|By activating immune cells in tumors, an immune-modulating molecule shows early promise. Image courtesy of SciePro/Shutterstock.
Early results indicate that a new cancer-fighting drug known as NJH395 can stimulate the immune system to attack tumors from within, a strategy that could be beneficial for future treatments. The findings of a phase one clinical trial, published recently in Cancer Immunology Research, show that, despite some safety concerns that will need to be addressed further, the drug works as intended at the molecular level, successfully delivering immune activators into tumors.
The drug is made up of two molecules: a tumor-seeking antibody that seeks out and binds to proteins on the surface of cancer cells, and an immune-stimulating "payload" that the antibody tows into the tumor. The payload is a Toll-like receptor-seven activator, a protein found in various types of immune cells. Activating these receptors has previously been shown to alter the tumor environment and boost tumor immunity. It's the first human study of this type of drug, known as an "immune stimulator antibody conjugate," according to co-author Vasileios Askoxylakis, a radiation oncologist who oversaw the drug's development at the Novartis Institutes for BioMedical Research in Cambridge, MA.
Although this research shows that this class of molecules "can do what they're supposed to do biologically," Askoxylakis warns that his team "identified some critical challenges." A single dose of the drug, in particular, induced a generalized immune response in some patients, resulting in the release of cytokines that could cause adverse events and damage to healthy organs. Second, some patients developed antibodies to the drug itself, resulting in drug resistance.
Because the trial identified these risks early on in toxicology studies, patients only received one dose, and thus NJH395 "didn't cure patients from their disease" or provide a clinical benefit, warns Askoxylakis. On the molecular level, however, he believes that this study is critical proof of concept that an antibody can effectively tow an immune-triggering payload into cancer cells. "We believe that these novel insights will help companies develop better drugs," Askoxylakis says, implying that future generations of immune-stimulator antibody conjugates will be both safe and effective.
To get here, researchers first designed the drug, testing a variety of antibodies linked to immune-stimulating payloads. In cell cultures and animal models, they sought the most effective and safe combination. Many current chemotherapies use antibodies to deliver tumor-killing compounds into cancer cells.
However, NJH395 employs a potentially significant new strategy. "What's new here," says Askoxylakis, "is that it doesn't kill the tumor cell." It stimulates the immune system in the tumor environment to attack and kill tumor cells." Ultimately, using the body's own immune system could be more effective, longer lasting, and less toxic than traditional chemotherapies. The researchers chose an antibody that was previously shown to be safe and effective at targeting the HER2 protein, which is overexpressed on cancer cells in the lung, gut, pancreas, bladder, and throat. They connected it to a payload that activates immune Toll-like receptor 7, a protein involved in the immune response.
The researchers worked with 18 patients diagnosed with a variety of treatment-resistant advanced metastatic cancers for the first-in-humans phase one clinical trial. Before the first NJH395 treatment, doctors took blood samples and a tumor biopsy, and then again five days later with a CT or MRI scan to assess tumor response at 21 days. Because the drug raised some safety concerns after a single dose, including a generalized immune response in some patients, the trial did not proceed to assess the drug's efficacy in fighting tumors.
Although this is an intriguing study, it is still "too early to tell" whether drugs similar to NJH395 will be clinically useful as cancer therapies, according to infectious diseases physician and immunologist Otto Yang of the University of California, Los Angeles' David Geffen School of Medicine. According to him, the latest research shows that an antibody can deliver an immune-modulating molecule to tumors, which has been a hot topic in recent years. However, 18 patients is a small sample size, and the treatment did not show any benefit in this study, indicating that it is a "very preliminary finding," he says. The next critical step will be to demonstrate clinical efficacy.
However, the discovery that this class of drug could activate immune cells in tumors at all "paves the way for the development of other molecules," according to Askoxylakis. Although this particular drug was not safe enough to administer multiple doses, he believes the findings will aid other researchers in "developing better molecules that can mitigate some of these challenges."
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