[18F]FB-IL2 imaging of T cell response as biomarker to guide treatment decisions in metastatic melanoma patients

T cell infiltration of tumor lesions is a known prognostic factor in several
tumor types and is used as treatment mechanism in some of these tumor types. In
metastatic melanoma, treatment with immune checkpoint inhibitors like
ipilimumab induces clinical benefit in about 30% of the patients. These
immune-based therapies are however accompanied by serious immune-related
adverse events and high costs. Besides ipilimumab, the immune checkpoint
inhibitors pembrolizumab, nivolumab and the combination of ipilimumab and
nivolumab are approved as treatment for advanced melanoma.
Tumor infiltrating T cells express a high affinity interleukin-2 (IL2) receptor
on their surface. These T cells could therefore been visualized by the
radio-labelled ligand of this receptor, [18F]FB-IL2. If [18F]FB-IL2 PET is able
to detect a response to treatment it could serve as a non-invasive early
indicator of response. If no treatment-induced T cell infiltrating of tumor
lesions is seen, patient could be spared further treatment. Besides,
accumulation in non-target tissue could predict the development of an
immune-related adverse event. This finding could be anticipated by timely
discontinuation of immunotherapy.
The value of the [18F]FB-IL2 PET is already tested in ex vivo and animal
models, but has not been proven yet in human beings. We hypothesized that a
high correlation exist between [18F]FB-IL2 uptake and the extend of T cell
infiltration of tumor lesions.

Main objective of this study is to determine if the [18F]FB-IL2 PET is able to
detect a treatment-induced immune response in tumor lesions of patients with
metastatic melanoma and if the tumor uptake of the tracer correlates with the
number of IL2 receptor positive cells in these lesions. Besides, kinetics of
the tracer will be measured with an extended PET protocol in the first 5
patients.
Secondary objectives are to correlate tumor uptake of [18F]FB-IL2 with response
to therapy. In addition, heterogeneity of tracer uptake in tumor lesions and
tracer uptake of non-target tissues will be investigated. Since this is the
first study with application of [18F]FB-IL2 PET in humans, a safety profile of
the [18F]FB-IL2 PET will be determined.

This study is a feasibility (observational) study for the use of [18F]FB-IL2 as
a PET tracer, which will be conducted in a single center. Patients will be
treated with ipilimumab, nivolumab, pembrolizumab or the combination of
ipilimumab and nivolumab conform standard of care. The study will consist of
two substudies. In both substudies patients will receive a [18F]FB-IL2 PET scan
at baseline and at week 2 of treatment with immunotherapy. In patients
participating in phase 2 of the study, two biopsies and two blood samples will
be taken, of which the results will be correlated to the scan results. Adverse
events of immunotherapy will be registrated and will be correlated to the
amount of infiltrating T cells on the [18F]FB-IL2 PET. If adverse events occur
in colon or skin and patients have given their consent, a biopsie can be taken
from this non-target tissue. Response to treatment will be determined on the CT
scans, which will made in week 12 and 16 as part of regular care.

Main intervention of this study is a [18F]FB-IL2 PET-CT scan. This scan will be
performed twice: at baseline and at week 2 of treatment with immunotherapy.

The investigational product, [18F]FB-IL2, is chemically almost identical to the
drug Proleukin. Since it will be used in a sub-therapeutic dose of 50 µg or
less, no drug interactions or adverse events are to be expected. Nevertheless,
vital signs will be monitored until one hour after tracer injection and blood
parameters will be checked before and after each scan. A total of 14 blood
samples in phase 1 and 2 blood samples in phase 2 of the study will be obtained
for study purposes, which will give minor discomfort. Subjects will undergo two
PET-CT scans, which are estimated to carry an added radiation burden of 11.8
mSv, and a diagnostic CT with an additional radiation burden of 18 mSv. Thus,
the total radiation burden (29.8 mSv) is substantial, but according to the
investigators is justified by the possibility of finding a noninvasive
biomarker for predicting response to immune-modulating therapy in metastatic
melanoma patients, as these therapies are only of clinical benefit in part of
the patients, but still can be accompanied by severe adverse effects. In
patients participating in phase 2 of the study, after each PET scan a biopsy
will be taken from an easy accessible lesion. This biopsy could be painful and
carries the risk of bleeding. To minimize the burden to the patient,
intervention and patients* visits are preferably planned on the same day.