management-respiratory-motion-artefacts-18f-fluorodeoxyglucose

Management of Respiratory Motion Artefacts in <sup>18</sup>F-fluorodeoxyglucose Positron Emission Tomography using an Amplitude-Based Optimal Respiratory Gating Algorithm

Positron emission tomography (PET) combined with X-ray computed tomography (CT) is an important molecular imaging platform that is required for accurate ...

Radboud university medical centre

Dendritic cells (DCs) are the most potent antigen-presenting cells of the immune system. Clinical trials have demonstrated that mature DCs loaded with tumor-associated antigens can induce tumor-specific immune responses. Theoretically, pediatric patients are excellent candidates for immunotherapy since their immune system is more potent compared to adults. We studied whether sufficient amounts of mature monocyte-derived DCs can be cultured from peripheral blood of pediatric cancer patients.

Phenotypic and functional characterization of mature dendritic cells from pediatric cancer patients.

The occurrence of vitiligo in patients with melanoma is especially reported for patients undergoing immunotherapy. While vitiligo in these patients is thought to be related to an immune response directed against melanoma cells, solid evidence is lacking. Here we report local cytotoxic T cell reactivity in three melanoma patients who developed vitiligo, after experimental immunotherapy using dendritic cell vaccinations. Tetramer analysis showed that vaccine-induced T cells recognizing gp100 and tyrosinase are present at the vitiligo lesions. These T cells secrete IFN-gamma and IL-2 upon peptide specific stimulation as well as upon recognition of the autologous tumor. We show that functional CD8(+) T cells specific for melanoma differentiation antigens used in a melanoma immunotherapy trial, do not only invade the tumor, but also the vitiligo lesions. This directly links vitiligo to the immuno-therapeutic intervention and supports the hypothesis that vitiligo is a marker of immunity against melanoma cells.

Vaccine-specific local T cell reactivity in immunotherapy-associated vitiligo in melanoma patients.

We initially observed that the presence of circulating NY-ESO-1- and/or Melan-A-specific T cells in patients with stage IV melanoma was significantly associated with prolonged survival. Here, we report the ways in which the phenotypes and functions of these T cells differentially affect survival in patients preselected for NY-ESO-1 and/or Melan-A reactivity.

Circulating CD4+ T cells that produce IL4 or IL17 when stimulated by melan-A but not by NY-ESO-1 have negative impacts on survival of patients with stage IV melanoma.

To assess the safety and efficacy of dendritic cell vaccination in metastatic uveal melanoma.

Long overall survival after dendritic cell vaccination in metastatic uveal melanoma patients.

Autologous dendritic cell (DC) therapy is an experimental cellular immunotherapy that is safe and immunogenic in patients with advanced melanoma. In an attempt to further improve the therapeutic responses, we treated 15 patients with melanoma, with autologous monocyte-derived immature DC electroporated with mRNA encoding CD40 ligand (CD40L), CD70 and a constitutively active TLR4 (caTLR4) together with mRNA encoding a tumor-associated antigen (TAA; respectively gp100 or tyrosinase). In addition, DC were pulsed with keyhole limpet hemocyanin (KLH) that served as a control antigen. Production of this DC vaccine with high cellular viability, high expression of co-stimulatory molecules and MHC class I and II and production of IL-12p70, was feasible in all patients. A vaccination cycle consisting of three vaccinations with up to 15×10 DC per vaccination at a biweekly interval, was repeated after 6 and 12 months in the absence of disease progression. mRNA-optimized DC were injected intranodally, because of low CCR7 expression on the DC, and induced de novo immune responses against control antigen. T cell responses against tyrosinase were detected in the skin-test infiltrating lymphocytes (SKIL) of two patients. One mixed tumor response and two durable tumor stabilizations were observed among 8 patients with evaluable disease at baseline. In conclusion, autologous mRNA-optimized DC can be safely administered intranodally to patients with metastatic melanoma but showed limited immunological responses against tyrosinase and gp100.

Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients.

Inflammatory bowel diseases (IBDs) are defined as chronic relapsing immune-mediated disorders of the gastrointestinal tract. IBD exacerbations are characterized by recruitment of mainly CXCL8 receptor-expressing activated neutrophils into the intestinal wall, leading to severe damage. Considering its chronic relapsing character, accurate and timely diagnosis of an exacerbation is pivotal for early adaptation of the treatment and reduction of the disease burden. However, endoscopic evaluation is invasive and associated with an increased risk of perforation. We previously developed a (99m)Tc-labeled CXCL8 preparation in preclinical models including colitis and clinical studies.

99mTc-CXCL8 SPECT to Monitor Disease Activity in Inflammatory Bowel Disease.

Dendritic cell (DC)-based immunotherapy is explored worldwide in cancer patients, predominantly with DC matured with pro-inflammatory cytokines and prostaglandin E2. We studied the safety and efficacy of vaccination with monocyte-derived DC matured with a cocktail of prophylactic vaccines that contain clinical-grade Toll-like receptor ligands (BCG, Typhim, Act-HIB) and prostaglandin E2 (VAC-DC). Stage III and IV melanoma patients were vaccinated via intranodal injection (12 patients) or combined intradermal/intravenous injection (16 patients) with VAC-DC loaded with keyhole limpet hemocyanin (KLH) and mRNA encoding tumor antigens gp100 and tyrosinase. Tumor antigen-specific T cell responses were monitored in blood and skin-test infiltrating-lymphocyte cultures. Almost all patients mounted prophylactic vaccine- or KLH-specific immune responses. Both after intranodal injection and after intradermal/intravenous injection, tumor antigen-specific immune responses were detected, which coincide with longer overall survival in stage IV melanoma patients. VAC-DC induce local and systemic CTC grade 2 and 3 toxicity, which is most likely caused by BCG in the maturation cocktail. The side effects were self-limiting or resolved upon a short period of systemic steroid therapy. We conclude that VAC-DC can induce functional tumor-specific responses. Unfortunately, toxicity observed after vaccination precludes the general application of VAC-DC, since in DC maturated with prophylactic vaccines BCG appears to be essential in the maturation cocktail. 

Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity.

Dynamic interactions between tumor cells and immune cells promote the initiation, progression, metastasis and therapy-resistance of cancer. With respect to immunotherapy, immune cell populations such as cytotoxic CD8+ T-cells, CD56+ NK cells and myeloid phagocytic cells play decisive roles. From an imaging perspective, the immune system displays unique challenges, which have implications for the design and performance of studies. The immune system comprises highly mobile cells that undergo distinct phases of development and activation. These cells circulate through several compartments during their active life span and accumulate in rather limited numbers in cancer lesion, where their effector phenotype further diversifies. Given these features, accurate evaluation of the tumor microenvironment and its cellular components during anti-cancer immunotherapy is challenging. In-vivo imaging currently offers quantitative and sensitive modalities that exploit long-lived tracers to interrogate, e.g. distinct immune cell populations, metabolic phenotypes, specific targets relevant for therapy or critical for their effector function. This review provides a comprehensive overview of current status for in-vivo imaging tumor-infiltrating immune cell populations, focusing on lymphocytes, NK cells and myeloid phagocytic cells, with emphasis on clinical translation.

In-vivo imaging of tumor-infiltrating immune cells: implications for cancer immunotherapy.

This review aims to emphasize the potential of in vivo imaging to optimize current and upcoming anti-cancer immunotherapies: spanning from preclinical to clinical applications. Immunotherapies are an emerging class of treatments for a variety of diseases. The agents include molecular and cellular therapeutics, which aim to treat the disease through re-education of the host immune system, often via complex mechanisms of action. In vivo imaging has the potential to contribute in several different ways: (1) as a drug development tool to improve our understanding of their complex mechanisms of action, (2) as a tool to predict efficacy, for example, to stratify patients into probable responders and likely non-responders, and (3) as a non-invasive treatment response biomarker to guide efficient immunotherapy use and to recognize early signs of potential loss of efficacy or resistance in patients. Areas where in vivo imaging is already successfully implemented in onco-immunology research will be discussed and domains where its use offers great potential will be highlighted. The focus of this article is on anti-cancer immunotherapy as it currently is the most advanced immunotherapy area. However, the described concepts can also be paralleled in other immune-mediated disorders and for conditions requiring immunotherapeutic intervention. Importantly, we introduce a new study group within the European Society of Molecular Imaging with the goal to facilitate and enhance immunotherapy development through the use of in vivo imaging.

The Potential of In Vivo Imaging for Optimization of Molecular and Cellular Anti-cancer Immunotherapies.

Metabolic parameters are increasingly being used to characterize tumors. Motion artifacts due to patient respiration introduce uncertainties in quantification of metabolic parameters during positron emission tomography (PET) image acquisition. The present study investigates the impact of amplitude-based optimal respiratory gating (ORG) on quantification of PET-derived image features in patients with pancreatic ductal adenocarcinoma (PDAC), in correlation with overall survival (OS).

Optimal respiratory-gated [F]FDG PET/CT significantly impacts the quantification of metabolic parameters and their correlation with overall survival in patients with pancreatic ductal adenocarcinoma.

Article	Year
Phenotypic and functional characterization of mature dendritic cells from pediatric cancer patients. Pediatric blood & cancer\| PubMed ID: 17486645	2007
Vaccine-specific local T cell reactivity in immunotherapy-associated vitiligo in melanoma patients. Cancer immunology, immunotherapy : CII\| PubMed ID: 18392619	2009
Circulating CD4+ T cells that produce IL4 or IL17 when stimulated by melan-A but not by NY-ESO-1 have negative impacts on survival of patients with stage IV melanoma. Clinical cancer research : an official journal of the American Association for Cancer Research\| PubMed ID: 24938524	2014
Long overall survival after dendritic cell vaccination in metastatic uveal melanoma patients. American journal of ophthalmology\| PubMed ID: 25038326	2014
Intranodal vaccination with mRNA-optimized dendritic cells in metastatic melanoma patients. Oncoimmunology\| PubMed ID: 26405571	2015
99mTc-CXCL8 SPECT to Monitor Disease Activity in Inflammatory Bowel Disease. Journal of nuclear medicine : official publication, Society of Nuclear Medicine\| PubMed ID: 26609182	2016
Prophylactic vaccines are potent activators of monocyte-derived dendritic cells and drive effective anti-tumor responses in melanoma patients at the cost of toxicity. Cancer immunology, immunotherapy : CII\| PubMed ID: 26861670	2016
In-vivo imaging of tumor-infiltrating immune cells: implications for cancer immunotherapy. The quarterly journal of nuclear medicine and molecular imaging : official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of...\| PubMed ID: 29191000	2018
The Potential of In Vivo Imaging for Optimization of Molecular and Cellular Anti-cancer Immunotherapies. Molecular imaging and biology\| PubMed ID: 30030697	2018
Optimal respiratory-gated [F]FDG PET/CT significantly impacts the quantification of metabolic parameters and their correlation with overall survival in patients with pancreatic ductal adenoc... EJNMMI research\| PubMed ID: 30868318	2019

Erik Aarntzen

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