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Marker may predict response to ipilimumab in advanced melanoma

Among patients with advanced melanoma, presence of higher levels of the protein vascular endothelial growth factor (VEGF) in blood was associated with poor response to treatment with the immunotherapy ipilimumab, according to a study published in Cancer Immunology Research, a journal of the American Association for Cancer Research.

The study suggests combining immunotherapy with VEGF inhibitors, also known as angiogenesis inhibitors, may be a potential option for these patients.

The immune-checkpoint inhibitor ipilimumab works by boosting the body's immune system to combat melanoma. VEGF is a protein that promotes new blood vessel formation and growth, a process called angiogenesis, thus providing nutrients to the growing tumor. The study found that among patients who had late-stage melanoma, those who had high levels of VEGF in their blood prior to treatment with ipilimumab had decreased clinical benefit, poor overall survival outcomes, and were 60 percent more likely to die of their disease, compared with those who had lower levels of VEGF.

"VEGF is known to suppress the maturation of immune cells and their antitumor responses, and evidence points toward an association between high serum VEGF levels and poor prognosis in melanoma patients," said F. Stephen Hodi, M.D., director of the Melanoma Center at Dana-Farber Cancer Institute, and associate professor of medicine at Harvard Medical School in Boston, Mass. "VEGF has also been shown to be a potential biomarker for other immunotherapies, thus it seemed logical to test the ability of VEGF to predict responses to ipilimumab.

"We found that VEGF may actually hinder some of the effects of the immune-checkpoint inhibitor," Hodi added. "We are beginning to better define predictive biomarkers for immune-checkpoint blockers, specifically ipilimumab. Our study further suggests that there is a potential interaction existing between the biology of angiogenesis and immune-checkpoint blockade."

Hodi and colleagues conducted retrospective analyses of blood samples collected from 176 patients with metastatic melanoma, before and after they were treated with ipilimumab, at Dana-Farber/Harvard Cancer Center and Memorial Sloan-Kettering Cancer Center. Patients were 16 to 91 years old, and the majority of them had stage 4 disease.

VEGF levels in patients' blood ranged from 0.1 to 894.4 picograms per milliliter (pg/ml). The investigators determined 43 pg/ml to be the cutoff value, and evaluated patient responses to treatment as those whose pretreatment VEGF levels were greater than (VEGF-high) or less than (VEGF-low) the cutoff value.

They found that at 24 weeks after starting ipilimumab treatment, 41 percent of the VEGF-low patients experienced clinical benefit, including partial or complete treatment responses; only 23 percent of the VEGF-high patients experienced a clinical benefit.

The median overall survival for VEGF-low patients was 12.9 months, compared with 6.6 months for VEGF-high patients.

The researchers found that while pretreatment VEGF levels had the potential to predict treatment outcomes, changes in VEGF levels during treatment were not linked to treatment outcomes.

"It may be worthwhile to investigate combining immune-checkpoint inhibitors and angiogenesis inhibitors in advanced melanoma with high serum VEGF levels," said Hodi. His team has initiated a randomized clinical trial to test ipilimumab in combination with bevacizumab, an angiogenesis inhibitor, in patients with advanced melanoma.

This study was funded by the National Institutes of Health. Hodi has declared no conflicts of interest.

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About the American Association for Cancer Research

Founded in 1907, the American Association for Cancer Research (AACR) is the world's oldest and largest professional organization dedicated to advancing cancer research and its mission to prevent and cure cancer. AACR membership includes more than 34,000 laboratory, translational, and clinical researchers; population scientists; other health care professionals; and cancer advocates residing in more than 90 countries. The AACR marshals the full spectrum of expertise of the cancer community to accelerate progress in the prevention, biology, diagnosis, and treatment of cancer by annually convening more than 20 conferences and educational workshops, the largest of which is the AACR Annual Meeting with more than 18,000 attendees. In addition, the AACR publishes eight peer-reviewed scientific journals and a magazine for cancer survivors, patients, and their caregivers. The AACR funds meritorious research directly as well as in cooperation with numerous cancer organizations. As the scientific partner of Stand Up To Cancer, the AACR provides expert peer review, grants administration, and scientific oversight of team science and individual grants in cancer research that have the potential for near-term patient benefit. The AACR actively communicates with legislators and policymakers about the value of cancer research and related biomedical science in saving lives from cancer. For more information about the AACR, visit

To interview F. Stephen Hodi, contact Teresa Herbert at or 617-632-5653. For other inquiries, contact Jeremy Moore at or 215-446-7109.

Jeremy Moore | EurekAlert!
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