Application of molecular imaging technology in tumor immunotherapy

Highlights

• Tumor immunotherapy is a new cancer treatment program emerging in recent years.

• Not every patient respond to tumor immunotherapy nor possibly lifelong medication.

• Molecular imaging offers means to visualize biological processes.

• Real-time monitoring of tumor immunotherapy patients utilize molecular imaging.

• The development trend of molecular imaging guided tumor immunotherapy.

Abstract

Cancer immunotherapy, due to its high anti-tumor efficacy, has attracted considerable attention globally from experts in various fields. However, immunotherapy could be severely toxic; not all patients may respond, thus requiring combination therapy. Therefore, a reasonable selection strategy for early treatment is urgently needed. It is vital to capture the dynamic, heterogeneous, and complex tumor behavior considering the absence of ideal companion biomarkers. Since tumor immune response involves tumor cells, several other cell types, and molecules in the tumor microenvironment, detection is very complex and variable. However, molecular imaging technology, namely the non-invasive whole-body molecular imaging by positron emission tomography and single-photon emission computed tomography, has shown considerable promise in tumor detection and cancer immunotherapy response. Identification of potential novel imaging biomarkers will allow a personalized treatment plan for every patient. Future imaging strategies for these molecules used alone or in combination or continuously, might help stratify patients before or during the early stages of immunotherapy, and might address the immunotherapy challenges encountered by the oncologists.

Introduction

In addition to surgery, radiotherapy, and chemotherapy, immunotherapy is another treatment modality essential for the treatment of malignant tumors [1]. In recent years, tumor immunotherapy has markedly improved the treatment of cancers such as melanoma [2], lymphoma [3], and lung cancer [4], and its rapid development has revolutionized the traditional cancer treatment. The emergence of immune checkpoint inhibitors also marks a critical milestone in cancer immunotherapy [5]. Preclinical studies and clinical trials have demonstrated that immunological checkpoint targeted drugs have superior clinical therapeutic effects. The US Food and Drug Administration (FDA) has approved several immunological checkpoint inhibitors for the treatment of melanoma, kidney cancer, non-small cell lung cancer, and other malignancies [6], [7]. Another form of immunotherapy, Chimeric antigen receptor T cell(CAR-T) therapy, has been recognized as a promising treatment for cancer control and targets monoclonal antibodies to T-cells targeting specific cancer cells. In 2017, the FDA approved two CAR-T products, which are used in clinical practice. However, since immunotherapy could be severely toxic and may require combination therapy, there exists an unmet need for a reasonable selection strategy for early treatment [8], [9], [10]. The absence of ideal companion biomarkers that capture the dynamic, heterogeneous, and complex tumor behavior, makes immunotherapy challenging.

The tumor diagnosis technology enables health care workers to make informed clinical choices. Traditionally, cancer diagnosis and classification are based primarily on the histological examination of biopsy specimens; however, this technique destroys the tissue, is invasive, and unable to detect individual differences that exist specifically in the tumor tissue. It is difficult to identify clinically relevant cancer subtypes based on tumor cell type [11], [12]. Considering the deficiencies in the pathological evaluation of tumor tissues, non-invasive medical imaging, such as magnetic resonance (MR) imaging, computed tomography (CT), and positron emission tomography (PET), could be used to assess tumor location and extent of tissue invasion [13]. In addition, imaging provides valuable information to design tailored treatment strategies for personalized medicine of each patient and tumor type. Non-invasive medical diagnosis enables earlier tumor identification when combined with traditional histology and new high-throughput platforms, for a more accurate immunotherapy prognosis and to achieve the goals of precision medicine [14]. Although medical imaging techniques could be used to assess tumor heterogeneity, imaging features are primarily characterized qualitatively by radiologists or nuclear medicine physicians; however, internal tumor conditions, lymph node inflammatory hyperplasia, can influence this visual assessment process, and also subject to individual’s image assessment ability. Therefore, improving the objectivity and reproducibility of imaging techniques for comprehensively quantifying the internal conditions of the tumor, will reveal imaging features such as potential biological changes during immunotherapy [15], [16]. Hence, molecular imaging offers means to visualize biological processes at the molecular and cellular levels in humans and other living systems and is easy to quantify. Molecular imaging typically includes 2- or 3-dimensional imaging and quantification over time. Techniques used include radiotracer imaging/nuclear medicine, MR imaging, MR spectroscopy, optical imaging, and ultrasound for extracting the most valuable prognostic information for personalized immunotherapy.

The tumor immune response involves tumor cells and cells in the tumor microenvironment and numerous molecules [17]. Molecular imaging techniques such as positron emission tomography and single-photon emission computed tomography are used for non-invasive whole-body molecular imaging of cancer immunotherapy to identify potential novel imaging biomarkers [18]. First, radiolabeled immunological checkpoint targeting molecules are used for molecular imaging; second, immune cells are imaged in vitro or in vivo with radiolabeled tracers; and third, extracellular matrix components, including adhesion molecules, growth factors, and cytokines, are imaged. These molecular imaging strategies used alone or in combination or continuously might help stratify patients before or during the early stages of immunotherapy. In this review, we discuss the latest advances in molecular imaging technology for tumor immunotherapy.