Immunotherapy is becoming the mainstay for treatment of a variety of malignancies, but only a subset of patients responds to treatment. Tumor-infiltrating CD8-positive (CD8+) T lymphocytes play a central role in antitumor immune responses. Noninvasive imaging of CD8+ T cells may provide new insights into the mechanisms of immunotherapy and potentially predict treatment response. We are studying the safety and utility of ⁸⁹Zr-IAB22M2C, a radiolabeled minibody against CD8+ T cells, for targeted imaging of CD8+ T cells in patients with cancer. Methods: The initial dose escalation phase of this first-in-humans prospective study included 6 patients (melanoma, 1; lung, 4; hepatocellular carcinoma, 1). Patients received approximately 111 MBq (3 mCi) of ⁸⁹Zr-IAB22M2C (at minibody mass doses of 0.2, 0.5, 1.0, 1.5, 5, or 10 mg) as a single dose, followed by PET/CT scans at approximately 1–2, 6–8, 24, 48, and 96–144 h after injection. Biodistribution in normal organs, lymph nodes, and lesions was evaluated. In addition, serum samples were obtained at approximately 5, 30, and 60 min and later at the times of imaging. Patients were monitored for safety during infusion and up to the last imaging time point. Results:⁸⁹Zr-IAB22M2C infusion was well tolerated, with no immediate or delayed side effects observed after injection. Serum clearance was typically biexponential and dependent on the mass of minibody administered. Areas under the serum time–activity curve, normalized to administered activity, ranged from 1.3 h/L for 0.2 mg to 8.9 h/L for 10 mg. Biodistribution was dependent on the minibody mass administered. The highest uptake was always in spleen, followed by bone marrow. Liver uptake was more pronounced with higher minibody masses. Kidney uptake was typically low. Prominent uptake was seen in multiple normal lymph nodes as early as 2 h after injection, peaking by 24–48 h after injection. Uptake in tumor lesions was seen on imaging as early as 2 h after injection, with most ⁸⁹Zr-IAB22M2C–positive lesions detectable by 24 h. Lesions were visualized early in patients receiving treatment, with SUV ranging from 5.85 to 22.8 in 6 target lesions. Conclusion:⁸⁹Zr-IAB22M2C imaging is safe and has favorable kinetics for early imaging. Biodistribution suggests successful targeting of CD8+ T-cell–rich tissues. The observed targeting of tumor lesions suggests this may be informative for CD8+ T-cell accumulation within tumors. Further evaluation is under way.

Purpose: Standard imaging for assessing osseous metastases in advanced prostate cancer remains focused on altered bone metabolism and is inadequate for diagnostic, prognostic, or predictive purposes. We performed a first-in-human phase I/II study of ⁸⁹Zr-DFO-huJ591 (⁸⁹Zr-J591) PET/CT immunoscintigraphy to assess performance characteristics for detecting metastases compared with conventional imaging modalities (CIM) and pathology. Experimental Design: Fifty patients with progressive metastatic castration-resistant prostate cancers were injected with 5 mCi of ⁸⁹Zr-J591. Whole-body PET/CT scans were obtained, and images were analyzed for tumor visualization. Comparison was made to contemporaneously obtained bone scintigraphy and cross-sectional imaging on a lesion-by-lesion basis and with biopsies of metastatic sites. Results: Median standardized uptake value for ⁸⁹Zr-J591–positive bone lesions (n = 491) was 8.9 and for soft-tissue lesions (n = 90), it was 4.8 (P < 0.00003). ⁸⁹Zr-J591 detected 491 osseous sites compared with 339 by MDP and 90 soft-tissue lesions compared with 124 by computed tomography (CT). Compared with all CIMs combined, ⁸⁹Zr-J591 detected an additional 99 osseous sites. Forty-six lesions (21 bone and 25 soft tissue) were biopsied in 34 patients; 18 of 19 ⁸⁹Zr-J591–positive osseous sites and 14 of 16 ⁸⁹Zr-J591–positive soft tissue sites were positive for prostate cancer. The overall accuracy of ⁸⁹Zr-J591 was 95.2% (20 of 21) for osseous lesions and 60% (15 of 25) for soft-tissue lesions. Conclusions: ⁸⁹Zr-J591 imaging demonstrated superior targeting of bone lesions relative to CIMs. Targeting soft-tissue lesions was less optimal, although ⁸⁹Zr-J591 had similar accuracy as individual CIMs. This study will provide benchmark data for comparing performance of proposed prostate-specific membrane antigen (PSMA) targeting agents for prostate cancer. Clin Cancer Res; 21(23); 5277–85. ©2015 AACR.

Given the bone tropism of prostate cancer, conventional imaging modalities poorly identify or quantify metastatic disease. ⁸⁹Zr-huJ591 positron emission tomography (PET) imaging was performed in patients with metastatic prostate cancer to analyze and validate this as an imaging biomarker for metastatic disease. The purpose of this initial study was to assess safety, biodistribution, normal organ dosimetry, and optimal imaging time post-injection for lesion detection.

We conducted a phase I dose-escalation study with ⁸⁹Zr-desferrioxamine-IAB2M (⁸⁹Zr-IAB2M), an anti–prostate-specific membrane antigen minibody, in patients with metastatic prostate cancer. Methods: Patients received 185 MBq (5 mCi) of ⁸⁹Zr-IAB2M and Df-IAB2M at total mass doses of 10 (n = 6), 20 (n = 6), and 50 mg (n = 6). Whole-body and serum clearance, normal-organ and lesion uptake, and radiation absorbed dose were estimated, and the effect of mass escalation was analyzed. Results: Eighteen patients were injected and scanned without side effects. Whole-body clearance was monoexponential, with a median biologic half-life of 215 h, whereas serum clearance showed biexponential kinetics, with a median biologic half-life of 3.7 (12.3%/L) and 33.8 h (17.9%/L). The radiation absorbed dose estimates were 1.67, 1.36, and 0.32 mGy/MBq to liver, kidney, and marrow, respectively, with an effective dose of 0.41 mSv/MBq (1.5 rem/mCi). Both skeletal and nodal lesions were detected with ⁸⁹Zr-IAB2M, most visualized by 48-h imaging. Conclusion: ⁸⁹Zr-IAB2M is safe and demonstrates favorable biodistribution and kinetics for targeting metastatic prostate cancer. Imaging with 10 mg of minibody mass provides optimal biodistribution, and imaging at 48 h after injection provides good lesion visualization. Assessment of lesion targeting is being studied in detail in an expansion cohort.

Introduction: Iodine-123-meta-iodobenzylguanidine (¹²³I-MIBG) imaging is currently a mainstay in the evaluation of many neuroendocrine tumors, especially neuroblastoma. ¹²³I-MIBG imaging has several limitations that can be overcome by the use of a PET agent. ¹⁸F-MFBG is a positron emission tomography (PET) analog of MIBG that may allow for single-day, high-resolution quantitative imaging. We conducted a first-in-human study of ¹⁸F-MFBG PET imaging to evaluate the safety, feasibility, pharmacokinetics, and dosimetry of ¹⁸F-MFBG in neuroendocrine tumors (NETs). Methods: Ten patients (five with neuroblastoma and five with paraganglioma/ pheochromocytoma) received 148-444 MBq (4-12 mCi) of ¹⁸F-MFBG IV followed by serial whole-body imaging at 0.5-1 h, 1-2 h, and 3-4 h post-injection (p.i.). Serial blood samples (a total of 6) were also obtained starting at 5 min p.i. to as late as 4 h p.i. whole-body distribution and blood clearance data, lesion uptake, and normal tissue uptakes were determined; radiation-absorbed doses to normal organs were calculated using Organ Level INternal Dose Assessment (OLINDA). Results: No side effects were seen in any patient after ¹⁸F-MFBG injection. Tracer distribution showed prominent activity in bloodpool, liver, and salivary glands that decreased with time. Mild uptake was seen in kidneys and spleen, which also decreased with time. Urinary excretion was prominent, with an average of 45% of the administered activity in bladder by 1 h p.i. whole-body clearance was monoexponential with mean biologic half-life (T1/2b) of 1.95 h, while blood clearance was bi-exponential with mean T1/2b of 0.3 h (58 %) for the rapid α phase and 6.1 h (42%) for the slower β phase. Urinary bladder received the highest radiation dose with a mean absorbed dose of 0.186 ± 0.195 mGy/MBq. Mean total body dose was 0.011 ± 0.011 mGy/MBq and the effective dose was 0.023± 0.012 mSv/Mbq. Both skeletal and soft tissue lesions were visualized with high contrast. The maximum standard uptake value (SUV_MAX) [mean ± standard deviation (SD)] of lesions at 1-2 h p.i. was 8.6 ± 9.6. Conclusion: Preliminary data show that ¹⁸F-MFBG imaging is safe and has favorable biodistribution and kinetics with good targeting of lesions. PET imaging with ¹⁸F-MFBG allows for same-day imaging of NETs. ¹⁸F-MFBG appears highly promising for imaging of patients with NETs, especially children with neuroblastoma.