Enhanced Immune Response Seen With Ipilimumab Plus Radiation in Melanoma

Pro-inflammatory cytokines were elevated in patients with melanoma undergoing the combination treatment of radiation therapy and the systemic anti�CTLA-4 immunotherapy, ipilimumab.

Susan Hiniker, MD

Pro-inflammatory cytokines were elevated in patients with melanoma undergoing the combination treatment of radiation therapy and the systemic anti—CTLA-4 immunotherapy, ipilimumab, according to findings presented by Susan Hiniker, MD, an instructor in radiation oncology radiation therapy at the Stanford University School of Medicine, during the 2015 ASTRO annual conference. The findings suggest a relationship between elevated CD8-activated T cells among responders (eg, MCP-1, MIG, and IP-10).

“One method to potentiate ipilimumab responses is through applying local radiation,” said Hiniker. “Radiation can work to modulate the local tumor environment to promote an immune response—including through the upregulation of MHC class I, through the release of tumor antigens and neoantigens, and through the release of dendritic cells.”

In the prospective phase II trial, 20 patients with stage IV melanoma were treated with palliative radiation therapy and ipilimumab (3 mg/kg) every 3 weeks for a total of 4 cycles. Patients had 1 to 2 irradiated sites and at least 1 nonirradiated measureable site to assess for abscopal response. Safety and efficacy were the primary objectives of the trial, and secondary objectives included assessment of induction of antimelanoma immune responses using laboratory correlative studies. Radiation was administered within 5 days after the initiation of ipilimumab.

Imaging studies of the tumor were obtained at baseline prior to treatment, at 2 to 4 weeks following the fourth dose of ipilimumab, and every 3 months until disease progression.

“In a subset of patients, we also performed immune response assays on serum, in order to identify potential biomarkers of response,” said Hiniker.

Patients were predominantly male with a median age of 62 years, and 60% had received previous systemic therapy, “a number of whom actually received ipilimumab monotherapy, but 40% had not, so there was a mix of fairly heavily pretreated as well as untreated patients.”

The researchers observed a grade 3/4 combined toxicity rate of approximately 15%. The primary adverse events (AEs) seen were immune related, including colitis, hypophysitis, and rash. “Three of 22 patients did not receive all 4 cycles of ipilimumab because of colitis,” noted Hiniker. An additional three patients showed clear progression and did not complete all 4 cycles of ipilimumab. These patients required a change in treatment.

Tumor responses were measured using Response Evaluation Criteria in Solid Tumors (RECIST) and Immune Response Criteria (IRC) assessments. Patients were monitored for safety, and laboratory immune response parameters were measured before and during the treatment period, including enumeration of major cell subsets, as well as myeloid-derived suppressor cells (MDSC), and antigen-specific T-cell responses by intracellular cytokine staining.

Of the 20 evaluable patients treated to date, 11 patients (55.0%) had an initial response to therapy, including complete and partial responses (CR, PR) as well as stable disease (SD) at median follow-up of 38 weeks. Of the responders, three (14%) patients have achieved ongoing CR at the median of 55 weeks follow-up; three (14%) had initial PR for a median of 40 weeks; and five (22%) had initial SD for a median of 39 weeks.

“Interestingly, these patients all had grade 3/4 hypophysitis, which was not seen in patients who did not have a clear response and suggests a possible sign of a robust immune response,” Hiniker said.

Nine patients had progressive disease by IRC on the first posttreatment scan. Hiniker reported that combined treatment had been well tolerated with no unexpected toxicities, and no apparent exacerbation of either radiation or ipilimumab-associated toxicities.

Hiniker said cytokine analysis was performed on the serum collected in the subset of patients using a multiplexed Luminex assay. Additionally, peripheral blood mononuclear cells were analyzed by flow cytometry and mass spectrometry.

“Using this, we identified IL-2 and CD 8 T central memory cells as predictors of response,” said Hiniker. She emphasized, however, that “this was performed in a subset of patients and only serves as hypothesis-generating, but it was interesting.”

“We feel that radiation can be safely combined with ipilimumab, with no additional toxicity from the combination, although ipilimumab is a toxic agent on its own. We are in support of future studies looking at this combination,” concluded Hiniker.

Hiniker SM, Reddy SA, Maecker HT, et al. A prospective clinical trial combining radiation therapy with systemic immunotherapy in metastatic melanoma. Presented at: ASTRO 2015; October 18-21; San Antonio, Tx. Abstract 215.