Keyword

37.1 Prof. Zhi Yang and His Team

Dr. Yang received his PhD in radiochemistry from China Institute of Atomic Energy (401 Institute) and got his visiting scholar training in the University of Texas MD Anderson Cancer Center. He started his assistant professorship in 1992 and became a professor and the director of Nuclear Medicine Department at Peking University Cancer Hospital in 2014. Dr. Yang focused on the clinical translational research of nuclear medicine. The research interests of the department include nuclear medicine clinical research, as well as the development of multimodality/multiplexed molecular probes for tumor diagnosis and therapy. Dr. Yang’s current research interest mainly focuses on the production, labeling, and clinical application of solid target-based nuclides (64Cu, 89Zr, 124I). Dr. Yang has published about 100 research papers and a number of book chapters, conference proceedings, and other publications. Now, 4 postdoctoral scholars, 11 PhD students, and 2 master students are under his supervision. Three students have received master degrees (Figs. 37.1 and 37.2).

Fig. 37.1
A group photograph of Professor Yanga and her colleagues.

Group photo of Prof. Yang and the students (Sep 10, 2019, teacher’s day celebration)

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Fig. 37.2
A group photograph of Professor Yang and the staff members of Beijing Cancer Hospital.

Group photo of Prof. Yang and the faculty and staff at the nuclear medicine department (summer 2019)

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37.2 Beijing Cancer Hospital: Nuclear Medicine Department Clinical Translation Platform

37.2.1 Introduction of the Department

Research activities in Nuclear Medicine Department, Beijing Cancer Hospital (BCH-NM) are primary focused on three areas:

  1. 1.

    The translational medical research. The department aims to improve the health of individuals (especially tumor patients) and the community by translating basic scientific findings into radiopharmaceuticals or radiotracers.

  2. 2.

    The development of targeted imaging probes for noninvasive characterization of molecular events associated with tumor progression and regression. Molecular imaging probes which used in nuclear, optical imaging modalities are developed to enhance the sensitivity and selectivity of early tumor detection, tumor-marker profiling, and the monitoring of early treatment responses.

  3. 3.

    The development of new target, novel drug-delivery systems for selective delivery of diagnostic and therapeutic agents.

Our long-term goal is to apply the “seek and treat” strategy in the development of targeted imaging/therapeutic agents that eventually translate to the clinics to improve the management of cancer through early tumor detection and individualized therapy.

In a word, the overall objective of the laboratory is to develop novel molecular imaging probes for clinical noninvasive detection of tumor.

BCH-NM holds great advantages in clinical translational studies (Table 37.1). Two PET/CT scanners, an HM-20 cyclotron, two SPECT/CT scanners, two 68Ge-68Ga generators, and more than ten hot cells equipped in the NM departments. The department holds the fourth level (highest) of radiopharmaceutical certification approved by China-FDA (CFDA) which allows independent clinical studies (Fig. 37.3).

Table 37.1 Present clinical translational studies in BCH-NM department
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Fig. 37.3
A flowchart of radionuclide production, automatic synthesis, quality control, micro PET or C T imaging, and clinical PET application.

Typical clinical translation study in BCH-NM “from bench to bedside”

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37.2.2 PKUCH-NM Honored to be the First ICPO Partner

On August 27, 2019, the signing ceremony for the cooperation between Peking University Cancer Hospital (PKUCH) and the International Centers for Precision Oncology (ICPO) was held successfully in the scientific research building of BCH-NM. The cooperation agreement was signed by President Ji Jiafu from PKUCH and President Richard P. Baum from ICPO Academy and Founding ICPO Board Member (Fig. 37.4).

Fig. 37.4
A group photograph of Professors after a ceremony.

Signing ceremony attendees tour PKUCH-NM facilities

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PKUCH is one of the most recognized large specialty hospitals in the field of cancer research and treatment in China. PKUCH is aiming to build a prestigious international cancer center. Initial talks in cooperation between PKUCH and ICPO initiated in December 2018. After half a year of intense preparations, both parties established an official document in June 2019 and signed the agreement on August 27, 2019. As such, PKUCH-NM becomes the first ICPO Cooperation Partner, significantly supporting the large-scale development of PRRT and PRLT in clinical trials. PKUCH-NM is also aiming to establish a Precision Radionuclide Oncology Center for tumor therapy, contributing to cancer prevention and treatment, and provide a platform for deepening bilateral education/medical cooperation between China, Germany, and other countries.

37.3 Clinical Translational Study

37.3.1 Concise Introduction

Peking University Cancer Hospital’s nuclear medicine department holds great advantages in clinical translational studies. More than 1200 clinical PET/CT diagnosis are performed annually, and this guarantees a large spectrum of malignancies to enable clinical translational studies. Approximately 25% of those patients participate in the novel radiopharmaceutical researches (Table 37.1).

37.3.2 Clinical Evaluation of 99mTc-Rituximab for Sentinel Lymph Node Mapping

Rituximab is a chimeric monoclonal antibody against the CD20 antigen presenting on the membrane of pre-B and mature B lymphocyte. Considering the large number of B cells presenting in LNs, we hypothesized that radiolabeled rituximab can serve as an effective imaging tool for SLN identification. Therefore, in this work rituximab was directly labeled with the most widely used SPECT radionuclide, 99mTc. The resulting tracer, 99mTc-rituxmab, was further evaluated in a large cohort of breast cancer patients (total no. of patients 2317; typical images shown in Fig. 37.5) [1]. This tracer showed great feasibility, safety, and effectiveness for SLN mapping in breast cancer patients. Further clinical research and related evaluation on large cohorts of breast cancer and/or melanoma lymphoscintigraphy are in process.

Fig. 37.5
3 photos of a digital image followed by a SPECT image which is merged further to obtain an S L N point.

JNM Highlight picture. Lymphoscintigraphy of a patient (2016. J Nucl Med. 57(8), 1214–1220)

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37.3.3 Tumor Amino Metabolism PET Imaging

Glucose is the most common source of nutrient in normal cells, and glucose generates energy via aerobic metabolism (TCA cycle in the mitochondria). In certain cancer cells, due to various mutations and the unmet needs for high metabolic energy, glucose is consumed via the less efficient anaerobic glycolysis. This phenomenon is common referred as the “Warburg effect.” Adaptations of cancer cells (and sometimes occurring in fast-dividing cells) will switch to use glutamine as a source for energy production. Thus, glutamine plays an important role in proliferation, especially in cancer cells. Changes in cellular metabolic mechanism are essential in order to adapt to glutamine metabolism, which is an important functional adjustment of fast-growing cells. PET imaging with 18F-(2S,4R)-4- fluoroglutamine (18F-FGln) has been demonstrated as a highly attractive approach for studying glutamine metabolism in cancer patients. 18F-FGln was synthesized in PKUCH NM department by using a radio-synthesizer module equipped with a semi-preparation HPLC in 10% radiochemical yield (decay corrected).

Our preliminary studies evaluated 18F-FGln in a small number of different cancer patients suggested that certain tumors (brain metastases, breast cancers, or gliomas) could display high uptake of 18F-FGln [2].

18F-FGln displayed a bio-distribution profile dominated by fast uptake and was excreted via kidneys. 18F-FGln is most likely to have significant uptake in the pancreas because of its exocrine function and high rates of amino acid and protein turnover. Additionally, the very low uptake in the brain, breast, lungs, and muscle could represent an advantage in PET imaging. In our most recent study in a cohort of 44 subjects (13 healthy volunteers, 8 lung cancer patients, 17 breast cancer patients, and 6 thyroid cancer patients), 18F-FGln PET demonstrated higher uptake in the trabecular bone of the ribs, vertebrae, and pelvis, which are rich in red marrow [3]. This finding may be because that the proliferation of rapidly dividing bone marrow-derived cells is strongly dependent on the availability of free glutamine, whose uptake might be mediated through different amino acid transporters. With regard to the 18F-FGln dynamic PET/CT imaging in 17 breast cancer patients, two breast tumors, ductal carcinoma in situ, and mucinous carcinoma showed slight 18F-FGln activity (SUVmax <3) at all stages. Nevertheless, two tumors appeared unclear on the 18F-FDG scan but were clear on 18F-FGln images.

Furthermore, we reported that using clinical PET VOI-based quantification analysis, 18F-FGln gradually accumulated in the bone marrow of cervical, thoracic, and lumbar vertebra in three healthy controls, with [SUV(s)mean] from 3.1 to 3.6. Myelosuppression patients (n = 3) showed reduced 18F-FGln uptakes in bone marrow of the corresponding regions. The average SUV(s) mean was 2.0 ± 0.2. Significant difference (P < 0.001) in bone marrow uptake was observed in healthy volunteers (HV) and myelosuppression patients (MP). The skull cortical bone (bone-only) in both healthy volunteers and myelosuppression patients exhibited similar uptake, with the average SUVmean from 0.4 to 1.0. 18F-FGln/PET imaging may be a useful tool for assessing reduced bone marrow activity in cancer patients, who may be at risk of myelosuppression after chemotherapy [4].

One hundred and ten patients have been subjected to 18F-FGln PET scans since 2018, and the results indicate that 18F-FDG was not an ideal tracer for identifying benign and malignant mediastinal lymph nodes, while 18F-FGln appeared to be a suitable agent in these situations. In the future, additional cancer patients will need to be enrolled for 18F-FGln PET imaging studies, and the results will provide sufficient statistical power to differentiate between the different types of tumor metabolism that drives the proliferation. An increased understanding of tumor metabolism could be essential not only for assisting diagnoses but also for better patient management strategies based on their tumor metabolism status.

37.4 Solid Target Radionuclide Production and Labeling Process

The nonstandard positron nuclides copper-64 (64Cu, T1/2 = 12.7 h), zirconium-89 (89Zr, T1/2 = 78.41 h), and iodine-124 (124I) have become some of the most fascinating PET nuclides because of their long half-lives compared with fluorine-18 (18F, T1/2 = 110 min) or carbon-11 (11C, T1/2 = 20.4 min). As a result, it is very popular for using labeled pharmaceuticals with these isotopes to carry out some long-term clinical examinations and experiments. For example, 64Cu-labeled monoclonal antibodies or peptides can provide a period of several days to allow PET imaging in vivo which will show the therapeutic effect of monoclonal antibodies in tumors. The combination of PET with mAb is referred to as immunological positron emission tomography (immune-PET).

We presented a routinely and robust method for the preparation of novel next-generation PET radioisotope 124I. Key points for the method are: (1) casting the 124TeO2/Al2O3 mixture by pressing; (2) adhering the layer to Pt-disk by sintering; (3) purifying 124I through dry distillation; (4) reduce 123I contamination by optimizing the decay time between the end of irradiation and purification. The micro-PET/CT imaging indicated that 124I we produced could be used for PET imaging, and as the starting material to synthesize other radioligands [5].

As it known, there are no commercial supplies of such kinds of radionuclides in mainland China. We are the only center in China that provides high-quality 124I for research.

37.5 The Development of New Target, Novel Drug-Delivery Systems

37.5.1 Noninvasive Micro-PET Predicting Tumor Resistance to Radiotherapy

Galectins are members of huge carbohydrate-binding lectins, and characterized by high-affinity binding to β-galactosides through a highly conserved carbohydrate recognition domain. Increasing evidence indicates that the overexpression of galectin-1, a member of the galectin family, is related to tumor progression and invasion, as well as tumor resistance to therapies (e.g., radiotherapy). We investigated whether near-infrared fluorescence (NIRF) imaging and positron emission tomography (PET) were sensitive approaches for detecting and quantitating galectin-1 upregulation in vivo. An anti-galectin-1 antibody was labeled with either an NIRF dye or 64Cu, and NIRF and PET imaging using the resulting probes (Dye-aGal-1 and 64Cu- 1,4,7-triazacyclononane-1,4,7-triacetic acid [NOTA]-aGal-1) were performed in 4 T1 breast cancer-bearing mice treated with several rounds of sorafenib [6].

37.5.2 Synthesis of Site-Specific Radiolabeled Antibodies for RIT Via Genetic Code Expansion

Radio-immunotherapy (RIT) delivers radioisotopes to antigen-expressing cells via monoclonal antibodies for the imaging of lesions or as the therapeutics. Chelators are conjugated to the antibody through cysteine or lysine residues, resulting in heterogeneous chelator-to-antibody ratios and various conjugation sites. To overcome this heterogeneity, we developed an approach for site-specific radiolabeling of antibodies by a combination of genetic code expansion and click chemistry [7]. As a proof-of-concept study, model systems including anti-CD20 antibody rituximab, PET isotope 64Cu, and a newly synthesized bifunctional linker (4-dibenzo-cyclooctynol-1,4,7,10-tetraazacyclotetradecane-1,4,7,10-tetraacetic acid, DIBO-DOTA) were used. We used heavy-chain A122NEAK rituximab and obtained a homogeneous radio-conjugate with precisely two chelators per antibody, incorporated only at the chosen sites. The conjugation did not alter the binding and pharmacokinetics of the rituximab, as indicated by in vitro assays and in vivo PET imaging. We believe this research is a good supplement to the genetic code expansion technique for the development of novel radio-probes.