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Turning up the heat on resistant tumours with novel immunotherapies

9 Apr 2018

A promising class of drugs known as CD40 monoclonal antibodies could be the spark needed to light the fire in the immune system of patients who don't respond to the newer cancer immunotherapies.

Robert H. Vonderheide, MD, DPhil, director of the Abramson Cancer Center at the University of Pennsylvania and an internationally renowned cancer immunotherapy expert, makes the case for the drugs in a new perspective piece published this week in Cancer Cell, as part of a series in the issue focusing on the next phase of the evolving field of cancer immunotherapy.

"The 'immuno revolution' is upon us: We're battling cancers like never before by tapping into the power of the immune system with checkpoint inhibitors and personalized cellular therapies that have elicited stellar responses in patients," Vonderheide said. "But there is a bittersweet quality to these successes: many patients do not respond or quickly relapse after an initial response."

The PD-1 antibody pembrolizumab, for example, is approved for use as a first-line therapy for patients with metastatic non-small cell lung cancer that overexpresses PD-L1, which cancer cells use to hide from the immune system, yet nearly 30 percent of patients don't respond to the therapy and another 25 percent have tumor progression at one year.

"To overcome the resistance in these patients, we need to go back to the beginning and prime the T cells before we jumpstart their immune system with other therapies to attack the cancer," Vonderheide said.

The CD40 antibodies activate antigen-presenting cells, such as dendritic or B cells, to prime tumour-specific T cell responses, effectively "pushing the gas" on the immune system to make it work harder.

This "lead-in" therapy, which is being investigated in clinical trials around the world, including at Penn Medicine, has been shown to turn so-called "cold" tumours hiding from the body's defenses into "hot" ones by "priming" the T cells before other treatments.

Think of the body's immune response like an assembly line, with points A, B, C, D, and E, that kill the tumour at the end, Vonderheide said.

For example, a T cell starts, it expands, it gets exhausted, and stops because of the PD-1 pathways.

Checkpoint inhibitors take that brake off toward the end, so the T cells can then attack the tumour.

"We've been drugging the very last step," said Vonderheide, who serves as a principal investigator on several CD40 combination trials at Penn, including a national trial through the Parker Institute of Cancer Immunotherapy. "In many patients, however, that won't work because points A through E hasn't happened. You can give them a checkpoint inhibitor, but there are no T cells to take the brakes off."

"With the CD40 drugs, we're back at point A to prime the T cells in the body to continue on in the immune response," he added. "Once you get A going, you can potentially treat more patients."

 

Source: University of Pennsylvania School of Medicine