CD40-Activating Monoclonal Antibodies Boost Response to Immunotherapy

It may be possible to turn up the heat on resistant tumors by priming T cells in the body with an agonist CD40 antibody. Researchers at the University of Pennsylvania theorize that many more cancer patients may benefit from immunotherapies with the help of a new class of drugs known as CD40 monoclonal antibodies.

Robert Vonderheide, MD, director of the Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvannia, said CD40 agents could be the spark needed to light the fire in the immune systems of patients who do not respond to immunotherapies. “Activation of the CD40 molecule on dendritic cells holds a key to initiating a T-cell response to tumors. This observation is important because numerous, next-generation agonists are being tested and rapidly advanced in the clinic,” said Dr. Vonderheide.

In a new perspective piece published in Cancer Cell, he writes that the “immuno revolution” is upon us. While chimeric antigen receptor (CAR) T-cell therapy and checkpoint inhibitors have ushered in a new era in immunotherapy, they only work in a limited number of patients and many of those who initially respond experience a relapse. Vonderheide said a larger percentage of patients would benefit if immunotherapies were combined with CD40 agents. He and his colleagues have found that CD40 activation plays a critical role in generating T-cell immunity, by activating dendritic cells and “heating up” tumors.

In preclinical studies, Vonderheide and colleagues found that agonistic CD40 antibodies demonstrated T-cell–dependent antitumor activity. These findings were confirmed when agonistic CD40 antibodies were used in combination with chemotherapy, checkpoint inhibitors, and other immune modulators.

“Our findings suggest that the use an agonist CD40 antibody is a reliable way to sensitize tumors to immune destruction in concert with PD-1 [programmed death 1] or CTLA-4 [cytotoxic T-lymphocyte antigen-4] antibodies. This approach may represent a way to convert tumors that are currently unresponsive to checkpoint antibodies to becoming therapeutically responsive, by exploiting the ability of CD40 activation to prime T cells in patients for whom priming otherwise has failed,” Dr. Vonderheide told Cancer Network.

Currently, The PD-1 antibody pembrolizumab is approved for use as a first-line therapy for patients with metastatic non–small-cell lung cancer (NSCLC) that overexpresses programmed death ligan 1.  However, approximately 30% of patients do not respond to the therapy, and another 25% have tumor progression at 1 year. It is hoped that those numbers can be altered through the addition of an agonist CD40 antibody.

Dr. Vonderheide is conducting a phase I study investigating whether adding the investigational anti-CD40 drug RO7009789 to nab-paclitaxel and gemcitabine both before surgery and after surgery is safe, feasible, and beneficial in patients with pancreatic cancer. Another study is underway to evaluate the efficacy of the combinations of APX005M, nivolumab, gemcitabine, and nab-paclitaxel compared with APX005M, gemcitabine, and nab-paclitaxel in treating patients with metastatic pancreatic adenocarcinoma. An additional study is underway to investigate APX005M in combination with nivolumab in adults with metastatic melanoma.