Avelumab's Unique Mechanism of Action in Cancer Immunotherapy Revealed

Abu Dhabi, June 26, 2025 — In groundbreaking research, scientists at the Cleveland Clinic have uncovered significant differences in the mechanisms of action between two PD-L1 checkpoint inhibitors, avelumab and durvalumab, which are crucial in the treatment of various cancers. The findings, published in the Journal of Immunotherapy Research, highlight the enhanced activation of natural killer (NK) cells and the interactions with dendritic cells (DCs) triggered by avelumab, suggesting its potential preference in specific clinical scenarios.

The study was led by Dr. Raghvendra Srivastava, Director of the Discovery Laboratory at Cleveland Clinic's Center for Immunotherapy and Precision Immuno-Oncology. Dr. Srivastava emphasized the unique attributes of avelumab compared to durvalumab, stating, "Despite belonging to the same drug family, the backbone of each of these medications has notable differences. Without understanding the mechanistic performance of one drug versus another, clinicians won’t know which is best for each type of cancer."

In their research, the team utilized innovative two- and three-cell coculture models comprising human NK cells, dendritic cells, and tumor cells treated with either avelumab or durvalumab. The motivation behind selecting these two drugs was their distinctive designs in their Fc portions, which influence their interactions with immune cells. Avelumab possesses an active Fc portion that binds to Fc receptors on various immune cells, while durvalumab has a mutated Fc portion that inhibits such binding.

"By directly comparing avelumab against durvalumab, we saw a massive difference in terms of avelumab’s ability to activate NK cells and enhance dendritic cell function, facilitating robust NK-DC crosstalk, which plays a crucial role in initiating an adaptive anti-tumor response," stated Nicole Osborne, Research Technologist at the Cleveland Clinic. This research elucidates that while both drugs target PD-L1, their effects on immune responses differ significantly.

The investigation revealed that avelumab not only induces NK-cell-mediated antibody-dependent cellular cytotoxicity but also significantly alters the transcriptome of NK cells. The study identified critical gene upregulations, including IFN-gamma, which is essential for immune responses, and CD137, which supports NK cell activation. Furthermore, chemokines aiding in DC recruitment were found to be upregulated in avelumab-treated cultures. "In avelumab-treated cultures, we saw huge upregulation of immune-related genes compared to durvalumab-treated cultures," said Osborne.

However, the researchers also cautioned about potential negative findings. It was observed that avelumab-activated NK cells killed approximately 7-10% of dendritic cells in vitro. Despite this, surviving DCs still exhibited activation and maturation. Clinicians need to consider this effect, especially if avelumab is used alongside DC-based therapies.

Additionally, the study noted that in the absence of immune cells, both avelumab and durvalumab could inadvertently accelerate tumor growth, raising concerns about hyper-progression in certain cases. Dr. Srivastava pointed out, "This data suggests that you need to have a strong supply of immune cells in the tumor microenvironment for this immunotherapy to be effective; otherwise, you may see tumor progression."

Looking ahead, the research team plans to compare all FDA-approved PD-L1/PD-1 targeting drugs to further delineate their mechanisms and identify new immune targets. They hope that their findings will encourage the use of triple cell coculture models to uncover differences in antibody-dependent cellular cytotoxicity (ADCC)-stimulating drugs. Moreover, recent advancements in optimizing Fc portions of monoclonal antibodies may lead to enhanced innate immune function, paving the way for more personalized cancer treatments. Dr. Srivastava concluded, "Our hope is that our study will provide the rationale for further examination of therapies that differ in their Fc portion, improving treatment response and patient outcomes."

This research not only advances the understanding of PD-L1 inhibitors but also emphasizes the importance of tailored therapies in oncology, reinforcing the need for continuous exploration of immune mechanisms to enhance patient care in cancer treatment.