1. Tuma, Rabiya S. PHD

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In rare cases, cancer patients have a distant response to localized radiotherapy, a phenomenon called the abscopal effect. Researchers have hypothesized that the localized therapy triggers a systemic anti-tumor immune response, but data proving that concept has been limited. Now, investigators at Memorial Sloan-Kettering Cancer Center have detailed the immune system activity in a melanoma patient who had a systemic response following localized radiation therapy and maintenance ipilimumab.

Figure. No caption a... - Click to enlarge in new windowFigure. No caption available.

The data, published in the New England Journal of Medicine(2012;366:926-931) show the patient had both cellular and antibody responses and that the timing of the immune responses correlated with distant tumor regression.


"This is not a new idea but being able to prove it is another thing," said Jedd Wolchok, MD, PhD, Associate Attending Physician and Director of Immunotherapy Clinical Trials at Sloan-Kettering, who led the work. "We had the opportunity to dig into the mechanisms and we could see a real systemic effect in response to a local tumor event."


The patient initially received 12 weeks of ipilimumab for metastatic melanoma starting in September 2009 as part of a clinical trial. Although she did not show any objective tumor response, she continued on maintenance therapy. Her disease worsened over the course of 2010 and she underwent radiotherapy to treat back pain caused by a paraspinal tumor in December 2010. In January 2011, there was no evidence of tumor shrinkage in the target lesion or distant tumors. In February 2011 she received the first of four additional maintenance doses of ipilimumab.


"By April 2011, her targeted paraspinal lesion had regressed significantly," Wolchok and colleagues write in the paper. "Remarkably, lesions in areas not targeted by radiotherapy had also regressed (right hilar lymphadenopathy and splenic lesions).[horizontal ellipsis]A subsequent CT scan obtained in October 2011 (10 months after radiotherapy) showed stability, with the continued presence of minimal disease."


To assess the patient's immune responses over the course of therapy, the investigators analyzed serum samples collected prior to the first ipilimumab dose and before and after radiotherapy.


The patient had antibodies against the NY-ESO-1 protein prior to starting ipilimumab therapy; however, the titer increased and the epitopes recognized by the antibodies shifted during therapy. The investigators also found that CD4-positive T-cell activation increased more than eightfold during ipilimumab induction therapy, dropped nearly to baseline three months later, and then rose again several-fold in response to radiation therapy.


Shifts were also detected in the abundance and activity of other immune system cells as well, and the shifts appeared to correlate with treatments, the team wrote.

JEDD WOLCHOK, MD, PH... - Click to enlarge in new windowJEDD WOLCHOK, MD, PHD: "This is not a new idea but being able to prove it is another thing[horizontal ellipsis].We could see a real systemic effect in response to a local tumor event."

Kim Margolin: 'Beautiful Story'

"This is a very beautiful story," said Kim Margolin, MD, Professor at the University of Washington and Member of the Fred Hutchinson Cancer Research Center. "You could say, 'it is only one patient,' but it is really proof of concept. And it can form the basis for writing clinical trials in which the effects can be studied systematically."


In fact, as Wolchok noted in an interview, the team is already working on such a trial. They plan to maintain an emphasis on measuring immune system correlates, as well as patient responses to the combined therapy.


Two other groups already have clinical trials under way to test the combination of ipilimumab and radiation in advanced melanoma patients. One trial, at Stanford University (NCT01449279), combines standard palliative radiation with ipilimumab, while a second one, at the Abramson Cancer Center at the University of Pennsylvania (NCT01497808), is testing the combination of ipilimumab and stereotactic radiation.