Team: Willemien Menke, Ronald Boellaard, Elsmarieke van de Giessen, Danielle Vugts, Jort Vijverberg

Biologicals are medicines that are derived from living organisms or blood. They influence processes like growth signaling, immune system modulation and tissue homeostasis in order to slow down or inhibit a disease process. Many biologicals like monoclonal antibodies (mAbs) are currently being applied successfully for patients with cancer and many are in development for both oncology and neurology. In oncology new therapies that use the patient’s own immune cells (tumor infiltrating lymphocytes, or TILs) targeting the cancer cells show great promise for the treatment of cancer (1). In neurology there is a large pipeline of mAbs in development for neurodegenerative diseases (2, 3).

Especially in the field of Alzheimer’s disease (AD) developments are advancing quickly, as evident with recent FDA approval of the first two anti-amyloid mAbs. A major challenge for treatment with biologicals is the limited delivery to the brain (estimated ~1%), since the blood brain barrier mostly prevents large molecules such as mAbs from entering and reaching their target (4, 5). Since TILs are even larger than mAbs, potentially the percentage entering the brain will also be very limited. The amount of biologicals that reaches the brain is unknown, as until now, it has been impossible to directly measure brain delivery. Effectively bringing biologicals across the blood brain barrier (BBB) is one of the primary challenges to overcome for the treatment of patients with brain diseases.

This proof-of-concept study will assess whether we can measure the brain delivery and distribution of TILs and mAbs in patients with Positron Emission Tomography (PET) imaging. In patients with melanoma with/without brain metastases we will administer 89Zr-labeled TILs and measure the biodistribution and (tumor) uptake in the brain using PET. Likewise, we will administer 89Zr-labeled antiβamyloid mAbs in patients with Alzheimer’s disease and measure brain uptake with PET. When this approach proves successful we anticipate to be able to answer questions like why certain biologicals are (not) effective, what dosing would be optimal and how novel techniques can enhance the delivery of medication across the blood brain barrier.