INTRODUCTION: Immune checkpoint inhibitors (ICI), like targeting programmed death receptor ligand 1 (PD-L1), have revolutionized anti-cancer treatments, including non-small cell lung cancer (NSCLC) [1, 2]. Assessment of PD-L1 expression on tumor biopsies is current practice, but there is a need for additional biomarkers correlating to the complex mechanism of action of ICI. The presence of tumor-infiltrating CD8+ T-cells (TILs) is a robust biomarker associated with immune therapy success [3-6]. Tools to track TILs in patients during ICI treatment would allow further development of immune-oncology drugs. METHODS: This ongoing single-center prospective study (NCT03853187) includes patients with histologically proven T1b-3N0-1M0 NSCLC eligible for resection. Exclusion criteria are previous anti-cancer therapy <6 months and immune disorders or suppression. Patients receive two courses neo-adjuvant durvalumab (750mg Q2W) and consecutive TIL imaging. Cohort 1 underwent apheresis and magnetic-activated cells sorting (CliniMACS) to isolate 100 x10e6 autologous CD8+ T-cells for ex vivo labeling with 111In-oxine. Re-injection was followed by 4h post-injection (p.i.) planar imaging, 70h p.i. SPECT imaging, standard-of-care surgery and 78h p.i. uSPECT of the resected lobe. Patients in cohort 2 (ongoing) receive 1.5mg 89Zr-Df-crefmirlimab followed by PET/CT 24h p.i. and 74h p.i. uPET/CT of the resected lobe. RESULTS/DISCUSSION: In cohort 1, 8/10 patients completed TIL imaging; one procedure was withdrawn due to COVID-19 restrictions and one due to unsuccessful T-cell isolation. CliniMACS yield ranged 240-714 x10e6 CD8+ T-cells, purity 84-97% and cell viability 92-100%. Labeling efficacy of 100 x10e6 cells for re-injection ranged 42-64% with injected activity of 22,4-36,7 MBq In-111. TIL imaging was completed by 2/3 patients in cohort 2, one subject discontinued neo-adjuvant treatment due to pneumonia. To determine the potential for visual assessment of TILs, we analyzed ratios between tumor uptake and contralateral lung. We observed large variations within cohort 1, dependent on tumor localization. Ratios between tumor and bloodpool activity were determined to quantify specific accumulation in the tumor. Our results favor quantification of T-cells on PET over SPECT given its higher sensitivity and spatial resolution. Correlation of imaging with CD8+ T-cells in the resected tumor is ongoing (will be presented). CONCLUSIONS: We implemented two methods for tracking CD8+ T-cells in early-stage NSCLC patients after neo-adjuvant durvalumab. Although ex vivo cell labeling perhaps more specifically targets migrating TILs into the tumor, 89Zr-Df-crefmirlimab has the potential to also target residing cells. Quantitative correlation with presence of TILs in the resected tumor will help to determine the role of these imaging tools in the development of immune-oncology drugs.
Imaging tumor-infiltrating CD8 (+) T-cells in non-small cell lung cancer patients upon neo-adjuvant treatment with durvalumab
E. van Genugten, B. Piet, G. Schreibelt, T. van Oorschot, G. van den Heuvel, F. Ciompi, C. Jacobs, J. de Vries, M. van den Heuvel and E. Aarntzen
European Molecular Imaging Meeting 2022.