In a study published in Science Advances, researchers at Brigham and Women’s Hospital, a founding member of the Mass General Brigham healthcare system, created a new nanomedicine therapy that delivers anticancer drugs to lung cancer cells while also improving the immune system's ability to fight cancer.
An image sowing phagocytosis of a cancer cell by macrophages in the presence of a bispecific antibody conjugated drug-loaded nanotherapeutic. Image Credit: Tanmoy Saha, Brigham and Women’s Hospital
The team demonstrated encouraging outcomes with the new therapy on cancer cells in laboratory settings and in mouse models of lung tumors. This therapy shows potential for enhancing treatment and outcomes for patients whose tumors have not responded to conventional 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. Here, we have essentially connected these two approaches in one drug delivery system to treat non-small cell lung cancer.
Tanmoy Saha, PhD, Study Lead Author and Researcher, Division of Engineering in Medicine, Brigham and Women’s Hospital
Lung cancer remains the most common cause of cancer-related deaths worldwide, responsible for over 25 % of all cancer fatalities. Non-small cell lung cancer (NSCLC) accounts for approximately 85 % of all lung cancer diagnoses.
Among the treatments for NSCLC, immune checkpoint inhibitors are notable; these drugs work by inhibiting proteins that prevent the immune system from attacking cancer cells. Despite this, the majority of NSCLC patients do not benefit from these treatments. This is largely because these drugs typically target a single protein, often PD-L1, which is not sufficiently expressed in many lung cancer tumors. Consequently, numerous patients require a combination of chemotherapy and immunotherapy, which can lead to significant side effects and toxicities.
This innovative therapy works by delivering a nanoparticle containing a cancer-fighting drug directly to the tumor site, while antibodies associated with the nanoparticle bind to two distinct proteins (CD47 and PD-L1) on cancer cells. This dual strategy enables both the innate and adaptive immune systems to detect and eliminate cancer cells while limiting the side effects usually associated with current cancer treatments.
This system operates with a kind of Velcro effect. 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.
Shiladitya Sengupta, PhD, Study Senior Author and Associate Professor, Division of Engineering in Medicine, Brigham and Women’s Hospital
The researchers set out to determine which proteins were expressed in lung cancers. They examined samples from more than 80 people with lung cancer. After identifying the proteins, they chose antibodies to target them. They then functionalized the antibodies with a nanoparticle pre-loaded with an anticancer drug.
Saha and his colleagues then evaluated the nanoparticle’s effectiveness by first seeing how effectively the antibodies bound to cancerous cells in the lab. They carried out several studies to evaluate and visualize the nanoparticle’s binding and drug delivery properties.
They then evaluated the complex’s effectiveness in mouse models of two types of lung cancer. They discovered that the drug was internalized by the mice’s cancer cells, resulting in a reduction in tumor growth with no significant side effects or toxicities.
One of the study’s shortcomings is that the treatment has only been tested on human tissue in the lab and in mice models. Before proceeding to clinical testing, it must first undergo significantly more extensive toxicological examinations.
In the future, the researchers intend to adapt this technique to treat different forms of cancer by investigating new antibodies and treatments that might complement this nanomedicine approach.
Saha stated, “While we are seeing some success with this drug delivery platform in preclinical testing, it is 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 are excited to see how this approach could transform cancer care.”
Michaela Fojtů, Astha Vinay Nagar, Liya Thurakkal, Balaaji Baanupriya Srinivasan, Meghma Mukherjee, Astralina Sibiyon, Heena Aggarwal, Akash Samuel, Chinmayee Dash, and HaeLin Jang are also listed as authors from Bringham.
NIH-NCI National Cancer Institute CA236702; American Lung Association, 2019A001055, 2022A016553; US Army Medical Research Acquisition Activity W81XWH2210619, US Army Medical Research Acquisition Activity CA201065; NIH-NCI National Cancer Institute CA276525-A1; Melanoma Research Alliance, 2022A015448 funded the study.
Journal Reference:
Saha, T., et. al. (2024) Antibody nanoparticle conjugate–based targeted immunotherapy for non–small cell lung cancer. Science Advances. doi:10.1126/sciadv.adi2046