Nanobody constructs, targeting growth factors and their receptors, for PET imaging and cancer therapy

Dongen, G.A.M.S. van [Promotor]Visser, G.W.M. [Copromotor]Bergen en Henegouwen, P.M.P. van [Copromotor

High power conical-shaped Niobium targets for reliable [18F-] production and lower [18O] water consumption: High power conical-shaped Niobium targets for reliable [18F-] production and lower [18O] water consumption

Introduction In order to address the increasing demand for Fluorine-18 and the rising cost per mL of 18O enriched water, IBA developed improvements to their 18F- production systems. For this new design we started from scratch, with the main objectives of reducing the required enriched water volume and improving the cooling of the insert. A better cooling allows increasing the target current and thus the produced activity. Finally, we aimed to reduce the number of parts and improve the design of auxiliary components. Material and Methods Six Niobium conical inserts with different target chamber volumes were machined and tested. Only 4 of these were selected to create the new range of IBA 18F− targets shown in TABLE 1. The new Niobium target inserts have a complex shape with drilled channels on the outside of the chamber and a deep channel next to the beam strike area (FIG. 1, green circle) to ensure efficient cooling. The 18O water inlet lines are now directly inserted in the Niobium body (FIG. 1, blue circle) to improve 18F- quality (no more contact with small o-rings). In operation, a 35µm Havar® target window is used. All tests were performed using IBA Cyclone® 18 cyclotron. The targets were filled with different volumes of enriched 18O water (enrichment > 92 %) and irradiated with 18 MeV protons on target with beam currents up to 145 μA for 30 to 150 minutes, while the internal pressure rise of the target was recorded. For each target, a pressure-current curve was plotted and an optimum balance between target water fill volume, pressure and current has been determined, which maximises available activity after two hours, in each case. Results and Conclusion Radionuclidic impurities were measured and more than 100 FDG syntheses on various synthesizers confirmed the effectiveness of the new design. Increasing the current up to 145µA in Conical 16, the production reached 18 Ci in 2 hours, single beam, with a target pressure under 43 bar. Today, the use of these new targets for daily commercial production is increasing within the IBA Cyclone® installed base

Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells

Immunotherapy using checkpoint-blocking antibodies against targets such as CTLA-4 and PD-1 can cure melanoma and non-small cell lung cancer in a subset of patients. The presence of CD8 T cells in the tumor correlates with improved survival. We show that immuno-positron emission tomography (immuno-PET) can visualize tumors by detecting infiltrating lymphocytes and, through longitudinal observation of individual animals, distinguish responding tumors from those that do not respond to therapy. We used 89 Zr-labeled PEGylated single-domain antibody fragments (VHHs) specific for CD8 to track the presence of intratumoral CD8 + T cells in the immunotherapy-susceptible B16 melanoma model in response to checkpoint blockade. A 89 Zr-labeled PEGylated anti-CD8 VHH detected thymus and secondary lymphoid structures as well as intratumoral CD8 T cells. Animals that responded to CTLA-4 therapy showed a homogeneous distribution of the anti-CD8 PET signal throughout the tumor, whereas more heterogeneous infiltration of CD8 T cells correlated with faster tumor growth and worse responses. To support the validity of these observations, we used two different transplantable breast cancer models, yielding results that conformed with predictions based on the antimelanoma response. It may thus be possible to use immuno-PET and monitor antitumor immune responses as a prognostic tool to predict patient responses to checkpoint therapies.National Institutes of Health (U.S.) (Grant R01-AI087879-06)National Institutes of Health (U.S.) (Grant DP1-GM106409-03)National Institutes of Health (U.S.) (Grant R01-GM100518-04)National Institutes of Health (U.S.) (Grant P01 CA080111