New Combo Therapy May Help Beat Immunotherapy Resistance in Skin Cancer

A new study sheds light on why many patients with advanced skin cancer fail to benefit from immune checkpoint blockade (ICB) therapies and suggests a potential fix using a drug already approved for blood cancers.

Published in Nature Immunology, the research identifies a biological mechanism that helps explain resistance to ICB drugs such as anti-PD-1 antibodies, a mainstay in treating melanoma and other solid tumors. Although these therapies can produce durable responses, more than 60% of patients see no benefit, while experiencing high toxicity side effects and the financial cost without any improvement.

Scientists at Newcastle University in Newcastle upon Tyne, United Kingdom, found that resistance may stem from the unintended effects of ICB therapy on a type of immune cell called regulatory T cells, or Tregs. These cells normally help keep immune responses in check. But when PD-1 is blocked on Tregs, it causes them to become more suppressive, allowing tumors to continue growing despite treatment.

To study this, the researchers engineered a mouse model where PD-1 was removed only from Treg cells. In these animals, tumor growth accelerated. A deeper look revealed that this PD-1 disruption drove up levels of CD30, a surface protein associated with immune suppression. When researchers blocked CD30 in addition to PD-1, the tumors became more vulnerable to immune attack.

That finding points to a possible treatment strategy: combining PD-1 inhibitors with CD30-targeting drugs. One such drug, Adcetris (brentuximab vedotin), is already approved for lymphoma and could be repurposed. In support of that idea, an ongoing Phase II trial is testing this combination in patients with metastatic melanoma who didn’t respond to standard checkpoint inhibitors. Preliminary data show a median survival of 24%.

Shoba Amarnath, Ph.D.

“By simply adding anti-CD30 for these patients, we can improve their response to cancer and avoid costly delays,” said Shoba Amarnath, Ph.D., reader in immune regulation at Newcastle University, who led the research, in a news release. “Although our work was limited to skin cancer, we believe this new combination treatment will also benefit patients with lung, bowel, pancreatic and other solid cancers who are currently not responding to treatment with ICB monotherapy.”

Checkpoint inhibitors have transformed care for patients with advanced skin cancer. A study published last year by Dana-Farber Cancer Institute found that about half of patients with metastatic melanoma who received a combination of immunotherapies were alive and cancer-free 10 years after treatment—compared to a median survival of just six and a half months before these drugs were available.

The Newcastle study also adds to the understanding of how Tregs behave in the tumor microenvironment. The research team found that Tregs in ICB-treated tumors begin to resemble stem cells and cluster near tumor cells, forming immunosuppressive hubs that protect the cancer from immune attack. This behavior may help explain why simply boosting T cell activity with checkpoint inhibitors doesn’t work for many patients.

The researchers also wrote that CD30 levels rose in human Tregs after exposure to PD-1 blockade, but not in untreated tumor environments. This suggests that CD30 activation is potentially a side effect of the therapy itself, one that could be anticipated and countered with combination treatment.

“We are very excited to find all these new aspects in ICB resistance biology,” Amarnath said. “We believe targeting immune molecules and tumor growth proteins will significantly enhance the efficacy of ICB in solid cancers.”