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Anti-PD-1/bacteria-emulating agent combination for advanced melanoma

An experimental combination of an immunotherapy medication and a bacteria-like agent could increase life expectancy in patients with advanced melanoma, according to early findings published online ahead of print in Cancer Discovery (Aug. 28, 2018).

In a press release, the paper’s investigators explain their goal was to see if they could overcome the resistance metastatic melanoma tumours can develop to the PD-1 inhibitor pembrolizumab.

“We have found that the reason patients with metastatic melanoma do not initially respond to immunotherapy with an anti-PD-1 is that their immune system was not ready,” said lead author Dr. Antoni Ribas, a professor of medicine at the David Geffen School of Medicine at the University of California, Los Angeles (UCLA) and director of the UCLA Jonsson Comprehensive Cancer Center Tumor Immunology Program. “So we thought, ‘What if we change that by injecting the therapy drug into the metastatic lesions and change the microenvironment of the cancer?’

Dr. Antoni Ribas, professor of medicine, David Geffen School of Medicine UCLA. Photo by: Milo Mitchell/UCLA Jonsson Comprehensive Cancer Center

In the phase 1b trial, patients with unresectable or metastatic malignant melanoma were treated with a combination of pembrolizumab and intratumoural injections of SD-101, a synthetic sequence of nucleic acids that mimics a bacterial infection and stimulates Toll-like receptor 9 (TLR9).

The activity of SD-101 both directs T cells to cancer cells and alters the local microenvironment to be more hospitable for the T cells so the latter can more effectively destroy the abnormal cells, according to the release.

Of the 22 participants, nine were receiving immunotherapy for the first time as part of this study, and 13 had received some form of immunotherapy previously. Seven of the immunotherapy-naive patients had a positive response to the combination therapy, with two having their tumours disappear completely. Of the 13 who had previously been treated with immunotherapy, two had partial response—shrinkage of their tumours was observed but they did not disappear, five others had their disease stabilize, and five had progressive disease. One patient in this group could not be evaluated.

“For all patients with advanced cancer, immunotherapy using PD-1 inhibitors has really changed the face of cancer treatment. Unfortunately, this therapy still only works in a subset of patients,” said Dr. Deborah Wong, in the release. Dr. Wong is an assistant clinical professor of medicine at the Geffen School of Medicine and an oncologist at the Ronald Reagan UCLA Medical Center in Los Angeles, who was also an author of the paper.

“This particular combination has been especially gratifying because not only does the SD-101 therapy drug induce tumour shrinkage at the actual site where it’s injected, but it’s working in conjunction with pembrolizumab to shrink tumours outside of the ones we’re directly injecting.”

Dr. Ribas said that the understanding of the mechanisms by which immunotherapies work in patients is still limited, but that through growing that understanding “we can find more ways to make that therapy more active. One way is by combining the therapy with another agent that can overcome the resistance that some cancers have to these therapies.”

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