It is unknown whether the current dose of fulvestrant, an estrogen receptor (ER) antagonist, is suffi cient for maximal ER downregulation in patients with metastatic breast cancer. We performed a feasibility study to assess ER availability before and during fulvestrant. Sixteen patients with ER-positive metastatic breast cancer underwent positron emission tomography/ computed tomography (PET/CT) at baseline (scan 1), day 28 (scan 2), and day 84 (scan 3) to monitor tumor [ 18 F]fl uoroestradiol (FES) uptake. Incomplete reduction in ER availability was predefi ned as <75% decrease in median tumor FES uptake and a residual standardized uptake value (SUV max ) of ≥1.5.In total, 131 FES-positive lesions were identifi ed (median SUV max of 2.9; range, 1.7-6.5). The median change in patients during fulvestrant treatment was −85% at scan 2, but varied widely (−99% to +60%). Fulvestrant reduced tumor FES uptake incompletely at scan 2 in 6 (38%) of the 16 patients, which was associated with early progression. SIGNIFICANCE:Serial imaging of tumor estrogen uptake by FES-PET can give insight into the dose needed for ER antagonists to completely abolish ER. FES-PET showed signifi cant residual ER availability in tumors during fulvestrant therapy in 38% of patients, which was associated with early progression. Cancer Discov; 5(1);[72][73][74][75][76][77][78][79][80][81]

3508 Background: SPECT imaging with 111In-DTPA-trastuzumab has recently identified new tumor lesions, undetected with conventional staging, in 13/15 patients with HER2++ breast cancers (Perik et al., J Clin Oncol 2006). The aim of this study was to develop an immunoPET label, suitable for clinical use, which would allow excellent detection of HER2 positive tumor lesions and quantification of HER2 expression levels in vivo. Methods: Trastuzumab has essentially been radiolabeled as described by Verel et al. (J Nucl Med 2003). Radiochemical purity (rcp) and stability were determined by SEC-HPLC, immunoreactivity with a Lindmo assay. Biodistribution was performed in nude mice bearing HER2 positive (SKOV3) or HER2 negative (GLC4) xenografts. Five animals per group were co-injected with 111In-ITC-DTPA-trastuzumab and 89Zr-trastuzumab, imaged on a microPET (Focus 220) and sacrificed 144 hours post injection. Results: The immunoreactive fraction of 89Zr-trastuzumab was 0.96, labeling efficiency > 90% and rcp > 95%. 89Zr-trastuzumab was stable for 7 days in buffer at 4 °C and in human serum at 37 °C. MicroPET imaging showed excellent tumor uptake and could easily detect metastases with a size approximating the spatial resolution of the microPET scanner. 89Zr- and 111In-ITC-DTPA-trastuzumab showed similar biodistribution. Highest uptake was found in HER2 positive tumors at 144 hours post injection (40% ID/g tissue for 89Zr-trastuzumab and 47% ID/g for 111In-ITC-DTPA-trastuzumab) compared to 8% ID/g tissue in HER2 negative control tumors. Liver uptake was low (8–12% ID/g tissue). Preliminary results in HER2 positive breast cancer patients show excellent tumor tracer uptake and a resolution unapproachable by 111In-DTPA-trastuzumab. Conclusions: 89Zr-trastuzumab is stable, shows excellent and specific tumor uptake and is suitable for clinical use. Minimal aspecific tracer uptake in the liver allows detection of abdominal metastases. No significant financial relationships to disclose.

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The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.

BackgroundProbody® therapeutics are antibody prodrugs designed to be activated by tumor-associated proteases. This conditional activation restricts antibody binding to the tumor microenvironment, thereby minimizing ‘off-tumor’ toxicity. Here, we report the phase 1 data from the first-in-human study of CX-072 (pacmilimab), a Probody immune checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1), in combination with the anti-cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA-4) antibody ipilimumab.MethodsAdults (n=27) with advanced solid tumors (naive to PD-L1/programmed cell death protein 1 or CTLA-4 inhibitors) were enrolled in the phase 1 combination therapy dose-escalation portion of this multicenter, open-label, phase 1/2 study (NCT03013491). Dose-escalation pacmilimab/ipilimumab followed a standard 3+3 design and continued until the maximum tolerated dose (MTD) was determined. Pacmilimab+ipilimumab was administered intravenously every 3 weeks for four cycles, followed by pacmilimab administered every 2 weeks as monotherapy. The primary objective was identification of dose-limiting toxicities and determination of the MTD. Other endpoints included the rate of objective response (Response Evaluation Criteria In Solid Tumors v.1.1).ResultsTwenty-seven patients were enrolled in pacmilimab (mg/kg)+ipilimumab (mg/kg) dose-escalation cohorts: 0.3+3 (n=6); 1+3 (n=3); 3+3 (n=3); 10+3 (n=8); 10+6 (n=6); and 10+10 (n=1). Dose-limiting toxicities occurred in three patients, one at the 0.3+3 dose level (grade 3 dyspnea/pneumonitis) and two at the 10+6 dose level (grade 3 colitis, grade 3 increased aspartate aminotransferase). The MTD and recommended phase 2 dose was pacmilimab 10 mg/kg+ipilimumab 3 mg/kg administered every 3 weeks. Pacmilimab-related grade 3–4 adverse events (AEs) and grade 3–4 immune-related AEs were reported in nine (33%) and six (22%) patients, respectively. Three patients (11%) discontinued treatment because of AEs. The overall response rate was 19% (95% CI 6.3 to 38.1), with one complete (anal squamous cell carcinoma) and four partial responses (cancer of unknown primary, leiomyosarcoma, mesothelioma, testicular cancer). Responses lasted for >12 months in four patients.ConclusionsThe MTD and recommended phase 2 dose of pacmilimab (10 mg/kg)+ipilimumab (3 mg/kg) every 3 weeks is active and has a favorable tolerability profile.

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&lt;0.001). Tumors with immune desert vs CD8+ cell stromal/inflamed profile had a \bar{x}$ SUVmax of 4.7 vs 8.3 (p=0.042). In tumor biopsies, autoradiography signal and CD8 staining were linearly associated (p&lt;0.001). Conclusion: 89ZED88082A PET imaging is safe and shows high uptake in normal lymphoid organs. Uptake in tumor lesions is heterogeneous within and between patients. Tumor uptake is higher pretreatment in dMMR tumors and correlated with patient outcome. 89ZED88082A uptake on PET and by autoradiography reflects CD8 expression in tumor biopsies. 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.

11064 Background: Positron emission tomography (PET) using the catecholamine precursor 6-[F-18]fluoro-L-dihydroxyphenylalanine (18F-DOPA) has emerged as promising technique to localize tumors with catecholamine excess. This study investigated the sensitivity of 18F-DOPA PET, compared to 123I-metaiodobenzylguanidine (123I-MIBG) scintigraphy and computer tomography (CT)/ magnetic resonance imaging (MRI) in patients with catecholamine excess. Methods: In a single center prospective study 18F-DOPA PET was compared to 123I-MIBG and CT/MRI in patients with catecholamine excess. The performance of each imaging modality was analyzed for individual patients and individual lesions. 18F-DOPA PET, 123I-MIBG, and CT/MRI were compared using a composite reference standard derived from all available imaging, clinical and histological information. Sensitivities were calculated and discordance between imaging techniques was compared. 18F-DOPA PET uptake was measured to determine whole body metabolic burden. Correlations between 18F-DOPA PET imaging and biochemical data were evaluated. Results: 48 patients were included. The tumor localization was found in 45 patients, 43 with 18F-DOPA PET, 31 with 123I-MIBG and 32 with CT/MRI, resulting with surgery in final diagnosis of pheochromocytoma in 40, adrenal hyperplasia in 2, paraganglioma in 2, ganglioneuroma in 1 and 3 unknown (as yet no lesion detected). Per patient based analysis showed sensitivities for 18F-DOPA PET, 123I-MIBG and CT/MRI of 90, 65 and 67% (P<.01 18F-DOPA PET vs 123I-MIBG, P<.01 18F-DOPA PET vs CT/MRI, P=1.0 123I-MIBG vs CT/MRI). Corresponding sensitivities in the lesion based analysis were 73, 48 and 44%, respectively (P<.001 for both 18F-DOPA PET vs 123I-MIBG and vs CT/MRI, P=.51 123I-MIBG vs CT/MRI). The 8F-DOPA PET+CT/MRI combination was superior to 123I-MIBG+CT/MRI (93 vs 76%, P<.001) Whole body metabolic burden measured with 18F-DOPA PET correlated with plasma free normetanephrine (r=.82) and 24h urinary total normetanephrine (r=.84) and metanephrine (r=.57). Conclusions: The sensitivity of 18F-DOPA PET to localize tumors with catecholamine excess is superior to either 123I-MIBG scintigraphy or CT/MRI. No significant financial relationships to disclose.