Recent findings suggest that a new drug The cancer drug, called NJH395, could stimulate the immune system to attack tumors from the inside, 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 that require further research, but the drug works as intended at the molecular level and successfully delivers immune activators into tumors.
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Tumors, new drug NJH395 uses the immune system: how it works
The drug consists of two molecules: an antibody, which seeks out the tumor and binds to proteins on the surface of cancer cells, and an immune-stimulating “payload” that’s pulled into the tumor by the antibody. The payload is an activator of toll-like receptor seven, a protein found in different classes of immune cells. Activation of these receptors has previously been shown to alter the tumor environment and increase immunity to tumors. It is the first human study testing this class of drugsknown as “antibody-immune-enhancing 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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criticisms
While this study provides mechanistic evidence that this class of molecules “can do what they’re supposed to do biologically,” Askoxylakis also warns that his team “has identified some critical challenges.” Remarkably, in some patients, a single dose of the drug stimulated an overall immune response, resulting in this Release of cytokines that can cause side effects and damage healthy organs. Second, some patients have developed antibodies to the drug itself, which could lead to this drug resistance.
The experimentation
Because the study identified these risks early on in toxicology studies, patients only received one dose. And so NJH395 has “not cured patients of their disease” or provided any clinical benefit, Askoxylakis warns. However, at the molecular level, this study represents a crucial evidence that an antibody can effectively draw an immune load into cancer cells. “We believe these new findings will help companies design better medicines,” Askoxylakis says, so that future generations of antibody-immunostimulator conjugates can be safe and effective.
To get to this point, the researchers first designed the drug and tested a variety of antibodies attached to immune-stimulating payloads. They looked for the most effective and safest combination in cell culture and animal models. Many existing chemotherapies already use antibodies to deliver tumor-destroying compounds into cancer cells.
The new system
But NJH395 uses a potentially important new type of strategy. “What’s new,” Askoxylakis explains, “is that our system doesn’t kill the cancer cell. It activates the immune system around the tumor to attack and kill the cancer cells.” Ultimately, utilizing the body’s immune system may be more effective, longer lasting, and less toxic than general chemotherapy. For NJH395, the researchers chose an antibody similar to one already shown to be safe and effective to target the HER2 protein, which is expressed in a variety of cancer cells, including those of the lung, colon, pancreas, bladder, and colon pharynx, is overexpressed. 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 human clinical trial, researchers worked with 18 patients diagnosed with a variety of advanced, treatment-resistant metastatic cancers. Doctors took 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 this is an interesting study, it’s “too early to say” whether drugs similar to NJH395 will be clinically useful as cancer therapies, says infectious disease physician and immunologist Otto Yang of the David Geffen School of Medicine University of California, Los Angeles. This latest work demonstrates that an antibody can deliver an immunomodulatory molecule into tumors, an area of current and intense research interest. But 18 patients is still a small sample, and the treatment showed no benefit in this work, meaning it’s a “very preliminary finding,” she says. The next important step will be proof of 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 results could help other researchers “design better molecules that may mitigate some of these challenges.”