The current coronavirus disease 2019 (COVID-19) pandemic is a challenge for physicians in triaging patients in emergency rooms. We found a potentially dangerous overlap of classical urinary symptoms and the as yet not fully described symptoms of COVID-19. After a patient was primarily triaged as a urosepsis case and then subsequently diagnosed with COVID-19, we focused on an increase in urinary frequency as a symptom of COVID-19 and identified this in seven males out of 57 patients currently being treated in our COVID-19 wards. In the absence of any other causes, urinary frequency may be secondary to viral cystitis due to underlying COVID-19 disease. We propose consideration of urinary frequency as an anamnestic tool in patients with infective symptoms to increase awareness among urologists during the current COVID-19 pandemic to prevent fatal implications of misinterpreting urological symptoms.

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.

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 18F-FDG-PET/CT and aims at describing future trends of immunotherapy and additional aspects of molecular imaging within the field of immunotherapy.

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.

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BackgroundThe anti-CD19 CAR T-cell products Axicabtagene Ciloleucel (Axi-cel) and Tisagenlecleucel have been approved by the EMA for the treatment of patients (pts) with relapse/refractory (r/r) diffuse large B-cell lymphoma (DLBCL) in August 2018. In clinical trials, both cell products induced ongoing complete responses in heavily pretreated patients. However, this activity was associated with significant toxicity. We evaluated the outcomes of DLBCL pts treated with Axi-cel and Tisagenlecleucel at the LMU Munich.Materials and MethodsCAR T cell product characteristics, toxicity and response rates of pts treated at our center between January and October 2019 were retrospectively assessed.ResultsAs of October 2019, 24 out of 34 r/r DLBCL pts (71%) with confirmed CAR T cell treatment indication were leukapheresed. Four apheresed pts died before CAR T cell therapy due to rapidly progressive disease. So far, 17 DLBCL pts have been treated. Median age was 60 years (range 19–74). ECOG was 0–1 in eleven, and 2–3 in six pts. Eight pts had undergone prior stem cell transplant (6 autologous, 2 allogeneic SCT). 13 pts received bridging chemotherapy between leukapheresis and CAR T cell transfusion. Only 6 (35%) of the 17 transfused pts would have met the inclusion criteria of the pivotal clinical trials (JULIET, ZUMA-1).CRS occurred in all pts (53% CRS °1, 29% °2 and 18% °3) with a median onset on day 2 (range days 0–7) and a median duration of 4 days (range 1–21). Tocilizumab was administered at least once in all pts. Ten pts (59%) experienced Immune Effector Cell associated Neurotoxicity Syndrome (ICANS, 30% °1, 10% °2, 30% °3, 20% °4 and 10% °5) with a median onset between day 7 and 8 and a median duration of 8 days (range 3–49). Cytopenia was significant following CAR T-cell treatment: all but one pts had neutropenia <500/µl for more than seven days.Response assessment four weeks after CAR T-cell transfusion was available for 15 pts.Objective response rate (ORR) at this early follow-up was 67%, with complete remission (CR) in four (27%) and partial remission (PR) in six pts (40%). Interestingly, ORR was higher in the four pts not receiving bridging chemotherapy between leukapheresis and CAR T-cell therapy than in pts in which bridging was applied (100% vs. 55%). Responders had significantly higher LDH levels at apheresis, start of lymphodepletion and CAR T-cell transfusion than non-responders.ConclusionsSince January 2019, the CAR T cell program has been successfully initiated at the LMU Munich, and 17 r/r DLBCL pts have been treated at our center to date. CAR T cells induced responses in heavily pretreated pts with response rates within the expected range. Toxicity was significant but manageable in most pts. Involvement of a multidisciplinary ImmunoTaskforce was a key element for adequate patient care. Preliminary data supports the hypothesis that low tumor dynamics are associated with favorable outcomes of CD19 CAR T cell therapy.Disclosure InformationV. Bücklein: None. V. Blumenberg: None. C. Schmidt: None. K. Rejeski: None. M. Ruzicka: None. N. Müller: None. A. Reischer: None. L. von Baumgarten: None. A. Völkl: None. B. Wagner: None. A. Humpe: None. J. Tischer: None. H. Stemmler: None. M. von Bergwelt: None. M. Subklewe: None.

Purpose 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. Methods 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. Results 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. Conclusion 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.