A Designer “Bridge” Molecule to Improve Current Most cancers Immunotherapies

A molecule that engages both antibodies and tumor cells may piggyback cancer killing atop a robust antiviral immune response.

Immune cells in the tumor microenvironment often function just fine, but cancer cells have various means to evade detection, making them difficult to eradicate.

Cancer researcher Fan Zou from Shenzhen University of Advanced Technology wondered, what if scientists could harness the body’s naturally robust immune response: antiviral immunity?

In a recent study, Zou and his colleagues designed a “bridge” molecule that tags cancer cells with a varicella virus antigen.¹ This allowed antibodies produced in response to the chickenpox vaccine, which over 90 percent of children in the US have received, to recognize tumor cells. The molecule promoted tumor cell killing both in vitro and in mice. The researchers’ findings, published in Advanced Science, offer a new strategy to enhance existing immune responses to fight cancer.

The idea of targeting tumor cells with foreign antigens isn’t new. For example, researchers explore the use of engineered oncolytic viruses to develop cancer vaccines.² Oncolytic viruses can also introduce exogenous proteins onto tumor cells that trigger the immune system to reject and eliminate them.³

Several studies have indicated that T cells in the tumor environment are better at recognizing antigens from viruses than from tumors.^4,5 So, in the present work, Zou’s team sought to redirect some of the body’s existing immunity against viruses towards tumors. They fused the varicella virus antigen glycoprotein E (gE) to a fragment of the programmed cell death protein 1, which binds to tumor cells via programmed death-ligand 1 (PD-L1), an immune checkpoint regulator whose expression is commonly upregulated in various types of cancer. They called the molecule PD-L1-binding antigen presenter-glycoprotein E (PBAP-gE).

To test the molecule’s ability to enhance tumor killing in vitro, the researchers pre-incubated mouse breast tumor cells that overexpressed PD-L1 with PBAP-gE. Then, they cultured these cells alongside mouse natural killer (NK) cells that had been exposed to serum from varicella-vaccinated mice. There was significantly more tumor cell death in this condition than when the cells had not been exposed to PBAP-gE or the varicella-vaccinated serum.

Next, the team evaluated how PBAP-gE performed in vivo. They vaccinated mice against varicella on days 0 and 21, implanted melanoma cells on day 28, then once the tumor had reached a pre-defined size, delivered PBAP-gE intravenously using chimeric antigen receptor T (CAR T) cells.

The researchers compared the effects of various treatments on tumor size: PBAP-gE-expressing CAR T cells, non-PBAP-gE-expressing CAR T cells, as well as the latter supplemented with separate administration of PBAP-gE (intravenously, intraperitonially, and intratumorally). They observed the most dramatic reduction in tumor size relative to control when the mice received PBAP-gE-expressing CAR T cells. The next most effective condition was the administration of non-PBAP-gE-expressing CAR T cells in combination with intratumorally injected PBAP-gE. These results suggest that CAR T cells are optimal delivery vehicles for PBAP-gE. They also demonstrate PBAP-gE’s potential, both as a supplement to—and maybe even a replacement for—traditional cancer immunotherapies.

“This strategy represents a lower-cost, safer avenue for tumor immunotherapy,” Zou said in a statement. “It opens a transformative pathway that repurposes the body’s natural antiviral defenses for therapeutic gain, with significant promise for clinical translation.”