“Immuno-PET” merges the high target selectivity and specificity of antibodies and engineered fragments toward a given tumor cell surface marker with the high spatial resolution, sensitivity, and quantitative capabilities of positron emission tomography (PET) imaging techniques. In this review, we detail and provide examples of the clinical limitations of current imaging techniques for diagnosing PDAC.
Despite multiple diagnostic and therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) presents a high mortality rate, representing the fourth cause of cancer death in developing countries [1][2]. This lethality can be associated with a late diagnosis, caused by the absence of symptoms at an early stage of the disease. Most cases of PDAC are located in the head of the pancreas (70%), followed in frequency by the uncinate process (18.66%), body (10–20%), and tail (5–10%) [3][4]. At present, complete surgical resection is the only potentially curative treatment for these tumors. However, only the initial stages benefit from surgery, representing only 10–15% of patients [5][6][7]. In only 10% of cases, the lesion is limited to the pancreatic gland and surrounded by normal pancreatic tissue [5][8]. At the time of diagnosis, 40–50% of cases present distant metastases, and approximately 40% of patients present signs of locally advanced disease; therefore, surgery in these cases is not indicated.
Several imaging techniques for PDAC diagnosis are available, including computed tomography (CT), magnetic resonance imaging (MRI), or endoscopic ultrasound (EUS) [9][10]. While they are widely used in the clinic and are very useful for the diagnosis of PDAC, they present several limitations.
Unlike other neoplastic processes (breast, colon, prostate…) there are no effective diagnostic screening methods for PDAC. Furthermore, due to the absolute low risk of developing this disease, population screening is not indicated. Only, in those groups [11] considered to be at-risk population, monitoring by pancreatic MRI or Cholangio-MRI, and EUS is indicated to detect small precursor lesions, such as cystic neoplasms. In these cases, CT would provide a suboptimal degree of lesion detection, compared to EUS and MRI, besides being a source of radiation [11]. Additionally, the probability of detecting lesions using these techniques is low, no more than 20% [12][13].
The development of “omics” has identified potentially relevant alterations in PDAC that still need to be integrated into the clinical management of PDAC patients. This is due, in part, to the deficiency of non-invasive imaging biomarkers [14]. “Immunotargeted imaging” represents a novel, innovative, and attractive option that combines the target specificity and selectivity of antibodies, and their variants, toward a biomarker with given imaging technique capabilities.
The revolution in cancer genomics has uncovered clinically relevant alterations that have yet to be integrated into patients’ clinical management, in part due to the lack of non-invasive imaging biomarkers [14]. An innovative and attractive option is termed “immunotargeted imaging”. This approach combines the target selectivity and specificity of antibodies and engineered fragments toward a given tumor cell surface marker with the capabilities of a given imaging technique.
To develop immunotargeted imaging, three features must be taken into account (Figure 4Figure 1): I)Selection of a specific molecular target for imaging; II) Selection of the optimally engineered antibodies for imaging applications; III) Selection of a suitable radionuclide modality-specific imaging agent. For immunoPET. it is important to match the physical half-life of the positron-emitting radionuclide with the biological half-life of the antibody or fragment being used.
Representation of the three main components of immuno-PET techniques: target, antibodies, and radionuclides. Abbreviations: Ab-Antibody; Fab-Fragment antigen-binding; F(ab’)
-Fab dimer; scFv- single-chain variable fragment; Nb-Nanobody,
F-fluorine;
Sc-scandium;
Mn-manganese;
Cu-copper;
Ga-gallium;
Br-bromine;
Y-yttrium;
Zr-zirconium;
I-iodine
. Image generated with BioRender.
As shown in Table 1, membrane proteins that are overexpressed on tumor or tumor-associated cells have been potentially suitable for tumor-targeted imaging; other components of the tumor microenvironment, such as extracellular matrix proteins, have also been promising candidates for the development of diagnostic approaches in PDAC.
Immuno-PET applications in PDAC.
With the rise of immunotherapy in recent years, PET imaging of immune checkpoint inhibitors (ICIs) may serve as a robust biomarker to predict and monitor responses to ICIs, complementing the existing immunohistochemical techniques
; it has been described that PET imaging using antibodies against the programmed cell death receptor 1 (PD-1)/programmed cell death ligand 1 (PD-L1) pathway can be a useful method for evaluating PD-L1 expression in orthotopic pancreatic cancer models
. To date, most of the PET imaging probes have been designed to target PDAC tumors in preclinical models (Figure 2), and only one study has been conducted with an [
Zr]Zr-labeled human monoclonal antibody in patients with pancreatic cancer or other CA19-9 positive malignancies
.
ImmunoPET–CT of MT1-MMP metalloproteinase in a preclinical model of PDAC. (
) Coronal, (
) axial, and (
) sagittal views of fused Immuno-PET and CT images of an orthotopic pancreatic patient-derived xenograft mouse. White arrows indicate tumor location. The imaging probe used was [
Zr]Zr-DFO-LEM2/15, a mAb developed against the MT1-MMP metalloproteinase
. Owing to the central role that this metalloproteinase plays in collagen-induced gemcitabine resistance, this probe could be used for the early prediction of resistance to gemcitabine in metastatic PDAC patients.