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Purpose Monoclonal antibody (mAb)-based PET (immunoPET) imaging can characterise tumour lesions non-invasively. It may be a valuable tool to determine which patients may benefit from treatment with a specific monoclonal antibody (mAb) and evaluate treatment response. For 89Zr immunoPET imaging, higher sensitivity of state-of-the art PET/CT systems equipped with silicon photomultiplier (SiPM)-based detector elements may be beneficial as the low positron abundance of 89Zr causes a low signal-to-noise level. Moreover, the long physical half-life limits the amount of activity that can be administered to the patients leading to poor image quality even when using long scan durations. Here, we investigated the difference in semiquantitative performance between the PMT-based Biograph mCT, our clinical reference system, and the SiPM-based Biograph Vision PET/CT in 89Zr immunoPET imaging. Furthermore, the effects of scan duration reduction using the Vision on semiquantitative imaging parameters and its influence on image quality assessment were evaluated. Methods Data were acquired on day 4 post 37 MBq 89Zr-labelled mAb injection. Five patients underwent a double scan protocol on both systems. Ten patients were scanned only on the Vision. For PET image reconstruction, three protocols were used, i.e. one camera-dependent protocol and European Association of Nuclear Medicine Research Limited (EARL) standards 1 and 2 compliant protocols. Vision data were acquired in listmode and were reprocessed to obtain images at shorter scan durations. Semiquantitative PET image parameters were derived from tumour lesions and healthy tissues to assess differences between systems and scan durations. Differently reconstructed images obtained using the Vision were visually scored regarding image quality by two nuclear medicine physicians. Results When images were reconstructed using 100% acquisition time on both systems following EARL standard 1 compliant reconstruction protocols, results regarding semiquantification were comparable. For Vision data, reconstructed images that conform to EARL1 standards still resulted in comparable semiquantification at shorter scan durations (75% and 50%) regarding 100% acquisition time. Conclusion Scan duration of 89Zr immunoPET imaging using the Vision can be decreased up to 50% compared with using the mCT while maintaining image quality using the EARL1 compliant reconstruction protocol.

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8+ T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8+ T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUVmax) 5.2, IQI 4.0–7.4). Higher SUVmax was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8+ T cell distribution and pharmacodynamics within and between patients. In conclusion, 89ZED88082A can characterize the complex dynamics of CD8+ T cells in the context of ICIs, and may inform immunotherapeutic treatments.

Purpose Immune checkpoint inhibitors can induce a T cell–mediated anti-tumor immune response in patients with melanoma. Visualizing T cell activity using positron emission tomography (PET) might allow early insight into treatment efficacy. Activated tumor–infiltrating T cells express the high-affinity interleukin-2 receptor (IL-2R). Therefore, we performed a pilot study, using fluorine-18-labeled IL-2 ([18F]FB-IL2 PET), to evaluate whether a treatment-induced immune response can be detected. Methods Patients with metastatic melanoma received ~ 200 MBq [18F]FB-IL2 intravenously, followed by a PET/CT scan before and during immune checkpoint inhibitor therapy. [18F]FB-IL2 uptake was measured as standardized uptake value in healthy tissues (SUVmean) and tumor lesions (SUVmax). Response to therapy was assessed using RECIST v1.1. Archival tumor tissues were used for immunohistochemical analyses of T cell infiltration. Results Baseline [18F]FB-IL2 PET scans were performed in 13 patients. SUVmean at baseline was highest in the kidneys (14.2, IQR: 11.6–18.0) and liver (10.6, IQR: 8.6–13.4). In lymphoid tissues, uptake was highest in spleen (10.9, IQR: 8.8–12.4) and bone marrow (2.5, IQR: 2.1–3.0). SUVmax in tumor lesions (n = 41) at baseline was 1.9 (IQR: 1.7–2.3). In 11 patients, serial imaging was performed, three at week 6, seven at week 2, and one at week 4. Median [18F]FB-IL2 tumor uptake decreased from 1.8 (IQR: 1.7–2.1) at baseline to 1.7 (IQR: 1.4–2.1) during treatment (p = 0.043). Changes in [18F]FB-IL2 tumor uptake did not correlate with response. IL-2R expression in four archival tumor tissues was low and did not correlate with baseline [18F]FB-IL2 uptake. No [18F]FB-IL2-related side effects occurred. Conclusion PET imaging of the IL-2R, using [18F]FB-IL2, is safe and feasible. In this small patient group, serial [18F]FB-IL2-PET imaging did not detect a treatment-related immune response. Trial registration Clinicaltrials.gov: NCT02922283; EudraCT: 2014-003387.20

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8

Background Immune checkpoint inhibitors (ICIs) can induce durable responses in multiple different tumor types. Lymphocyte activation gene-3 (LAG-3) is one of the immune checkpoints for which therapeutic antibodies are being developed. PET imaging with radiolabeled ICIs can visualize whether the drug reaches the tumor, and might serve as a target expression readout. Therefore, we aimed to evaluate the safety of the radiolabeled LAG-3 antibody 89Zr-DFO-REGN3767, to determine the optimal tracer dose and imaging time point, and to get insight into 89Zr-DFO-REGN3767 whole body distribution. Methods Patients with advanced solid tumors received 37 MBq 89Zr-DFO-REGN3767 together with unlabeled antibody to achieve a 2, 5, 10, 20, or 40 mg total protein dose (NCT04706715). Patients underwent PET/CT scans on days 0, 2, 4, and 7 after injection, followed by a tumor biopsy. After that, they received treatment with cemiplimab alone or combined with platinum-containing chemotherapy. PET scans were analyzed by placing volumes of interest (VOIs) in tumor lesions and normal tissues. Tracer uptake was measured in the VOIs and expressed as the maximum standardized uptake value (SUVmax) for tumor lesions and as the mean standardized uptake value (SUVmean) for normal tissues. Results The 16 included patients experienced no 89Zr-DFO-REGN3767-related side effects. Tumor-to-blood ratios for all dose levels increased from days 0 to 7. Therefore, imaging 7 days after tracer injection was deemed optimal to achieve the highest contrast. The 40 mg tracer dose resulted in the most favorable blood kinetics. At this dose, tracer uptake in tumor lesions (n = 17) varied between patients (geometric mean SUVmax 6.2; SD 1.7). In normal tissues, uptake was seen in the spleen (x̄ 11.2; SD 1.6), and bone marrow (x̄ 2.2; SD 0.7), which increased from days 0 to 7. Tracer uptake was visually present in regions with inflammation. Conclusion 89Zr-DFO-REGN3767 PET imaging is feasible and studied patients did not experience tracer related side effects. Optimal imaging results were achieved with the 40 mg protein dose and imaging on day 7 89Zr-DFO-REGN3767 shows specific accumulation in LAG-3 rich tissues and tumor lesions. Citation Format: Pim P. van de Donk, Lotte M. Smit, Joyce van Sluis, Wim Timens, Adrienne H. Brouwers, Marjolijn N. Lub- de Hooge, Sjoerd G. Elias, Jourik A. Gietema, Claudia A. van Winkel, JuAn Wang, Jason Giurleo, Thomas Uldrick, Hung Kam Cheung, Hilde Jalving, Sjoukje F. Oosting, Daan G. Knapen, Derk-Jan A. de Groot, Elisabeth G. de Vries. LAG-3 PET imaging in patients with cancer before immune checkpoint inhibitor therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5611.

Immune checkpoint inhibitors (ICIs) have substantially changed the field of oncology over the past few years. ICIs offer an alternative treatment strategy by exploiting the patients’ immune system, resulting in a T cell mediated anti-tumor response. These therapies are effective in multiple different tumor types. Unfortunately, a substantial group of patients do not respond to ICIs. Molecular imaging, using single-photon emission computed tomography (SPECT) and positron emission tomography (PET), can provide non-invasive whole-body visualization of tumor and immune cell characteristics and might support patient selection or response evaluations for ICI therapies. In this review, recent studies with 18F-fluorodeoxyglucose-PET imaging, imaging of immune checkpoints and imaging of immune cells will be discussed. These studies are until now mainly exploratory, but the first results suggest that molecular imaging biomarkers could have a role in the evaluation of ICI therapy.

3573 Background: Immune checkpoint inhibitors (ICI) targeting programmed cell death protein-1/ligand-1 (PD-1/PD-L1) have shown activity in R/M squamous cell carcinoma of the head and neck (SCCHN). Positron-emission-tomography (PET) with 89Zr-labeled anti-PD-L1 antibodies could aid in predicting response to ICI. We present the dose-finding results of the first-in-human 89Zr-durvalumab PD-L1 PET-imaging in patients with SCCHN participating in the ongoing phase II PINCH study (NCT03829007). Methods: Following baseline [18F]FDG-PET and CT/MRI imaging, patients with incurable R/M SCCHN received 37 MBq 89Zr-durvalumab and protein dose 2mg, 10mg or 50mg durvalumab. 89Zr-durvalumab PD-L1 PET-scan was acquired day 5 post-injection. Plasma pharmacokinetic analyses were performed at day 0 and 5. Standardized uptake values (SUV, mean ± SD) were measured in [18F]FDG-positive tumor lesion, liver, spleen, bone marrow and bloodpool. PD-L1-expression was assessed on archival tumor tissue using the Ventana PD-L1 (SP263) assay. Results: 14 patients were enrolled and no adverse events were reported. High tracer-retention was observed in liver and spleen, most prominent in patients receiving 2 or 10mg durvalumab. 89Zr-durvalumab accumulation within tumors and between patients was heterogeneous and not all [18F]FDG-positive lesions showed 89Zr-durvalumab uptake. Tumor lesions were visualized best using 10 or 50mg durvalumab (SUVpeak 2mg: 3.86 ± 0.79, 10mg: 7.46 ± 2.18, 50mg: 5.57 ± 1.74). Tumor-to-blood-ratios for 10mg durvalumab were highest (2mg: 2.27 ± 0.33, 10mg: 3.44 ± 0.76, 50mg: 1.73 ± 0.99; p = 0.019). PK-analyses confirmed visual prolonged tracer-retention in bloodpool with increasing protein dose. PD-L1-expression was equally distributed amongst dose-groups. Conclusions: This is the first study to show feasibility of 89Zr-durvalumab PD-L1 PET in SCCHN patients, demonstrating the highest tumor-to-blood radio with a total dose of 10mg durvalumab. So far, no correlation of tumor PD-L1 expression with 89Zr-durvalumab-uptake and PD-L1 expression on archival tissue was found. Next step will be to correlate 89Zr-durvalumab PD-L1 PET tumor uptake with durvalumab treatment response in the phase 2 part of the PINCH study. Clinical trial information: NCT03829007 .

T cell enhancing immune checkpoint inhibitors (ICI) are effective across several tumor types in a subset of patients. Insights into systemic localization of cytotoxic CD8+ T cells might support early treatment decisions. To address this, we performed a PET imaging study with a zirconium-89 (89Zr) labeled one-armed CD8-specific antibody 89ZED88082A to assess tracer performance, safety, and pharmacokinetics (PK) before and during treatment. Here we report preliminary data on uptake in tumor lesions before ICI. Methods: Patients with locally advanced or metastatic solid tumors that may benefit from ICI are eligible. In part A (imaging before treatment) and part B (imaging before and during treatment), 37 MBq (1 mCi) 89ZED88082A is administered with unlabeled one-armed antibody CED88004S to vary total protein dose. PET images are acquired at up to 4 time points: 1 h, and days (d) 2, 4, 7 post-injection followed by a tumor biopsy for CD8 immunohistochemistry and autoradiography (NCT04029181). Subsequently, patients receive atezolizumab (NCT02478099) or standard of care nivolumab ± ipilimumab. Tumor and lymph node 89ZED88082A uptake are assessed as (geometric mean) maximum standard uptake value (SUVmax), in other organs as SUVmean. Serum 89ZED88082A/CED88004S levels are measured for PK. Tumor response is according to (i)RECIST1.1. Results: For pretreatment imaging results, 32 patients (9 part A, 23 part B) were evaluable; 3 received 4 mg total tracer protein dose, 29 received 10 mg. No tracer infusion-related reactions occurred. Here we show results on d2 PET imaging with 10 mg protein dose, which was considered optimal based on superior 89Zr blood pool activity, clinical feasibility and serum antibody PK with a half-life of 28.6 h. 89ZED88082A uptake was observed within 1 h in spleen, and strong d2 imaging signal was seen across lymphoid organs including spleen (\bar{x}$ SUVmean 47.2), lymph nodes (SUVmax 4.2), bone marrow (\bar{x}$ SUVmean 5.0), small bowel and Waldeyer's ring. 89ZED88082A tumor uptake was seen at all main metastatic organ sites (overall lesion SUVmax 5.5, range 0.6-30.9) and varied across patients (\bar{x}$ per patient SUVmax 5.4, IQR 3.8-7.4). Higher tumor uptake showed a trend with better response (p=0.059) and longer PFS (p=0.033). Tumor uptake was higher in patients with mismatch-repair deficient (dMMR) than MMR proficient tumors (SUVmax 9.3 vs 4.9, p Citation Format: Laura Kist de Ruijter, Pim P. van de Donk, Jahlisa S. Hooiveld-Noeken, Danique Giesen, Alexander Ungewickell, Bernard M. Fine, Simon P. Williams, Sandra M. Sanabria Bohorquez, Mahesh Yadav, Hartmut Koeppen, Jing Jing, Sebastian Guelman, Mark T. Lin, Michael J. Mamounas, Jeffrey Eastham, Patrick K. Kimes, Andor W. Glaudemans, Adrienne H. Brouwers, Marjolijn N. Lub-de Hooge, Jourik A. Gietema, Carolina P. Schröder, Wim Timens, Mathilde Jalving, Sjoerd Elias, Sjoukje F. Oosting, Derk J. de Groot, Elisabeth G. de Vries. 89ZED88082A PET imaging to visualize CD8+ T cells in patients with cancer treated with immune checkpoint inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB037.