Recent findings suggest that a new drug anticancer drug called NJH395 may stimulate the immune system to attack tumors from within, a strategy that could prove fruitful for future treatments. The study is in phase one and was recently published in Cancer Immunology Research. There are indeed still some safety issues, which will require further research, but the drug works as intended at the molecular level, successfully delivering immune activators into tumours.
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Tumors, new drug NJH395 exploits the immune system: how it works
The drug is composed of two molecules: an antibody that seeks out the tumor and binds to proteins on the surface of cancer cells, and an immunostimulating “payload” pulled 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. Activation of these receptors has previously been shown to change the tumor environment and increase immunity against tumors. It is the first human study to test this class of drugknown as “antibody-immune-boosting conjugates,” says co-author Vasileios Askoxylakis, a radiation oncologist who led the drug development program at the Novartis Institutes for BioMedical Research in Cambridge, MA.
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Criticalities
While this study provides mechanistic evidence that this class of molecules “can do what it is supposed to do biologically,” Askoxylakis also cautions that his team “identified some critical challenges.” Notably, a single dose of the drug stimulated a generalized immune response in some patients, leading to release of cytokines that could cause adverse events and damage healthy organs. Second, some patients have developed antibodies to the drug itself, which could lead to drug resistance.
The experimentation
Because the trial identified these risks in toxicology studies early on, patients received only one dose. And so NJH395 “didn’t cure patients of their disease” or provide a clinical benefit, warns Askoxylakis. However, at the molecular level, this study represents a critical evidence that an antibody can effectively pull an immune load into cancer cells. “We think these new insights will help companies develop better drugs,” says Askoxylakis, so that future generations of antibody-immunostimulator conjugates can be safe and effective.
To get to this point, the researchers first designed the drug, testing a variety of antibodies bound to immunostimulating payloads. They searched for the most effective and safest combination in cell culture and animal models. Many existing chemotherapies already use antibodies to drive tumor-killing compounds into cancer cells.
The new system
But NJH395 uses a potentially important new type of strategy. “What’s new,” explains Askoxylakis, “is that our system doesn’t kill the cancer cell. It activates the immune system in the tumor environment to attack the cancer cells and kill them.” Using the body’s immune system could ultimately be more effective, longer lasting and less toxic than generalized chemotherapies. For NJH395, the researchers chose an antibody similar to one already proven safe and effective at targeting the HER2 protein, which is overexpressed in a variety of cancer cells, including those of the lung, intestine, pancreas, bladder and throat. They linked it to a payload that activates Toll-like immune receptor seven, a protein that plays a role in the immune response.
For the first phase one human clinical trial, the researchers worked with 18 patients diagnosed with various advanced, treatment-resistant metastatic cancers. Doctors collected blood samples and a biopsy of the tumor before the first NJH395 treatment and again five days after treatment, with a CT scan or MRI 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, this study did not proceed with multiple doses of the drug to evaluate its effectiveness in fighting cancer.
While an interesting study, it’s still “too early to tell” whether drugs similar to NJH395 will be clinically useful as cancer therapies, says physician and infectious disease immunologist Otto Yang of the University’s David Geffen School of Medicine. of California, Los Angeles. This latest work demonstrates that an antibody can deliver an immune-modulating molecule into tumors, an area of recent and intense research interest. But 18 patients is still a small sample, and the treatment didn’t show any benefit in this work, meaning it’s a “very preliminary finding,” he says. The next key step will be to demonstrate clinical efficacy.
But demonstrating that this class of drugs can activate immune cells in tumors “opens the door for the development of other molecules,” says Askoxylakis. While this particular drug wasn’t safe enough to be given in multiple doses, the findings may help other researchers “develop better molecules that can mitigate some of these challenges.”