Research published March 8 in the New England Journal of Medicine by scientists at the Ludwig Institute for Cancer Research (LICR) and Memorial Sloan-Kettering Cancer Center (MSKCC) showed that combining targeted radiation therapy with immunotherapy (ipilimumab), fostered a strong immune response and a favorable clinical outcome in a patient with melanoma, the most dangerous form of skin cancer. The size of both the tumor that was treated with radiation and distant tumors in the patient were reduced. This study is a rare example of a documented case of an immune response, known as the abscopal effect, in cancer treatment.
The research team led by Jedd Wolchok, M.D., Ph.D., Assistant Member of LICR, Associate Attending Physician and Director of Immunotherapy Clinical Trials at MSKCC and Director of the CRI/LICR Cancer Vaccine Collaborative, took their findings a step further by investigating how the immune system may have played a role in the enhanced tumor regression. "We evaluated whether there were changes in the blood, which would help us to understand why the combined ipilimumab/radiation treatment improved the patient's response," said Dr. Wolchok.
What the team found was that the patient had a pre-existing immune response to an antigen known as NY-ESO-1, which was discovered by LICR researchers more than a decade ago. Select cancer patients produce antibodies and develop T-cell responses to NY-ESO-1, and research has shown that cancer patients who have pre-existing immunity to NY-ESO-1 are more likely to respond to the immunotherapy treatment, ipilimumab, than those who do not.
"The use of radiation therapy modulated the patient's immune system, resulting in an increased antibody response to one portion of the NY-ESO-1 protein, as well as increased antibody responses to other antigens," said Dr. Wolchok. "In addition, the radiation decreased the level of a population of suppressive cells, allowing the immune system to function more robustly and leading to better recognition and control of the disease."
Together, these data showed that radiation given locally can impact the immune system globally. Today, the patient continues to have a durable regression of melanoma both within and outside of the irradiated field. In the study, researchers followed the patient for seven years from her initial diagnosis of melanoma in 2004 through a series of treatments and eventual disease regression in April 2011 after a combination treatment of radiation and immunotherapy.
"The immune system differs in each of us. In studying one person's response, we were able to carefully investigate the clinical findings with in-depth laboratory studies, which suggested that a change in the immune system was vital to the successful results," added Dr. Wolchok.
The patient's dramatic systemic response following targeted radiation therapy in combination with immunotherapy has spurred interest in pursuing clinical trials to further validate this approach for prostate cancer and melanoma.
The team dedicated the study to the memory of Dr. Lloyd Old, a visionary leader in the field of tumor immunology. Dr. Old was Scientific Director of LICR from 1988 -- 2005 and Director of the New York Branch of LICR where much of the work in the paper was undertaken. Funding for this research was provided by LICR, as well as by the American Cancer Society, the Cancer Research Institute, the Commonwealth Foundation for Cancer Research, the Lita Annenberg Hazen Foundation, the Melanoma Research Alliance, MSKCC, the National Institutes of Health and Swim Across America.
- Michael A. Postow, Margaret K. Callahan, Christopher A. Barker, Yoshiya Yamada, Jianda Yuan, Shigehisa Kitano, Zhenyu Mu, Teresa Rasalan, Matthew Adamow, Erika Ritter, Christine Sedrak, Achim A. Jungbluth, Ramon Chua, Arvin S. Yang, Ruth-Ann Roman, Samuel Rosner, Brenna Benson, James P. Allison, Alexander M. Lesokhin, Sacha Gnjatic, Jedd D. Wolchok. Immunologic Correlates of the Abscopal Effect in a Patient with Melanoma. New England Journal of Medicine, 2012; 366 (10): 925 DOI: 10.1056/NEJMoa1112824
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