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currently know what they are. That means that if a therapy is affecting the immune system, we’re not able to detect those effects. This could explain some clinical results that have left people scratching their heads. NewLink Genetics CEO and chief scientific officer Charles Link, for instance, noted that a patient’s cancer in one of the studies of a NewLink immunotherapy drug initially progressed before a response to the therapy kicked in a year and a half later. “I don’t understand how that’s possible,” he says.
The effectiveness of cancer drugs is currently measured using FDA-required criteria known as “Response Evaluation Criteria in Solid Tumors,” or RECIST, which is based on whether a patient’s tumor shrinks or not. Monday’s panelists believe that as immunotherapies become more common, it’s going to be just as important to measure how a person’s immune system is reacting as well. Perhaps a patient is responding, but the effects aren’t showing up on a RECIST scan, says Infinity Pharmaceuticals CEO Adelene Perkins. The problem: “We have a lot to learn about how to measure that,” she says. “We’re at a real crossroads.”
Biomarkers for some, but not all?
There aren’t many broad, reliable biological predictors of response, known as biomarkers, for immunotherapy yet. The first to gain acceptance was expression of a protein called PD-L1, yet it has several limitations. Other biomarkers called microsatellite instability-high (MSI-H) and mismatch repair deficiency (dMMR), (meaning a cell can’t fix its own DNA errors) aren’t very common in cancer patients. Bristol-Myers last week declared one of its combination immunotherapy trials a success when it used tumor mutational burden (the number of genetic mutations seen within a tumor) as a biomarker, but that measure hasn’t been fully validated and has its own set of questions.
The problem may persist. Kassim, of Mustang Bio, warns that immunotherapy biomarkers simply “may not be universally applicable” across different tumors. For example, many immunotherapy drugs try to spur T cells, the immune system’s attack dogs, to fight cancer, so it would stand to reason that seeing T cells infiltrating tumors is a positive signal. That’s not the case though—in kidney cancer, he says, that’s a bad thing. When designing trials, companies need to keep in mind that these biomarkers might only be good measures for a specific cancer type, or a patient subset, Kassim says. “We need to keep in mind the context of the disease and the context of the patient’s history,” he says. “This is a tremendous opportunity to re-evaluate the way we do things.”
For CAR-T, Expect a Slow Build.
Over the past year, the FDA approved first two so-called CAR-T cell therapies, one from Novartis (NYSE: NVS) and the other from Gilead Sciences (NASDAQ: GILD), for two different types of blood cancer. More are likely on the way for other blood cancers, and the hope is these therapies might some day work for more common solid tumors, and be more than just last ditch treatments for people who have run out of options.
Out of the gate, these products, which involve extracting a patient’s cells, genetically modifying them and reinserting them, have reportedly struggled commercially due to reimbursement and other issues. Samuele Butera, a business leader with the Global Cell & Gene Therapies unit of Novartis, indicated that the uptake might remain slow, and that’s by design. He says cell therapy developers are taking a “very measured approach,” introducing CAR-T treatments by working with a select group of treatment centers in the U.S. and abroad that are familiar with the method, and know how to handle the sometimes severe side effects, like cytokine release syndrome. For the foreseeable future, it’ll likely to stay that way. There needs to be “a critical mass of knowledge and centers that can do this safely,” Butera says, before CAR-T is rolled out more broadly.
And reimbursement issues for the expensive CAR-T treatments still need to be worked out. Butera noted that the nonprofit Institute for Clinical and Economic Review, which evaluates the value of drug therapies, recently issued a draft report in favor of the high cost of CAR-T treatments. And in January, the Centers for Medicare & Medicaid Services gave CAR-T a product code, “which should help centers gain clarity on what reimbursement should look like.” But other panelists noted additional factors will help determine payer attitudes towards CAR-T. How long will the therapies prove to last before wearing off? And how much will the secondary costs associated with treatment, such as the care needed to manage its side effects, color their thinking?