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CD40 may be key to activating immune response in pancreatic cancer

Researchers at University of Pennsylvania are investigating anti-CD40 antibodies in a number of combinations in pancreatic cancer and other malignancies in which the baseline line immune response against the tumor is insufficient.

Robert H. Vonderheide, MD, DPhil, director of Abramson Cancer Center at Penn, is spearheading a phase 1 study designed to assess whether the addition of the anti-CD40 drug selicrelumab (RO7009789, Roche) to nab-paclitaxel (Abraxane, Celgene) and gemcitabine in the presurgical and postsurgical settings is safe and effective for pancreatic cancer treatment.

In a second phase 1b/phase 2 study, combination therapy with the immuno-activating anti-CD40 monoclonal antibody APX005M (Apexigen), nivolumab (Opdivo, Bristol-Myers Squibb), gemcitabine and nab-paclitaxel is being compared with APX005M-gemcitabine-nab-paclitaxel and nivolumab-gemcitabine-nab-paclitaxel for metastatic pancreatic adenocarcinoma.

….Q: Where does research stand in terms of human trials?

A: The momentum for studying CD40 antibodies is really surging because of this hypothetical reason to develop an upstream activator of the immune system. It seems nearly every major pharmaceutical company is looking at CD40. There are five or six agents in development. We’re part of that development at Penn. When used by themselves, anti-CD40 antibodies have only shown a modest range of activity. That’s why they’re really seen as a partner, best used in combination, such as with chemotherapy or immune checkpoint inhibitors. The study on which I’m serving as principal investigator, sponsored by the Parker Institute for Cancer Immunotherapy, involves newly diagnosed patients with metastatic pancreatic cancer. We are delivering standard chemotherapy and various combinations of CD40 and PD-1 antibodies. We are treating patients and the study is ongoing. One of the key components is to work through dosing and scheduling considerations. We hypothesize that there is particular synergy in combining anti-CD40 antibodies with a checkpoint blockade such as nivolumab. This is based on extensive lab models, as well as early-stage clinical studies of a number of combinations.

Q: Are you seeing any potential drawbacks, such as toxicity ?

A: No, it has been well tolerated. We are advancing quickly to the phase 2 portion of the study, where we are looking at chemotherapy plus CD40, chemotherapy plus PD-1, or chemotherapy plus both. We are working to understand if those combinations are safe and tolerable. So far, they are.

Q : Breakthrough approaches like this don’t come around very often. Is this your goal?

A: In the way we have designed these trials, we are looking for evidence that this is indeed a breakthrough. This trial is not designed to see a subtle advantage to combining these drugs. The trial is designed for more significant success than that.

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