Immunotherapy by Immune Checkpoint Inhibitors and Nuclear Medicine Imaging: Current and Future Applications

Abstract

Immunotherapy by using immune checkpoint inhibitors is a revolutionary development in oncology. Medical imaging is also impacted by this new therapy, particularly nuclear medicine imaging (also called radionuclide imaging), which uses radioactive tracers to visualize metabolic functions. Our aim was to review the current applications of nuclear medicine imaging in immunotherapy, along with their limitations, and the perspectives offered by this imaging modality. Method: Articles describing the use of radionuclide imaging in immunotherapy were researched using PubMed by April 2019 and analyzed. Results: More than 5000 articles were analyzed, and nearly 100 of them were retained. Radionuclide imaging, notably ¹⁸F-FDG PET/CT, already has a major role in many cancers for pre-therapeutic and therapeutic evaluation, diagnoses of adverse effects, called immune-related adverse events (IrAE), and end-of-treatment evaluations. However, these current applications can be hindered by immunotherapy, notably due to atypical response patterns such as pseudoprogression, which is defined as an increase in the size of lesions, or the visualization of new lesions, followed by a response, and hyperprogression, which is an accelerated tumor growth rate after starting treatment. To overcome these difficulties, new opportunities are offered, particularly therapeutic evaluation criteria adapted to immunotherapy and immuno-PET allowing us to predict responses to immunotherapy. Moreover, some new technological solutions are also promising, such as radiomic analyses and body composition on associated anatomical images. However, more research has to be done, notably for the diagnosis of hyperprogression and pseudoprogression. Conclusion: Immunotherapy, by its major impact on cancer and by the new patterns generated on images, is revolutionary in the field of medical images. Nuclear medicine imaging is already established and will be able to help meet new challenges through its plasticity.

Keywords: Adoptive; CD8-Positive T-Lymphocytes; CTLA-4 Antigen; Immunotherapy; diagnostic imaging; positron emission tomography; programmed cell death 1 receptor; radioactive tracers; radionuclide imaging.

Figure 1

Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart for studies selection.

Figure 2

Representation of the interaction between CD4 and CD8 lymphocytes with an antigen-presenting cell (APC) (here a macrophage) and a tumor cell. Different targets can be imaged by use of several labeled antibodies (immuno-PET). These targets may be immune-checkpoints (such as cytotoxic T-lymphocyte antigen 4 (CTLA-4), PD-L1, and its receptor programmed cell death protein-1 (PD-1)) or biomarkers of the immune response (such as interferon γ (IFNγ), granzyme and interleukin-2 (IL2)). ¹⁸F-fluorodeoxyglucose (18F-FDG), on the other hand, makes it possible to assess the expression of the glucose transporter (GLUT-1); it can be incorporated indifferently, both in tumor and immune cells. PET: positron emission tomography.

Figure 3

Patterns of response according to the size and number of the tumors and in function of time of examination. Complete response, partial response, stable disease, and progression are the four classical patterns of response in oncology. Concerning the atypical responses sometimes observed with immune-checkpoint inhibitors, a dissociated response corresponds to lesions shrinking and others growing; pseudoprogression is an initial increase in tumor size and/or number due to inflammation followed by a decrease, and hyperprogression is an accelerated tumor growth rate after starting treating.

Figure 4

Clinical case of a patient with a previous history of treated left breast cancer and melanoma of the right leg with melanoma pulmonary metastasis recently operated. The images of the upper line show the PET/CT examination before the start of immune checkpoint inhibitor (pembrolizumab), and the images in the lower line show the PET/CT examination performed 9 months after the start of the treatment with (in A) a maximum intensity projection (MIP) PET image; in B, an axial CT slice; in C, an axial PET slice; in D, an axial PET/CT fused slice; in E, a frontal PET/CT fused slice. The green arrow on the pre-therapeutic PET MIP indicates the post-operative inflammation of melanoma pulmonary metastasis. The blue arrows on the follow-up PET/CT examination indicate that an intense left axillary lymph node uptake (SUVmax 4.7) appeared, which was considered suspicious of disease progression when it was found to be an inflammatory reactive lymph node in histological analysis.

Figure 5

Summary diagram of the different immune-related adverse events. The nuclear symbol represents the side effects that can be visualized by ¹⁸F-FDG PET/CT.