CD40, a receptor on the surface of immune cells, has long been of interest in oncology research because activating it stimulates cancer-killing T cells. Several companies have developed antibody drugs targeting CD40, including Roche, but they’ve proven disappointing on their own in clinical trials.
Scientists at the University of Basel say they may have found a way to improve responses to CD40 antibodies. They combined a CD40 drug with two other antibodies that are anti-angiogenic, meaning they plug up leaky blood vessels that feed tumors. The combination accelerated tumor destruction in mouse models of several cancers, including breast, colon and skin cancers, they reported in the journal Proceedings of the National Academy of Sciences.
"Normally, the blood vessels of a tumor are leaky or stunted. Therefore, there is no good way for killer T-cells to get inside," explained lead author Abhishek Kashyap of the University of Basel in a statement.
Kashyap’s team collaborated with scientists at the Roche Innovation Center to test three of the company’s drugs in combination. They were Avastin, Roche’s blockbuster anti-angiogenic cancer treatment that blocks VEGF, and two experimental drugs: one targeting another anti-angiogenic molecule, Ang2, and the second aimed at CD40.
The two anti-angiogenic drugs stabilized the blood vessels surrounding the tumors, improving the flow of killer cells that attacked the cancer, the researchers reported. But the triplet also seemed to turn “cold” tumors “hot,” meaning the drugs changed the microenvironment in a way that made the cancer more vulnerable to immunotherapy.
Several clinical trials investigating the potential of CD40 combination treatments are already underway. Apexigen’s APX005M combined with chemotherapy and Bristol-Myers Squibb’s anti-PD1 blockbuster Opdivo has shown promise in early clinical trials in pancreatic cancer, for example. Apexigen is also testing a combination of APX005M, Opdivo and cabiralizumab, an anti-CSF-1 antibody that BMS and Five Prime Therapeutics are developing.
Roche is testing its CD40 drug, selicrelumab, with its anti-PD-L1 drug Tecentriq in solid tumors. It’s also investigating combining selicrelumab with either Avastin or vanucizumab, a bispecific antibody that targets both VEGF-A and Ang2.
The new study led by the University of Basel concluded that the key to targeting CD40 successfully in cancer “is likely to be realized in combination with other, nonredundant immune modulators,” the researchers wrote. “We consider our findings useful in the light of current early-phase clinical studies that investigate agonistic anti-CD40 antibodies in combination with various antiangiogenic agents.”