Researchers at the Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, reported on the development of a new type of nanomedicine called antibody-conjugated drug-loaded nanotherapeutics (ADN), that is designed to deliver anticancer drugs to lung cancer cells and enhance the immune system’s ability to fight cancer.
Tested in cancer cells in the lab and in mice, results from experiments in animals with aggressive lung cancers showed that the anti-CD47-PDL1-AND therapy exhibited better antitumor efficacy than current treatment options using anti-PDL1 immunotherapy. The findings suggest the approach could have potential applications for improving care and outcomes for patients with tumors that have failed to respond to traditional immunotherapy.
“Nanoparticles have been used for years to deliver targeted medication to tumor cells, while immunotherapy has also had a paradigm-shifting impact on how we treat cancer, by stopping cancer cells from evading our immune system,” said lead author Tanmoy Saha, PhD, an instructor of medicine and researcher in the Division of Engineering in Medicine at the Brigham. “Here, we’ve essentially connected these two approaches in one drug delivery system to treat non-small cell lung cancer.”
Saha and colleagues reported on their findings in Science Advances, in a paper titled “Antibody nanoparticle conjugate-based targeted immunotherapy for non-small cell lung cancer,” in which they stated, “Here, we introduce trifunctional nanotherapeutics to block PDL1 and CD47 immune checkpoints simultaneously while inhibiting the molecular driver PI3K/AKT/mTOR pathway…Dual antibody-drug–loaded nanotherapeutics can emerge as an attractive platform to improve outcomes with cancer immunotherapy.”
Lung cancer is the leading cause of cancer death globally, accounting for over a quarter of all cancer-related deaths, the authors wrote. Non-small cell lung cancer (NSCLC) is the most common form, making up roughly 85% of all lung cancer cases. Treatment for NSCLC can include traditionally used surgery, chemotherapy, radiation therapy, and more recently developed targeted therapy and immunotherapy, the team continued. “Over the past decade, immunotherapy has revolutionized the treatment modalities by increasing the overall survival in NSCLC.”
Current state-of-the-art immunotherapies approved for NSCLC are based on the use of immune checkpoint inhibitors. This class of drugs is designed to block proteins—including program cell death protein 1 (PD1), and programmed death ligand 1 (PDL1)—that stop the immune system from killing cancer cells.
However, most patients with NSCLC do not respond to immunotherapy, primarily because the treatment only targets one protein (most commonly PD-L1), and that is not abundantly expressed in most lung cancer tumors. As a result, many patients must undergo a combination of chemo and immunotherapies, resulting in enduring side effects and toxicities. “In the case of NSCLC, only 23 to 25% of patients exhibit high PDL1 expression on the cancer cells,” the investigators stated. “This highlights the need to develop more integrative therapies to improve immunotherapy outcomes for most patients with NSCLC.”
The researchers screened more than 80 human lung cancer tissue samples to evaluate expression of PDL1 and another immune checkpoint protein, CD47, which controls innate immunity, as targets on the tumor cells. “Traditional immunotherapy targeting the PD1-PDL1 axis has shown limited efficacy due to the limited PDL1 expression in most NSCLC tumors,” they wrote. “In contrast, overexpression of CD47 has been observed in NSCLC tumors, and it regulates innate immunity by controlling phagocytosis and antigen presentation.” The team found that while only 33% of patients showed high PDL1 expression, 64.6% of the patients had high CD47 expression in NSCLC tumors.
Having selected the protein targets, the team then generated antibodies to target them. Next, they functionalized the antibodies with a nanoparticle that was already loaded with an anticancer drug. The resulting ADN construct effectively directs nanoparticle, which is filled with a dual PI3K/mTOR inhibitor, PI103, straight to the tumor site, while the antibodies attached to the nanoparticle bind to the CD47 and PD-L1 proteins on the cancer cells.
This dual approach is designed to allow both the innate and adaptive immune systems to locate and destroy cancer cells while minimizing the toxicities commonly associated with existing cancer treatments. “… using both anti-CD47 and anti-PDL1 in a single platform as therapeutics offers better coverage, and simultaneous inhibition of PDL1 and CD47 can offer increased immunotherapy outcomes in NSCLC,” they suggested.
“This system operates with a kind of Velcro effect,” said senior author Shiladitya Sengupta, PhD, an associate professor of medicine and bioengineer in the Division of Engineering in Medicine at the Brigham. “Rather than just looking for one protein on a cancer cell that the antibody can grab onto, these nanoparticles have two. So, if a cancer cell does not express one of the proteins that our nanoparticle targets, it can still attach to the other one, and deliver the drug loaded into the nanoparticle straight to the cancerous tissue.” As the authors noted, “The ADNs are even effective in tumors with a lower expression of either PDL1 or CD47, which makes it applicable in patients with low PDL1 expression, where traditional immunotherapy fails to respond.”
Saha and colleagues tested the nanoparticle’s efficacy by first visualizing how well the antibodies bound to cancerous cells in the lab. They performed a series of experiments to assess and visualize the nanoparticle’s binding and drug delivery capabilities. Subsequently, they tested the complex’s efficacy in mouse models of two forms of lung cancer. They confirmed that the animals cancer cells internalized the drug, leading to a decrease in tumor size without any major side effects or toxicities.
“… we have introduced a unified ADN platform that enables targeting multiple immune checkpoints and specific delivery of drugs to the tumor tissue,” the team concluded. “The dual activation of adaptive and innate immunity, together with the inhibition of molecular drivers of tumor progression, can emerge as a new paradigm in the treatment of NSCLC.”
The study’s limitations include that, so far, the therapy has only been tested on human tissue in the lab and in mouse models. It must undergo much more exhaustive toxicology studies before moving on to clinical testing. Looking ahead, the researchers hope to adapt this technology to treat other types of cancer by exploring additional antibodies and treatments that could work with this nanomedicine approach.
“While we are seeing some success with this drug delivery platform in preclinical testing, it’s important to remember that mouse and human physiology are quite different. We need more studies before we can bring this concept to clinical trials, but we’re excited to see how this approach could transform cancer care,” said Saha.