In vivo imaging of the immune response upon systemic RNA cancer vaccination by FDG-PET

Abstract

Background[18F]Fluoro-2-deoxy-2-d-glucose positron emission tomography (FDG-PET) is commonly used in the clinic for diagnosis of cancer and for follow-up of therapy outcome. Additional to the well-established value in tumor imaging, it bears potential to depict immune processes in modern immunotherapies. T cells enhance their glucose consumption upon activation and are crucial effectors for the success of such novel therapies. In this study, we analyzed the T cell immunity in spleen after antigen-specific stimulation of T cells via highly innovative RNA-based vaccines using FDG-PET/MRI. For this purpose, we employed systemic administration of RNA-lipoplexes encoding the endogenous antigen of Moloney murine leukemia virus (gp70) which have been previously shown to induce potent innate as well as adaptive immune mechanisms for cancer immunotherapy. Feasibility of clinical imaging of increased splenic FDG uptake was demonstrated in a melanoma patient participating in a clinical phase 1 trial of a tetravalent RNA-lipoplex cancer vaccine.ResultsWe observed exclusive increase of glucose uptake in spleen compared to other organs thanks to liposome-mediated RNA targeting to this immune-relevant organ. In vivo and ex vivo FDG uptake analysis in the spleen of vaccinated mice correlated well with antigen-specific T cell activation. Moreover, the use of an irrelevant (antigen non-specific) RNA also resulted in enhanced FDG uptake early after vaccination through the activation of several other splenic cell populations. The glucose uptake was also dependent on the dose of RNA administered in line with the activation and frequencies of proliferating antigen-specific T cells as well as the general activation pattern of splenic cell populations.ConclusionsOur preclinical results show rapid and transient vaccination-induced increase of FDG uptake within the spleen reflecting immune activation preceding T cell proliferation. FDG-PET/CT in patients is also capable to image this immune activation resulting in a new potential application of FDG-PET/CT to image immune processes in new immunological therapies.Electronic supplementary materialThe online version of this article (10.1186/s13550-018-0435-z) contains supplementary material, which is available to authorized users.

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

“…Another early sign of immune activity is an inversion of the liver-to-spleen ratio (normally >1) [89], possibly by reflecting the immune activation preceding T cell proliferation [91], but also the reactive nodes in the drainage basin of the primary tumor [89], which could be wrongly diagnosed as cancerous lymph nodes (cf Figure 4).…”

Positron Emission Tomography-Based Response to Target and Immunotherapies in Oncology

“…On the other side, the potential confounding effect of hypermetabolic lesions due to IRAE should be taken into account when reporting [ 18 F]FDG PET in patients treated with immunotherapy. Sarcoid-like lung lesions and reactive lymph nodes have been reported and should not be confounded with PMD [53][54][55]. Similarly, inversion of the liver-to-spleen ratio (normally >1), reflecting immune activation preceding T cell proliferation, has been reported [55].…”

“…Sarcoid-like lung lesions and reactive lymph nodes have been reported and should not be confounded with PMD [ 53 , 54 , 55 ]. Similarly, inversion of the liver-to-spleen ratio (normally >1), reflecting immune activation preceding T cell proliferation, has been reported [ 55 ]. In conclusion, despite the more effective way of assessing the [ 18 F]FDG PET-based response in patients treated with ICPIs, available studies suggest that [ 18 F]FDG PET can support decision-making about the continuation/discontinuation of therapy, as it can open several windows able to capture different aspects associated with the effect of treatment (i.e., pseudoprogression, hyperprogression, and IRAE) [ 56 ].…”

Dexamethasone premedication suppresses vaccine-induced immune responses against cancer

“…[23][24][25] First clinical data in patients with advanced melanoma indicate execution of the mode-of-action and activity of RNA-LPX vaccines in humans. [26][27][28][29][30][31] To understand potential interference of the long-acting GCS Dexamethasone with our RNA-LPX vaccine, we studied its effects on vaccine-induced innate and adaptive mechanisms when employed under circumstances typically occurring in clinical care.…”

“… 23 - 25 First clinical data in patients with advanced melanoma indicate execution of the mode-of-action and activity of RNA-LPX vaccines in humans. 26 - 31 …”