Tumor uptake and biodistribution of 89Zirconium-labeled ipilimumab in patients with metastatic melanoma during ipilimumab treatment

Introduction

Ipilimumab, a monoclonal antibody targeting CTLA-4, is approved for the treatment of metastatic melanoma and significantly improves overall survival. Because of the high costs and the potential serious toxicity of ipilimumab, it is of great importance to identify biomarkers that correlate with clinical activity and that can be used to select patients who will benefit from CTLA-4 blockade therapy.

We hypothesize that patients who do not respond to treatment with ipilimumab have lower drug levels in tumor tissues as compared to patients with a good response to therapy. In addition, we hypothesize that immune related adverse events (irAEs) are associated with high drug levels in the affected tissue. As irAEs usually occur approximately 6-8 weeks after the first injection of ipilimumab, we hypothesize that the drug levels in potentially affected tissues will increase at the second injection.

Experimental procedures

To visualize in vivo localization of ipilimumab in patients diagnosed with metastatic melanoma, 37 MBq, 10 mg 89Zr-labeled ipilimumab was injected within 2 hours after their first ipilimumab dose (3 mg/kg). Whole body PET/CT scans were obtained at 2h, 72h and 144h post injection and this procedure was repeated three weeks later at the second ipilimumab cycle. Biodistribution and tumor uptake were assessed visually by a nuclear physician. Focal uptake in tumor lesions exceeding local background was determined in volumes of interest (VOI) and SUVpeak values were obtained. Biodistribution was quantified by defining vital organs (i.e. lungs, kidneys, spleen, liver) and calculating mean %ID/kg. Blood was drawn for dosimetry and immunophenotyping at several time points during the trial. Presented here are initial results of the first three patients, up to 29 patients are planned to be included.

Results

Biodistribution of 89Zr-labeled ipilimumab showed a pattern distinctive for 89Zr-labeled antibodies with uptake in liver and spleen, as well as prolonged circulating antibody in the bloodstream corresponding to the pharmacokinetics of ipilimumab. Visual evaluation confirmed uptake of 89Zr-labeled ipilimumab in 5/12 evaluable tumor lesions, visible at both first and second injection of ipilimumab. Tumor uptake was comparable for 72h and 144h post injection with a mean of 6.9 %ID/kg (range 3.3-10.1) and a SUVpeak of 4.4 (range 2.3-8.9). There were no significant differences in tumor uptake between first and second dose of ipilimumab (mean 7.31 and 6.54 %ID/kg respectively).

Conclusions

Preliminary data of this ongoing study showed that the tracer is able to visualize and quantify uptake of ipilimumab in tumors. Correlations between tumor uptake and response to treatment will be presented. Furthermore, special interest will be given to uptake in lymphoid organs and locations for irAEs.