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.
In a third study, APX005M and nivolumab are being tested in metastatic melanoma and lung cancer, while a fourth study involves APX005M being administered to patients with solid tumors.
HemOnc Today spoke with Vonderheide about these studies and the future of anti-CD40 therapies.
Question: Can you provide some background on the research you are conducting?
Answer: We’ve been pursuing the clinical prospect of agonist CD40 antibodies for years. The strategy amounts to activating the immune system to start an immune response. This is particularly applicable for patients for whom the immune response against cancer is absent or insufficient. Like many others in the field, we have been amazed at the immune revolution, including checkpoint blockades and chimeric antigen receptor (CAR) T-cell therapies.
In terms of the thinking about checkpoint antibodies, it seems most patients who respond do so by reactivation of a previously existing immune response that was perhaps exhausted or subverted by the cancer. If you block these brakes that slow an immune response, you can resume immune activity and achieve a remarkable regression in many cases. If the patient has not mounted an immune response, simply giving checkpoint antibodies is not sufficient. That has been the situation for many patients who don’t respond to checkpoint inhibition alone. To use the terminology that has evolved, some tumors are cold, meaning they mount an insufficient immune response. Hot tumors show signs of having enabled an immune response, but somehow it got exhausted. In cold tumors, checkpoint inhibitors will be insufficient. Lab data shows that CD40 is an important switch for converting a tumor from cold to hot. If you can do that, a checkpoint blockade would have a new role. Our thinking is to combine a checkpoint inhibitor with an anti-CD40 therapy in pancreatic cancer, lung cancer or other nonresponding tumors. CD40 is an upstream mechanism of activation. We aim to switch the tumor from cold to hot, which then enables us to use PD-1 or CTLA-4.
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.
We must always be mindful that any drug or combination, despite compelling preclinical data, may turn out to be not efficacious or may be intolerable in the clinic. We are looking at multiple drug combinations and, so far, so good. The hope is that whatever toxicities may occur, they will be manageable. For phase 2, where we will examine clinical impact, patients will also be undergoing a rigorous biopsy plan. We are working with translational researchers to study these samples and understand the pharmacology of our therapy, whether we properly activated the immune system or can correctly identify any obstacles that may be standing in our way. If we understand those pathways, we can alter the therapy in new renditions. We’re not declaring victory; we’re declaring hope. In every preclinical model, the addition of CD40 has proven to be the single best maneuver to extend the range of immune therapy, whether it’s combined with chemotherapy, radiation or checkpoint blockades. The reason may be that CD40 is not expressed on T cells, it is expressed on dendritic cells. If you look at the literature in recent years, the enormous and critical role of dendritic cells has become more and more understood. And CD40 is a fundamental way to activate dendritic cells. There are other ways to activate dendritic cells. Hopefully, there will be other pathways we can explore therapeutically. – by Rob Volansky
For more information:
Robert H. Vonderheide, PhD, can be reached at Biomedical Research Building, 421 Curie Blvd., Philadelphia, PA 19104; email: firstname.lastname@example.org.
Disclosure: Vonderheide reports no relevant financial disclosures.