Early results suggest a new cancer-fighting drug named NJH395 can stimulate the immune system to attack tumors from within, a strategy that could prove fruitful for future treatments. Results of a phase one clinical trial, recently published in Cancer Immunology Research, show that despite some safety issues that will require further research, the drug works as intended on the molecular level, successfully delivering immune activators into tumors.
The drug is composed of two molecules: a tumor-seeking antibody that hunts down and binds to proteins on the surface of cancer cells, and an immune-stimulating “payload” towed into the tumor by the antibody. The payload is an activator of Toll-like receptor-seven, a protein found in various classes of immune cells. Activating these receptors has been previously shown to change the tumor environment and increase immunity against tumors. It’s the first study in humans to test this class of drug, known as an “immune stimulator antibody conjugate,” says co-author Vasileios Askoxylakis, a radiation oncologist who led the program to develop the drug at the Novartis Institutes for BioMedical Research, in Cambridge, MA.
Although this study provides proof of mechanism that this class of molecules “can do what they’re supposed to do biologically,” Askoxylakis says, he also cautions that his team “identified some critical challenges.” In particular, a single dose of the drug stimulated a generalized immune response in some patients, leading to the release of cytokines that could cause adverse events and damage healthy organs. Second, some patients also developed antibodies to the drug itself, which would lead to drug-resistance.
Because the trial identified these risks in toxicology studies early on, patients only received one dose and therefore NJH395 “didn’t cure patients from their disease,” or provide a clinical benefit, Askoxylakis cautions. But, he says, on the molecular level, this study is crucial proof of concept that an antibody can effectively tow an immune-triggering payload into cancer cells. “We think these novel insights will help companies develop better drugs,” Askoxylakis says, so that future generations of immune-stimulator antibody conjugates could be safe and effective.
To get to this point, researchers first designed the drug, testing a variety of antibodies that are linked to immune-stimulating payloads. They sought the most effective and safe combination in cell cultures and animal models. Many existing chemotherapies already use antibodies to tow tumor-killing compounds into cancer cells.
But NJH395 uses a potentially important new type of strategy. “What’s new here,” Askoxylakis says, is “ours doesn’t kill the tumor cell. It activates the immune system in the tumor environment to attack the tumor cells and kill them.” Using the body’s own immune system could ultimately be more effective, more durable, and less toxic than generalized chemotherapies. For NJH395, the researchers selected an antibody similar to one already shown to be safe and effective at targeting the HER2 protein, which is overexpressed on a variety of cancer cells including in the lung, gut, pancreas, bladder, and throat. They linked it to a payload that activates immune Toll-like receptor seven, a protein that plays a role in immune response.
For the first-in-humans phase one clinical trial, the researchers worked with 18 patients diagnosed with a variety of treatment-resistant advanced metastatic cancers. Doctors collected blood samples and a tumor biopsy before the first NJH395 treatment, and again five days after treatment, with a CT or MRI scan to assess tumor response at 21 days. Because the drug raised some safety flags after a single dose, including a generalized immune response in some patients, this trial did not progress through multiple doses of the drug to assess its efficacy at fighting tumors.
Although this is an interesting study, it is still “too early to tell” whether drugs similar to NJH395 will be clinically useful as cancer therapies, says infectious diseases physician and immunologist Otto Yang at the David Geffen School of Medicine at the University of California, Los Angeles. This latest work does show that an antibody can deliver an immune-modulating molecule to tumors, he says, which has been an area of recent and intense research interest. But 18 patients is still a small sample size, and the treatment didn’t show any benefit in this work, meaning it’s a “very preliminary finding,” he says. Proving clinical efficacy will be the next key step.
But showing that this class of drug could activate immune cells in tumors at all “opens the field for development of other molecules,” Askoxylakis says. Although this particular drug wasn’t safe enough to give multiple doses, the findings may help other researchers, he says, to “develop better molecules that can mitigate some of these challenges.”
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