Packing lipid nanoparticles with tumor proteins to boost cancer vaccine potency

The concept of using vaccines to treat cancers has been around for several decades. A vaccine was first approved for prostate cancer in 2010, and another was approved in 2015 for melanoma. Since then, many therapeutic—as opposed to preventive—cancer vaccines have been in development, but none are approved. One hurdle is the difficulty in finding antigens in tumors that look foreign enough to trigger an immune response.

Researchers at Tufts have now developed a cancer vaccine that effectively amplifies the visibility of tumor antigens to the immune system, leading to a potent response and a lasting immunological memory that helps prevent the return of tumors after they have been eliminated. Their vaccine avoids the need to hunt down a specific tumor antigen, instead relying on a digested mix of protein fragments called a lysate that can be generated from any solid tumor.

The vaccine they produced worked against multiple solid tumors in animal models, including melanoma, triple-negative breast cancer, Lewis lung carcinoma, and clinically inoperable ovarian cancer.

Developed by a team led by postdoctoral scholar Yu Zhao and Qiaobing Xu, professor of biomedical engineering, the method builds on earlier work expressing specific antigens for an enhanced immune response by making lipid nanoparticles that carry mRNA into the lymphatic system.

“We have significantly improved the cancer vaccine design by making it applicable to any solid tumor from which we can create a lysate, possibly even tumors of unknown origin, without having to select mRNA sequences, and then conjugating another component—called AHPC—that helps channel the protein fragments from the cancer cells into the immunological response pathway,” said Xu.

Unlike traditional vaccines designed to prevent infectious diseases caused by bacteria or viruses, cancer vaccines work by stimulating the body’s immune system to recognize and attack cancer cells. And unlike most vaccines against pathogens, they are designed to be therapeutic rather than preventive—acting to eliminate an existing disease.

Some preventive cancer vaccines do exist, but they are generally targeted to viruses that are linked to cancers, such as HPV linked to cervical cancer.

The key to the increased potency of the new cancer vaccine lies in its ability to direct tumor-derived antigens into a cellular pathway that efficiently presents the antigens to the immune system. Think of the presentation as a kind of police lineup, where each antigen is presented for the immune system to decide if it can be considered a “suspect.”

Rounding up the antigens and getting them into an antigen-presenting cell like a macrophage or dendritic cell (the police stations, if we continue with the analogy) is generally an inefficient process for tumor antigens. This is where the Tufts research team applied a two-stage method to power up the process.

First, to make sure they round up all tumor proteins-of-interest, they modified the mix of tumor proteins with the AHPC molecule, which in turn recruits an enzyme to put a tag on the protein called a ubiquitin. It allows the cell to identify and process the protein into fragments for presentation to the immune system.

The researchers then packaged the AHPC-modified tumor proteins into tiny lipid (fat molecule) nanoparticles, specifically designed to home in on lymph nodes, where most antigen-presenting cells can be found.

Tested in animal models of melanoma, triple-negative breast cancer, Lewis lung carcinoma, and inoperable ovarian cancer, the vaccine elicited a strong response by cytotoxic T cells, which attack the growing tumors, suppressing further growth and metastasis.

“Fighting cancer has always been an arsenal approach,” said Xu. “Adding cancer vaccines to surgical excision, chemotherapy, and other drugs used to enhance cytotoxic T cell activity could lead to improved patient responses and longer-term prevention of cancer recurrence.”