?
This week at the annual meeting of the American Society of Clinical Oncology, two University of Pennsylvania researchers described their team's efforts to define the best doses of T cell immunotherapies.
"We're at a point in the field where we're trying to maximize safety, but don't want to reduce the efficacy," Penn hematologist-oncologist Noelle Frey said in an interview.
At Penn, Children's Hospital of Philadelphia and other leading centers across the country, T cell therapies have produced dramatic, lasting remissions in small but growing numbers of patients with advanced leukemias and lymphomas. The success has spurred a many-billion-dollar pharmaceutical race to commercialize the complex technology.
While generally safer than chemotherapy, these T cell therapies do have bad side effects. Most patients develop fever, flu-like symptoms and sometimes delirium as molecules called cytokines signal the engineered T cells to hunt and kill malignant white blood cells. In severe cases, this "cytokine release syndrome" turns into a "cytokine storm," unleashing a tsunami of inflammation that quickly leads to organ failure, even death.
Four years ago, when a cytokine storm nearly killed Emily Whitehead, the first pediatric T cell recipient at Children's, researchers discovered by luck that a new anti-inflammatory drug for rheumatoid arthritis, tocilizumab, could calm the storm. That central Pennsylvania girl, now 11, remains cancer-free, as do 35 of the 59 children treated so far -- almost 60 percent.
Tocilizumab became a standard treatment for patients with severe reactions to the T cell therapy, Frey said. But researchers also have tried to figure out whether reducing or spreading out the dose of T cells would prevent such toxicity.
Frey described a dose optimization study of 30 adult patients with acute lymphoblastic leukemia. Researchers gave a high dose of T cells in a single intravenous infusion, or in graduated amounts over three days. They also tried giving a lower dose.
The single high dose infusion, given to six patients, turned out to be unsafe. Although three of the six had complete remissions -- their cancer disappeared -- the other three patients died of cytokine toxicity intensified by infections. The low dose was safer, but the response rate was only 33 percent.
The safest, most effective approach proved to be the high dose given over three days: 10 percent on the first day, 30 percent on the second day, and 60 percent on the third. This enabled doctors to monitor the patient and withhold later doses depending on signs of cytokine toxicity. With this dosing regimen, Frey said, 13 out of 15 patients, or 86 percent, responded.
Penn hematologist-oncologist David Porter presented results of a dose optimization study of 30 adults with another blood cancer, called chronic lymphocytic leukemia (CLL). Researchers tried a high dose and a lower dose of T cells, but saw no correlation between the dose and the development or severity of cytokine toxicity.
However, the lower dose was less effective. Only 31 percent of the CLL patients (4 of 13) responded to the lower dose, compared to 53 percent (9 of 17) with the higher dose. Six high-dose patients had a complete response rate -- meaning their cancer disappeared -- compared to one at the lower dose.
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