The Post COVID-19 condition (PCC) is a complex disease affecting health and everyday functioning. This is well reflected by a patient's inability to work (ITW). In this study, we aimed to investigate factors associated with ITW (1) and to design a machine learning-based model for predicting ITW (2) twelve months after baseline. We selected patients from the post COVID care study (PCC-study) with data on their ability to work. To identify factors associated with ITW, we compared PCC patients with and without ITW. For constructing a predictive model, we selected nine clinical parameters: hospitalization during the acute SARS-CoV-2 infection, WHO severity of acute infection, presence of somatic comorbidities, presence of psychiatric comorbidities, age, height, weight, Karnofsky index, and symptoms. The model was trained to predict ITW twelve months after baseline using TensorFlow Decision Forests. Its performance was investigated using cross-validation and an independent testing dataset. In total, 259 PCC patients were included in this analysis. We observed that ITW was associated with dyslipidemia, worse patient reported outcomes (FSS, WHOQOL-BREF, PHQ-9), a higher rate of preexisting psychiatric conditions, and a more extensive medical work-up. The predictive model exhibited a mean AUC of 0.83 (95% CI: 0.78; 0.88) in the 10-fold cross-validation. In the testing dataset, the AUC was 0.76 (95% CI: 0.58; 0.93). In conclusion, we identified several factors associated with ITW. The predictive model performed very well. It could guide management decisions and help setting mid- to long-term treatment goals by aiding the identification of patients at risk of extended ITW.

Cognitive complaints are common signs of the Post COVID-19 (PC) condition, but the extent and type of cognitive impairment may be heterogeneous. Little is known about neuropsychological treatment options. Preliminary evidence suggests cognitive symptoms may improve with cognitive training and naturally over time. In this clinical trial, we examined whether participation in a weekly group consisting of cognitive training and group psychotherapy is feasible and would exert beneficial effects on cognitive performance in PC and whether improvements were associated with intervention group participation or represented a temporal improvement effect during syndrome progression. 15 PC patients underwent an 8-week intervention. Cognitive performance was assessed before and after each intervention group participation. A control group of 15 PC patients with subjective neurocognitive or psychiatric complaints underwent two cognitive assessments with comparable time intervals without group participation. To attribute changes to the intervention group participation, interaction effects of group participation and time were checked for significance. This is an exploratory, non-randomized, non-blinded controlled clinical trial. Within the intervention group, significant improvements were found for most cognitive measures. However, significant time x group interactions were only detected in some dimensions of verbal memory and visuo-spatial construction skills. Significant time effects were observed for attention, concentration, memory, executive functions, and processing speed. The intervention setting was feasible and rated as helpful and relevant by the patients. Our results suggest that cognitive symptoms of PC patients may improve over time. Patients affected by both neurocognitive impairments and mental disorders benefit from group psychotherapy and neurocognitive training. The present study provides evidence for a better understanding of the dynamic symptomatology of PC and might help to develop further studies addressing possible therapy designs. The main limitations of this exploratory feasibility trial are the small sample size as well as the non-randomized design due to the clinical setting. DRKS00030974, 22 Dec 2022, retrospectively registered.

Post COVID-19 conditions (PCC) present with a wide range of symptoms. Headache is one of the most frequently reported neurological symptoms by patients with PCC. We aimed to assess the prevalence of headache in patients with PCC who attended the Post-COVIDLMU outpatient department at LMU University Hospital in Munich. We hypothesized that headaches occur more frequently in patients with PCC than in the control group. Patients answered a questionnaire containing sociodemographic characteristics, their current symptoms, and prior psychiatric and somatic diagnoses, the WHO Quality of Life assessment (WHOQOL-BREF), 9-item Patient Health Questionnaire (PHQ-9), and the Fatigue Severity Scale (FSS). 188 PCC patients were included in this study and compared to a control group of patients with a history of COVID-19 or a different infectious disease – but no consecutive post-infectious condition (nc=27). 115 (61

Background Innate lymphoid cells (ILCs) are key organizers of tissue immune responses and regulate tissue development, repair, and pathology. Persistent clinical sequelae beyond 12 weeks following acute COVID-19 disease, named post-COVID syndrome (PCS), are increasingly recognized in convalescent individuals. ILCs have been associated with the severity of COVID-19 symptoms but their role in the development of PCS remains poorly defined. Methods and results Here, we used multiparametric immune phenotyping, finding expanded circulating ILC precursors (ILCPs) and concurrent decreased group 2 innate lymphoid cells (ILC2s) in PCS patients compared to well-matched convalescent control groups at > 3 months after infection or healthy controls. Patients with PCS showed elevated expression of chemokines and cytokines associated with trafficking of immune cells (CCL19/MIP-3b, FLT3-ligand), endothelial inflammation and repair (CXCL1, EGF, RANTES, IL-1RA, PDGF-AA). Conclusion These results define immunological parameters associated with PCS and might help find biomarkers and disease-relevant therapeutic strategies.

There is a lack of interventions that treat the Post-Covid-19 Condition (PCC) itself. Accordingly, treatment guidelines recommend physiotherapy interventions to alleviate symptoms and enhance functioning. In cases where unimodal treatments prove ineffective, non-organ-specific multidisciplinary bio-psycho-social rehabilitation (MBR) programs are a suitable option. In a pilot observational study with assessments at the entry and end of treatment we aimed to evaluate the feasibility of a 3-week day clinic MBR program and explore its effects on physical functioning in PCC patients with fatigue and reduced physical capacity. Patient selection was based on an interdisciplinary assessment involving a physician, a psychologist and a physiotherapist. Feasibility was determined based on full participation (≥ 8 of 9 days) and maintenance of stable endurance in the 6-Minute Walk Test (6MWT). From 37 patients included in the study, 33 completed the MBR (mean age: 43 ± 12 years, 73% female). Four patients discontinued the MBR, with two of them having reported deterioration of PCC symptoms. The 6MWT showed a numerical improvement from 501 ± 97 m to 512 ± 87 m, although it did not reach statistical significance. These results support the feasibility of outpatient MBR with a focus on active physiotherapy interventions in PCC patients with fatigue. This study aligns with previous research supporting the effectiveness of physiotherapy and rehabilitation in PCC patients. However, further research is needed to address possible different treatment responses and varying treatment approaches in subgroups of PCC patients.

Cognitive symptoms (CS) belong to the most common manifestations of the Post COVID-19 (PC) condition. We sought to objectify CS in PC patients using routine diagnostic assessments: neurocognitive testing (NCT) and brain imaging (BI). Further, we investigated possible associations of CS with patient reported outcomes (PROs), and risk factors for developing CS. Clinical data and PROs of 315 PC patients were assessed at a mean of 6 months after SARS-CoV-2 infection. 231 (73.3

Background The severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) pandemic causes a high burden of acute and long-term morbidity and mortality worldwide despite global efforts in containment, prophylaxis, and therapy. With unprecedented speed, the global scientific community has generated pivotal insights into the pathogen and the host response evoked by the infection. However, deeper characterization of the pathophysiology and pathology remains a high priority to reduce morbidity and mortality of coronavirus disease 2019 (COVID-19). Methods NAPKON-HAP is a multi‐centered prospective observational study with a long‐term follow‐up phase of up to 36 months post-SARS-CoV-2 infection. It constitutes a central platform for harmonized data and biospecimen for interdisciplinary characterization of acute SARS-CoV-2 infection and long-term outcomes of diverging disease severities of hospitalized patients. Results Primary outcome measures include clinical scores and quality of life assessment captured during hospitalization and at outpatient follow-up visits to assess acute and chronic morbidity. Secondary measures include results of biomolecular and immunological investigations and assessment of organ-specific involvement during and post-COVID-19 infection. NAPKON-HAP constitutes a national platform to provide accessibility and usability of the comprehensive data and biospecimen collection to global research. Conclusion NAPKON-HAP establishes a platform with standardized high-resolution data and biospecimen collection of hospitalized COVID-19 patients of different disease severities in Germany. With this study, we will add significant scientific insights and provide high-quality data to aid researchers to investigate COVID-19 pathophysiology, pathology, and chronic morbidity.

Patient-reported outcome measures (PROMs) such as the Numeric Pain Rating Scale (NPRS) or Likert scales addressing various domains of health are important tools to assess disease severity in Post COVID-19 (PC) patients. By design, they are subjective in nature and prone to bias. Our findings reveal substantial differences in the perception of disease severity between patients (PAT), their attending internists (INT) and psychiatrists/psychologists (PSY). Patients rated almost all aspects of their health worse than INT or PSY. Most of the differences were statistically highly significant. The presence of fatigue and mood disorders correlated negatively with health perception. The physical health section of the WHO Quality of Life Assessment (WHOQoL-BREF) and Karnofsky index correlated positively with overall and mental health ratings by PAT and INT. Health ratings by neither PAT, PSY nor INT were associated with the number of abnormal findings in diagnostic procedures. This study highlights how strongly perceptions of disease severity diverge between PC patients and attending medical staff. Imprecise communication, different experiences regarding health and disease, and confounding psychological factors may explain these observations. Discrepancies in disease perception threaten patient-physician relationships and pose strong confounders in clinical studies. Established scores (e.g., WHOQoL-BREF, Karnofsky index) may represent an approach to overcome these discrepancies. Physicians and psychologists noting harsh differences between a patient's and their own perception of the patient's health should apply screening tools for mood disorders (i.e., PHQ-9, WHOQoL-BREF), psychosomatic symptom burden (SSD-12, FCV-19) and consider further psychological evaluation. An interdisciplinary approach to PC patients remains imperative. Trial Registration Number & Date of Registration: DRKS00030974, 22 Dec 2022, retrospectively registered.

PurposeHigh tumor burden has emerged as a negative predictor of efficacy in chimeric antigen receptor T-cell therapy (CART) in patients with refractory or relapsed large B-cell lymphoma. This study analyzed the deviation among imaging-based tumor burden (TB) metrics and their association with progression-free (PFS) and overall survival (OS).Materials and methodsIn this single-center observational study, we included all consecutively treated patients receiving CD19 CART with available baseline PET-CT imaging. Imaging-based TB was determined based on response evaluation criteria in lymphoma (RECIL), the Lugano criteria, and metabolic tumor volume. Total, nodal and extranodal TB were represented, according to the respective criteria, by sum of longest diameters (TBRECIL), sum of product of perpendicular diameters (TBLugano), and metabolic tumor volume (TBMTV). Correlation statistics were used for comparison. Proportional Cox regression analysis studied the association of TB metrics with PFS and OS.Results34 consecutive patients were included (median age: 67 years, 41% female) with total median baseline TBRECIL of 12.5 cm, TBLugano of 4,030 mm2 and TBMTV of 330 mL. The correlation of TBRECIL and TBLugano with TBMTV was strong (ρ=0.744, p<0.001 and ρ=0.741, p<0.001), with lowest correlation for extranodal TBRECIL with TBMTV (ρ=0.660, p<0.001). Stratification of PFS was strongest by total TBMTV>50% (HR=2.915, p=0.042), whereas total TBRECIL>50% and total TBLugano>50% were not significant (both p>0.05). None of the total TB metrics were associated with OS (all p>0.05).ConclusionPre-CART TB metrics vary significantly based on the assessment method, impacting their association with survival outcomes. The correlation between TBRECIL, TBLugano and TBMTV was influenced by disease phenotype and prior bridging therapy. TB method of assessment must be considered when interpreting the impact of TB on outcomes in clinical trials. Considering the heterogeneity, our results argue for standardization and harmonization across centers.

Chimeric antigen receptor T-cell therapy (CART) uses patient-derived tumor antigen-directed T cells for targeted elimination of cancer cells.1 The most common form applies modified T cells expressing a chimeric antigen receptor specific for the CD19 antigen to treat relapsed or refractory (rr) lymphoma2 and leukemia, leading to high rates of durable responses. CART has significantly improved progression-free survival (PFS) and overall survival (OS). Imaging-based response assessment for determination of PFS has most frequently relied on positron emission tomography-computed tomography (PET/CT). The current and ongoing phase III trials are mostly based on the Lugano criteria from 2014.3,4 Earlier trials have relied on Cheson criteria as published in 2007.5 In recent years, novel lymphoma imaging response criteria have been proposed, among them the response evaluation criteria in lymphoma (RECIL)6 and lymphoma response to immunomodulatory therapy criteria (LYRIC).7 The scientific literature on structured comparisons of these imaging response criteria is scarce for conventional lymphoma treatments and only 2 studies indicate concordance of RECIL and Lugano criteria in previously untreated lymphoma.8,9 As there are no reports on the prognostic value for lymphoma patients treated with CART, we aimed to assess the different imaging response criteria, their impact on PFS, and their relation to OS. The study population was based on a prospective registry of all consecutive patients who were treated at the Comprehensive Cancer Center Munich-Ludwig-Maximilian University Munich (CCCMLMU) with commercialized CD19-specific CART products. We included patients with refractory or relapsed lymphoma (DLBCL, FL, and MCL), any measurable disease on imaging according to Lugano criteria,3 and available (PET/CT) imaging studies at baseline and at least 2 follow-up timepoints (FU1 around 30 days and FU2 around 90 days). All medical records and imaging studies were reviewed with the approval of the LMU Munich Institutional Review Board (Ethikkommission der Medizinischen Fakultät der Ludwig-Maximilians-Universität München, Project Number 19-817) and informed patient consent. Patients received lymphodepletion with fludarabine and cyclophosphamide according to the manufacturers' instructions. Overall response was determined based on Lugano criteria with up to 6 target lesions (TLs) that were segmented. The sum of the product of diameters (SPD) was measured to determine tumor burden (TB) for Lugano criteria, Cheson criteria, and LYRIC. Moreover, spleen size was measured with splenomegaly being defined by a vertical length >13.0 cm according to Lugano criteria. To assess response according to RECIL, the sum of longest diameters (SLD) of ≤3 TLs was measured to define TB. All imaging analyses were performed with the dedicated trial reporting software mintLesion 3.8 (mint Medical GmbH; Heidelberg, Germany). For survival analysis, OS was visualized using Kaplan–Meier survival curves with categorization for the patients to the response categories complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) for all response criteria. The additional category of minor response (MR) was added for RECIL and indeterminate response (IR) for LYRIC. The overall response rate (ORR) was calculated as the rate of patients with CR and PR. Log-rank (Mantel-Cox) test was performed to examine the significance of the results. P values below 0.05 were considered to indicate statistical significance. Forty-one of 74 patients met the inclusion criteria (median age: 64 years, 41% female). According to Lugano criteria, 23 patients (56.1%) showed a CR, and 5 patients (12.2%) a PR at FU2. Thirteen patients (31.7%) had an overall PD at FU2 by Lugano criteria. Discordance in the classification of overall response was observed when applying other response criteria (Table 1). Notably, Cheson criteria and RECIL classified 4 patients as an SD, whereas there were none by Lugano criteria. In addition, 2 patients had a MR by RECIL, and 6 patients were assigned to the IR category according to LYRIC. ORR was 68% by Lugano criteria, 63% by Cheson criteria, 68% by RECIL, and 68% by LYRIC. There was a significant difference in survival between patients with CR, PR, and PD using Lugano criteria (Fig. 1A) at FU2 (P < 0.001). Patients with CR had longer OS than patients with PD. Patients with PR were between CR and PD (P = 0.046). Dichotomization into responding versus nonresponding patients allowed stratification of OS (HR = 18.2, P < 0.001). Using Cheson criteria (Fig. 1B), similar results were observed (P < 0.001), with the addition of Kaplan–Meier curve of SD patients falling between PR and PD. Survival curves by LYRIC (Fig. 1C) showed essentially the same results as by Lugano criteria with a significant difference between the categories CR, PR, and PD (P < 0.001). There was a small yet statistically nonsignificant difference between PD and IR patients. When categorized by RECIL (Fig. 1D), a difference between response categories was also demonstrated (P < 0.001); notably, the 2 patients with MR showed longer OS.Table 1: Overview of Different Imaging Response Criteria at 90 DaysFigure 1.: Overall survival stratification. Analysis of OS according to the response criteria Lugano (A), Cheson (B), LYRIC (C), and RECIL (D). The same color coding as in Table 3 was used to label the different response categories: CR (green), PR (yellow), MR (orange), SD (gray), PD (red), and IR (blue). CR = complete response; IR = indeterminate response; LYRIC = lymphoma response to immunomodulatory therapy criteria; MR = minor response; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PR = partial response; RECIL = response evaluation criteria in lymphoma; SD = stable disease.The most widely established lymphoma response criteria showed considerable differences in imaging endpoints in our study on patients that received CART. While the ORR was least affected, rates of CR and PR differed slightly. Notably, the response categories SD and PD were more strongly affected and thus the endpoint PFS varied (PFSLugano 153 d versus PFSCheson 169 d versus PFSRECIL 198 d versus PFSLYRIC 200 d). Interestingly, the immune-adapted LYRIC criteria yielded the strongest association of PFSLYRIC to OS in this patient population. The Cheson and Lugano criteria have evolved from the unidimensional Response Evaluation Criteria in Solid Tumors (RECIST1.1) criteria10 and capture bidimensional extension for this typically nodal-dominant tumor phenotype.3,5 As treated lymphomas are often characterized by morphologic residues, lymphoma criteria incorporate the metabolic status as visualized by 18F-FDG PET/CT to identify CR of the initially vital tumor tissue. RECIL was developed to facilitate the study assessment by reducing the number of TL to capture the same response.6 A reduction to 3 representative lesions yielded robust response classification as in the other criteria relying on 6 manifestations. Furthermore, RECIL incorporates the depth or response of the morphologic extension and is thereby not only based on metabolic changes. Yet, in the course of the disease with relapsed of refractory lymphomas, phenotypic and metabolic changes of the lymphoma manifestations occur. Typically, more widespread nodal locations are involved and extranodal lesions are more frequently encountered. Moreover, preexisting morphologic residues can be mistaken for active lymphoma if prior imaging exams are not reviewed. Notably, response criteria have not been adapted to such changes in the disease course and data on association of PFS with OS in lymphoma is scarce.3,10 Data characterizing response to CART is also limited and the optimally discriminating method remains ill-defined. In a single-arm, prospective study of 7 patients, early PET/CT data from lymphoma patients treated with CD19 CART were evaluated according to Lugano criteria. In this study, all patients with less than CR at 1-month subsequently relapsed.11 A recent multicenter study of 171 patients showed similar results. Patients with Deauville Score 1 + 2 at 1-month FU had an excellent long-term outcome, whereas 31% of patients with Deauville Score 3 + 4 were at risk for early relapse, and all patients with Deauville Score 5 relapsed by month 3.12 The evaluation of overall response and response patterns, including the impact of pseudoprogression associated with CAR T-cell therapy, has not yet been studied in detail.13 Some studies described pseudoprogression after CART analogous to solid tumors under immunotherapy.14 To face the challenge of pseudoprogression, LYRIC introduced the category of IR, with 3 subcategories: IR1, increase in overall tumor burden within the first 12 weeks of therapy, without clinical deterioration; IR2, appearance of new lesions, or growth of one or more existing lesions ≥50% at any time during treatment in the absence of overall progression; IR3, increase in FDG uptake of one or more lesions without a concomitant increase in lesion size or number.7 LYRIC encouraged biopsy for IR1 and IR2 and advised to evaluate these intermediate features by follow-up in all cases after 12 weeks. In contrast to LYRIC, Lugano or RECIL do not provide recommendations for lesion follow-up.6 Therefore, patients with assigned PD solely based on newly appearing lesions should be further investigated with regard to clinical benefit and may represent a new response category. Novel imaging endpoints and response criteria in lymphoma will likely evolve from selected lesion-based assessments to whole tumor burden quantification. In the first-line setting, the recently published International Metabolic Prognostic Index (IMPI) additionally integrates metabolic tumor volume and has outperformed the conventional IPI in estimating outcome of DLBCL patients.15 We investigated overall response by Lugano criteria, Cheson criteria, RECIL, and LYRIC. While the ORR was comparable between the different criteria, we found striking differences between the SD and PD response categories and thus discrepancies in the surrogate endpoint PFS. Response assessment by LYRIC exhibited superior association between PFS and OS. The response assessment method must therefore be considered when interpreting the impact of imaging endpoints on outcomes in clinical trials. Our study has limitations which need to be considered when interpreting the results. First, this is a single-center study with a limited number of subjects. Second, there were a few patients that were missed to follow up or had no measurable disease. Considering the heterogeneity, our results argue for standardization and harmonization across centers. AUTHOR CONTRIBUTIONS MW and WGK conceived and design the study; VLB, VB, KR, MR, MU, and CS collected the data; MW, VLB, VB, KR, and WGK analyzed and interpreted the data; and MW and WGK drafted the manuscript; and KR, FJD, PB, JR, MvB-B, and MS revised the manuscript. DISCLOSURES VB has received industry research support from BMS/Celgene, Kite/Gilead, Janssen, Novartis, Roche, and Takeda. KR declares having received research funding and travel support from Kite/Gilead and honoraria from Novartis. CS received travel support from Kite/Gilead. MvB-B received research funding and honoraria from Novartis, Kite Pharma, Miltenyi Biotec, Mologen, MSD, Astellas, and Roche. MS received industry research support from Amgen, Gilead, Miltenyi Biotec, MorphoSys, Roche, and Seattle Genetics; served as a consultant or advisor to Amgen, Bristol Myers Squibb, Celgene, Gilead, Pfizer, Novartis, and Roche; is on the advisory boards of Amgen, Celgene, Gilead, Janssen, Novartis, Pfizer, and Seattle Genetics; and serves on the speaker's bureau at Amgen, Celgene, Gilead, Janssen, and Pfizer. All the other authors have no conflicts of interest to disclose. SOURCES OF FUNDING The work was supported by funding from the research program "Förderung für Forschung und Lehre (FöFoLe) project number 1147" of the Medical Faculty of Ludwig Maximilian University (LMU) Munich and the Bavarian Cancer Research Center (BZKF) to MW. The work was further supported by the Else-Kröner-Fresenius Stiftung (to VB) and the German Cancer Consortium DKTK (to VB).

Following the emergency use authorization of BNT162b2 by the Food and Drug administration (FDA) in early December 2020, mRNA- and vector-based vaccines became an important means of reducing the spread and mortality of the COVID-19 pandemic. The European Medicines Agency labelled immune thrombocytopenia (ITP) as a rare adverse reaction of unknown frequency after vector-, but not mRNA-vaccination. Here, we report on the long-term outcome of 6 patients who were diagnosed with de-novo, vaccine-associated ITP (VA-ITP), and on the outcome of subsequent SARS-CoV-2 re-vaccinations. Patients were included after presenting to our emergency department. Therapy was applied according to ITP guidelines. Follow-up data were obtained from outpatient departments. Both mRNA- or vector-based vaccines were each used in 3 cases, respectively. In all patients, the onset of symptoms occurred after the 1st dose of vaccine was applied. 5 patients required treatment, 3 of them 2nd line therapy. All patients showed a complete response eventually. After up to 359 days of follow-up, 2 patients were still under 2nd line therapy with thrombopoietin receptor agonists. 5 patients have been re-vaccinated with up to 3 consecutive doses of SARS-CoV-2 vaccines, 4 of them showing stable platelet counts hereafter. Thrombocytopenia after COVID-19 vaccination should trigger a diagnostic workup to exclude vaccine-induced immune thrombotic thrombocytopenia (VITT) and, if confirmed, VA-ITP should be treated according to current ITP guidelines. Re-vaccination of patients seems feasible under close monitoring of blood counts and using a vaccine that differs from the one triggering the initial episode of VA-ITP.

Chimeric antigen receptor T-cell therapy (CART) prolongs survival for patients with relapsed/refractory B-cell non-Hodgkin’s lymphoma. The recently introduced International Metabolic Prognostic Index (IMPI) was shown to improve prognostication in the first-line treatment of large B-cell lymphoma. Here, we investigate the prognostic value of the IMPI for progression-free (PFS) and overall survival (OS) in the setting of CD19 CART. Consecutively treated patients with baseline 18F-FDG PET/CT imaging and follow-up imaging at 30 days after CART were included. IMPI is composed of age, stage, and metabolic tumor volume (MTV) at baseline and was compared with the International Prognostic Index (IPI). Both indices were grouped into quartiles, as previously described for IPI. In addition, the continuous IMPI was subdivided into tertiaries for better separation of risk groups. Overall response rate (ORR), depth of response (DoR), and PFS were determined based on Lugano criteria. Proportional Cox regression analysis studied association of IMPI and IPI with PFS and OS. Thirty-nine patients were included. The IPI was 1 in 23

Recent immunotherapeutic approaches have evolved as powerful treatment options with high anti-tumour responses involving the patient’s own immune system. Passive immunotherapy applies agents that enhance existing anti-tumour responses, such as antibodies against immune checkpoints. Active immunotherapy uses agents that direct the immune system to attack tumour cells by targeting tumour antigens. Active cellular-based therapies are on the rise, most notably chimeric antigen receptor T cell therapy, which redirects patient-derived T cells against tumour antigens. Approved treatments are available for a variety of solid malignancies including melanoma, lung cancer and haematologic diseases. These novel immune-related therapeutic approaches can be accompanied by new patterns of response and progression and immune-related side-effects that challenge established imaging-based response assessment criteria, such as Response Evaluation Criteria in Solid tumours (RECIST) 1.1. Hence, new criteria have been developed. Beyond morphological information of computed tomography (CT) and magnetic resonance imaging, positron emission tomography (PET) emerges as a comprehensive imaging modality by assessing (patho-)physiological processes such as glucose metabolism, which enables more comprehensive response assessment in oncological patients. We review the current concepts of response assessment to immunotherapy with particular emphasis on hybrid imaging with 18 F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

Retinoic acid-inducible gene-I (RIG-I) is a cytoplasmic immune receptor sensing viral RNA. It triggers the release of type I interferons (IFN) and proinflammatory cytokines inducing an adaptive cellular immune response. We investigated the therapeutic potential of systemic RIG-I activation by short 5′-triphosphate-modified RNA (ppp-RNA) for the treatment of acute myeloid leukemia (AML) in the syngeneic murine C1498 AML tumor model. ppp-RNA treatment significantly reduced tumor burden, delayed disease onset and led to complete remission including immunological memory formation in a substantial proportion of animals. Therapy-induced tumor rejection was dependent on CD4 + and CD8 + T cells, but not on NK or B cells, and relied on intact IFN and mitochondrial antiviral signaling protein (MAVS) signaling in the host. Interestingly, ppp-RNA treatment induced programmed death ligand 1 (PD-L1) expression on AML cells and established therapeutic sensitivity to anti-PD-1 checkpoint blockade in vivo. In immune-reconstituted humanized mice, ppp-RNA treatment reduced the number of patient-derived xenografted (PDX) AML cells in blood and bone marrow while concomitantly enhancing CD3 + T cell counts in the respective tissues. Due to its ability to establish a state of full remission and immunological memory, our findings show that ppp-RNA treatment is a promising strategy for the immunotherapy of AML.