In a UCLA-led study, more than two-thirds of people with a rare type of melanoma responded positively to treatment with anti-PD-1 immunotherapies. The findings counter the conventional wisdom that a cancer which is highly fibrotic with dense stroma could not respond to immunotherapy, and have the potential to help scientists identify those patients most likely to benefit from treatment.
Desmoplastic melanoma is an uncommon subtype of melanoma that has proven highly resistant to traditional treatment approaches, such as chemotherapy, radiation and surgery. Desmoplastic melanoma tumors are characterized by having a very dense tissue thought to limit the ability of immune cells to infiltrate and attack the cancer, as well as a lack of “driver” mutations, which are required for drug development and precision medicine strategies. This had previously led scientists to consider people with desmoplastic melanoma, and other dense cancers, unlikely to benefit from immunotherapy.
However, research has shown that anti-PD-1 antibodies, such as pembrolizumab and nivolumab, are effective for the treatment of some patients with advanced melanoma. To respond to anti-PD-1 immunotherapy the cancer needs to be recognized as abnormal by the patient’s immune system, and the immune system cells need to be blocked by PD-L1, the ligand to PD-1. A higher level of mutations induced by sun damage in melanoma tumors allows the immune system to recognize melanoma cells as abnormal cells that should be attacked, which is associated with improved clinical outcomes.
In the study, the UCLA team hypothesized that despite the dense stroma associated with desmoplastic melanoma tumors, patients may still respond well to anti-PD-1 or anti-PD-L1 therapies due to the high frequency of mutations induced by prior sun damage characteristic of this type of cancer. They further sought to understand how DNA damage from ultraviolet light (which is a common result of sun exposure and highly associated with desmoplastic melanoma) and PD-L1 expression levels in tumor cells affect patient response to immunotherapy.
The researchers assessed 60 people with advanced desmoplastic melanoma who had received anti-PD-1 or anti-PD-L1 therapies over a five-year period. The scientists found that 70 percent of patients (42 out of 60) had a significant response with reduction in tumor size, most of the cases ongoing after many months to years. In addition, 19 of these 42 patients had a complete response, meaning their cancer was no longer detectable, and none of these 19 patients had a disease recurrence to date.
The UCLA team further utilized state-of-the-art technologies to comprehensively profile disease-causing DNA damage, and discovered high mutational activity in a majority of the patient’s tumors (14 out of 17). They also conducted a comparative analysis of tumors from patients with desmoplastic melanoma to other types of melanoma, and found a higher percentage of PD-L1 positive cells in the desmoplastic melanoma tumors, which is associated with increased CD8 T cell density.
Though desmoplastic melanoma accounts for only four percent of all melanomas, current survival outcomes are poor and there is an urgent unmet need for new treatment strategies. The findings of this study have prompted the opening of a new clinical trial in over 100 sites across the United States of America sponsored by the National Cancer Institute, offering the anti-PD-1 therapy pembrolizumab (commercialized as Keytruda) to people with desmoplastic melanoma even before they undergo surgery.
UCLA’s Drs. Antoni Ribas and Siwen Hu-Lieskovan are co-corresponding authors. The co-first authors are Dr. Siwen Hu-Lieskovan, Zeynep Eroglu and Jesse Zaretsky at the David Geffen School of Medicine at UCLA. Other authors are Drs. Bartosz Chmielowski, Xiaoyan Wang, Peter Shintaku, Cody Wei and Alistair Cochran at UCLA. Ribas, Hu-Lieskovan, Chmielowski and Cochran are members of the UCLA Jonsson Comprehensive Cancer Center. The UCLA team collaborated with Drs. Dae Won Kim and Jane Messina from the Moffitt Cancer Center, Dr. Wen Jen Hwu from the MD Anderson Cancer Center, Dr. Alain Algazi from the University of California San Francisco, Dr. Jeffrey Sosman from the Northwestern University Medical Center, Dr. Douglas John from the Vanderbilt Ingram Cancer Center, Drs. Elizabeth Liniker, Matteo Carlino, Richard Scolyer and Georgina Long from the Melanoma Institute Australia, Dr. Ben Kong from the Westmead Hospital Sydney, Drs. Rodrigo Munhoz and Michael Postow from the Memorial Sloan Kettering Cancer Center, Dr. Suthee Rapisuown from the Georgetown Lombardi Cancer Center, Dr. Pier Federico Gherardini from the Parker Institute for Cancer Immunotherapy and Dr. Richard Joseph from the Mayo Clinic.