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, which counter the conventional wisdom that a cancer which is highly fibrotic could not respond to immunotherapy, 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 have a very dense tissue thought to limit the ability of immune cells to infiltrate and attack the cancer. They are also characterized by a lack of “driver” mutations, which are required for drug development and personalized medicine strategies. These factors had previously led scientists to consider people with desmoplastic melanoma and other dense cancers as unlikely to benefit from immunotherapy.
Anti-PD-1 antibodies target the protein PD-1, which is expressed by immune cells. When PD-1 binds to another molecule called PD-L1, it protects the cancer cells from immune cell attack. So, by blocking the interaction between PD-1 and PD-L1, anti-PD-1 antibodies unleash the patient's immune system to attack the cancer. Research has shown that anti-PD-1 antibodies, such as the drugs pembrolizumab and nivolumab, are effective for the treatment of some people with advanced melanoma. In addition, 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. To respond to anti-PD-1 immunotherapy, the cancer needs to be recognized as abnormal by the individual’s immune system, and the immune system cells need to be blocked by the interaction between PD-L1 and PD-1.
In the study, the UCLA team hypothesized that despite the dense tissue associated with desmoplastic melanoma tumors, patients may still respond well to anti-PD-1 or anti-PD-L1 therapies because of the high frequency of mutations induced by previous 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 affects patient response to immunotherapy.
The researchers evaluated 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, or 42 out of 60, had a reduction in tumor size that was sustained over many months or years. In addition, cancer was no longer detectable in 19 of these 42 people, and none of those 19 individuals had a recurrence of the disease to date.
The UCLA team also utilized state-of-the-art technologies to comprehensively profile disease-causing DNA damage, and discovered high mutational activity in a majority of the patients’ 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.
Though desmoplastic melanoma accounts for only 4 percent of all melanomas, current survival rates are poor and there is an urgent unmet need for new treatment strategies. The findings of this study have led to a new clinical trial in more than 100 sites across the United States 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.
Co-corresponding authors are Dr. Antoni Ribas and Dr. Siwen Hu-Lieskovan of UCLA. 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, all of UCLA, include Dr. Bartosz Chmielowski, Dr. Xiaoyan Wang, Dr. Peter Shintaku, Dr. Cody Wei and Dr. Alistair Cochran. The UCLA team collaborated with researchers from the Moffitt Cancer Center, the MD Anderson Cancer Center, the University of California San Francisco, Northwestern University Medical Center, Vanderbilt Ingram Cancer Center, Melanoma Institute Australia, Westmead Hospital Sydney, Memorial Sloan Kettering Cancer Center, Georgetown Lombardi Cancer Center, Parker Institute for Cancer Immunotherapy and the Mayo Clinic.
The research is published online in Nature.
The research was supported by the National Institutes of Health, the Grimaldi Family Fund, the Parker Institute for Cancer Immunotherapy, the Ressler Family Fund, the Samuels Family Fund and the Garcia-Corsini Family Fund.