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Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease. Electronic supplementary material The online version of this article (10.1007/s00262-020-02734-1) contains supplementary material, which is available to authorized users.

Background: Primary central nervous system lymphoma (PCNSL) is a rare type of aggressive lymphoma of the central nervous system. Treatment strategies improved significantly over the past decades differ regionally but mainly consist of rituximab and high-dosed methotrexate (MTX)-based therapies. Methods: We assessed clinical outcomes of 100 patients with newly diagnosed PCNSL between 2010-2020 at the University Hospital of Cologne, Germany. Results: Patients were 23-88 years of age and either treated with MTX-based regimens (PRIMAIN, MARTA, MATRix), individual regimens, or best supportive care, respectively. Overall response rates were generally high (66,7-83,8%), but different organ toxicities required dose adjustments in most groups. Two-year overall survival rates were 57,9% (PRIMAIN), 63,6% (MARTA), 65,4% (MATRix), and 37,5% (Other), respectively. Out of 9 patients suffering from relapse >12 months from primary diagnosis, 7 patients (77,8%) received methotrexate-based salvage therapy with 2-year overall survival of 4/6 patients (66,7%). Conclusion: Although a relevant proportion of patients are not eligible for clinical trials due to age, performance status, or comorbidities, these results prove feasibility of different MTX-based treatment strategies in clinical routine. Even elderly patients displayed surprisingly favorable outcomes. However, with compromising organ toxicities, reduction of intensity should be part of strategies in future clinical trials.

Background Thermal ablative therapies, such as microwave ablation (MWA) or radiofrequency ablation (RFA), are standard treatments for HCC. In addition to the local tumor destruction, abscopal effects (a reduction of a tumor mass in areas that were not included in the thermal ablation) could be observed. These systemic effects may be mediated by anti-tumor immune response, which has been described for RFA. MWA is rapidly replacing RFA, but systemic immunostimulatory effects of MWA treatment have been poorly studied. Materials and Methods Patients receiving MWA for localized HCC were included in this study. Effects of MWA on peripheral blood mononuclear cells (PBMC) of HCC patients treated with MWA were analyzed by multicolor flow cytometry. Tumor-specific immune responses against 7 shared tumor antigens were analyzed using peptide pools in 3-color Fluorospot assays (Interferon-y/Interleukin-5/Interleukin-10). The impact of type, density and localization of tumor-infiltrating lymphocytes was assessed by immunohistochemistry (IHC) of CD3, CD4, CD8, FoxP3, CD38 and CD20 and digital image analyses (Immunoscore) of tumor specimens in an additional cohort of patients who received combined surgical resection and thermal ablation. Results While comprehensive flow cytometric analyses in sequential samples (day 0, 7 and 90) of a prospective patient cohort (n=23) demonstrated only moderate effects of MWA on circulating immune cell subsets, Fluorospot analyses revealed de novo or enhanced tumor-specific immune responses in 30% of these patients. This anti-tumor immune response was related to tumor control. Interferon-y and Interleukin-5 T cell responses against cancer testis antigens were more frequent in patients with a long-time remission (>12 months) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients). Presence of tumor-specific T cell response (Interferon-y and/or Interleukin-5) was associated to longer progression-free survival (15.0 vs. 10.0 months). Immunohistochemical analyses of resected tumor samples revealed that a high T cell infiltration in a second tumor lesion at the time of thermal ablation was associated with superior disease-free survival (37.4 vs. 13.1 months). Conclusions Our data demonstrates remarkable immune-related effects of MWA in HCC patients. This study and provides additional evidence for a combination of thermal ablation and immunotherapy in this challenging disease. Funding ‘Koeln Fortune’ and ‘CAP-CMMC’ local research grant (to P.G. and H.A.S.) supported our research. Disclosure Information E. Staib: None. K. Leuchte: None. M. Thelen: None. P. Godel: None. A. Lechner: None. P. Zentis: None. M. Garcia-Marquez: None. D. Waldschmidt: None. R.R. Datta: None. R. Wahba: None. C. Wybranski: None. T. Zander: None. A. Quaas: None. U. Drebber: None. D.L. Stippel: None. C. Bruns: None. K. Wennhold: None. M. von Bergwelt-Baildon: None. H.A. Schlosser: None.

During the last decade the field of cancer immunotherapy has witnessed impressive progress. Highly effective immunotherapies such as immune checkpoint inhibition, and T-cell engaging therapies like bispecific T-cell engaging (BiTE) single-chain antibody constructs and chimeric antigen receptor (CAR) T cells have shown remarkable efficacy in clinical trials and some of these agents have already received regulatory approval. However, along with growing experience in the clinical application of these potent immunotherapeutic agents comes the increasing awareness of their inherent and potentially fatal adverse effects, most notably the cytokine release syndrome (CRS). This review provides a comprehensive overview of the mechanisms underlying CRS pathophysiology, risk factors, clinical presentation, differential diagnoses, and prognostic factors. In addition, based on the current evidence we give practical guidance to the management of the cytokine release syndrome.

Background: The genetic hallmark of BL is MYC gene rearrangement. However, due to histopathological, immunohistochemical and cytogenetic similarities, differentiation from Diffuse Large B-Cell Lymphoma (DLBCL) remains challenging in some cases. Although being suspected to negatively influence outcomes, detection of high expression of BCL2 and MYC (double expressor) as well as rearrangements of MYC and BCL2 and/or BCL6 (double/triple hit) did not lead to confirmation of different therapeutic approaches in DLBCL yet. The recent update of the World Health Organization (WHO) classification of lymphoid neoplasms has thus established a category termed High-Grade B-Cell Lymphoma (HGBL), defined by a distinct morphology and/or presence of double/triple hit status. While BL displays favorable outcomes in clinical routine upon treatment with intensive immunochemotherapeutic regimens, clear evidence regarding the optimal therapeutic approach for HGBL remains limited and the diagnostic discrimination of BL and HGBL can be challenging, too. Moreover, data on the frequency of revisions of the diagnosis of BL to DLBCL or HGBL and its impact on treatment and outcome are sparse. Methods: All consecutive patients managed with histopathological suspected diagnosis of BL upon preliminary assessment at the reporting institution between December 2010 and July 2020 were identified. Final diagnosis of the respective aggressive B-Cell lymphoma was grouped according to the most recent WHO classification and divided into four subgroups: a) BL, b) revision from DLBCL to BL, c) DLBCL, d) HGBL. General patient characteristics as well as response to treatment in Computed Tomography (CT) or Positron Emission Tomography (PET) (evaluation by individual investigator), information regarding survival supported by the register of deaths in North-Rhine Westphalia and the date of last follow-up were collected from individual patient files. Results: Overall, we identified n=66 patients with suspected diagnosis of BL within the preliminary assessment. Final histopathological results confirmed n=31 patients as BL (Group A), while n=23 patients were described as showing features of both BL and DLBCL (Uncertain & Grey-zone, Group D). Additionally, in n=12 patients the final diagnosis was revised either from DLBCL to BL (n=9, Group B) or B-ALL/BL to DLBCL (n=3, Group C). Regarding the reference histopathological reviews (RHR) and the latest version of the WHO classification of lymphoid neoplasms, all patients from Group C and Group D were finally classified as either DLBCL (n=12) or HGBL (n=14). In total, n=13 patients had revision of the final diagnosis, either upon receipt of RHR (n=8) or repeated biopsy upon progressive disease (PD) (n=5). When comparing patients with revised diagnosis due to PD or RHR, a median of six (range 4-8) and two (range 1-2) cycles of systemic therapy were applied prior to revision, respectively. Regarding outcomes, 2/5 patients (40%) with revised diagnosis upon PD and 7/8 patients (87,5%) with revised diagnosis upon RHR were alive at the time of last follow-up (median follow-up 15,07 months), respectively (Fig 1). Patients suffering from BL (Group A) displayed a significantly increased progression-free survival (PFS) compared to all other groups (p=0.034). In contrast, patients whose diagnosis was revised from DLBCL to BL after initiation of treatment with DLBCL protocols had an inferior PFS than patients initially diagnosed with BL (p=0.045) that was comparable to patients with the final diagnosis of DLBCL or HGBL. Two-year overall survival was generally favorable in all groups, ranging from almost 60% (HGBL) to 86,2% (BL) without showing statistically significant differences (p=0.2). Conclusion In conclusion, timely and precise histopathological diagnostic procedures seem to play a critical role for optimizing treatment strategies of BL, HGBL and high-risk DLBCL upfront. Since administration of BL treatment protocols seems feasible in clinical routine and may result in favorable results not only in BL but as well in HGBL, these results might encourage its upfront usage in doubtful situations regarding histopathological results. However, with only a small number of patients being evaluable in the present analysis, controlled clinical trials are necessary to confirm these trends. Figure 1 Figure 1. Disclosures Heger: Novartis: Research Funding; Gilead: Other: Travel funding. Gödel: Gilead: Other: Personal fees / travel support; Novartis: Other: Travel support. Balke-Want: Novartis: Research Funding. Simon: Gilead: Other: Travel support. Bröckelmann: BMS: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; MSD: Research Funding; BeiGene: Research Funding. Von Tresckow: Amgen: Consultancy, Honoraria; AstraZeneca: Honoraria, Other: Congress and travel support; AbbVie: Other: Congress and travel support; BMS-Celgene: Consultancy, Honoraria, Other: Congress and travel support; Kite-Gilead: Consultancy, Honoraria; MSD: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Novartis: Consultancy, Honoraria, Other: Congress and travel support, Research Funding; Pentixafarm: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Other, Research Funding.

Acquired immunoglobulin G (IgG) mediated thrombotic thrombocytopenic purpura (TTP) has not yet been described in non-twin siblings. We report two cases of acquired TTP in Caucasian sisters with inactive ADAMTS13 metalloprotease due to ADAMTS13 autoantibodies suggesting a role of genetic determinants in this life-threatening disease. However, human leukocyte antigen (HLA) class II types presumably associated with acquired thrombotic thrombocytopenic purpura were not identified in the patients, indicating that HLA class II typing may not be useful in acquired TTP risk assessment of family members. This article is protected by copyright. All rights reserved.

The success of chimeric antigen receptor (CAR)-T cell therapy with impressive response rates in hematologic malignancies but also promising data in solid tumors came along with the cognition of unexpected, potentially life-threatening immune-mediated toxicities, namely the cytokine release syndrome (CRS) and neurotoxicity recently referred to as “immune effector cell-associated neurotoxicity syndrome” (ICANS). These toxicities require urgent diagnostic and therapeutic interventions and targeted modulation of key cytokine pathways represents the mainstay of CRS treatment. However, as the underlying mechanisms of ICANS are not well understood, treatment options remain limited and further investigation is warranted. Importantly, after the recent market approval of 2 CAR-T cell constructs, the application of CAR-T cells will expand to nonacademic centers with limited experience in the management of CAR-T cell-associated toxicities. Here, we review the current evidence of CRS and ICANS pathophysiology, diagnostics, and treatment.

Background CD19 redirected chimeric antigen receptor (CAR) T-cell therapy has proven efficacy in relapsed or chemotherapy-refractory (r/r) aggressive B-cell non-Hodgkin lymphoma (B-NHL). However, targeting a single B-cell antigen leads to selective pressure with potential antigen-escape and subsequent relapse. A tandem CAR targeting CD20 and CD19 (pLTG1497) has been developed to overcome this limitation. Preclinical evaluation showed improved anti-lymphoma activity. Thus, we initiated a first-in-human, phase I clinical study of autologous pLTG1497-transduced CAR T-cells (MB-CART2019.1) in r/r B-NHL patients. Aims In this phase I prospective multi-center trial (NCT03870945) we aimed to evaluate the maximum tolerated dose (MTD) of MB-CART2019.1 in adult patients with CD20 and CD19 positive r/r B-NHL as determined by dose limiting toxicities (DLTs). Methods This was a 6+3 trial design with two predefined dose levels (DL1 1x106 and DL2 2.5x106 CAR T-cells/kg body weight, respectively). Secondary endpoints included adverse events (AEs) and best overall response rate (ORR). Pharmacodynamic assessments included maximum concentration (Cmax) of CAR T-cells, time to peak expansion (tmax), AUC (d0 to d28), and persistence. MB-CART2019.1 was produced by lentiviral transduction of autologous fresh leukapheresis in the closed automated CliniMACS Prodigy® System (Miltenyi Biotec, Bergisch Gladbach, Germany). Re-infusion (Day 0) of fresh MB-CART2019.1 was scheduled 14 days after leukapheresis. Fludarabine/cyclophosphamide lymphodepleting chemotherapy was administered from day -5 to -3. Results A total of 12 patients, 6 per dose level have been enrolled and treated between February and December 2019, 5 female and 7 male patients. Median age was 72 y (range 20, 78 y), with 10 patients >65 y and 8 >70 y. Histologies included aggressive B-NHL (11) and mantle cell lymphoma (1). Five (5) patients had refractory disease at study entry and IPI was ≥3 in 7 patients. Median time from leukapheresis to re-infusion was 14 d (range 13, 14 d). No DLT and no cytokine release syndrome (CRS) or neurotoxicity grade ≥3 were observed. One patient in dose level 1 experienced a grade 5 AE, which was due to disease progression. CRS grade 1 occurred in 3/6 patients on DL1 and DL2 each, and CRS grade 2 in 2 patients on DL2. Tocilizumab was given in 1 patient. Neurotoxicity grade 1 occurred in 1 patient on DL2. The above described CRS and neurotoxicity resolved completely. Mean Cmax of MB-CART2019.1 was 348.3 cells/µl (range 3.9, 830.4 cells/µl) on DL1 and 692 cells/µl (range 5.3, 3147.8 cells/µl) on DL2. Mean tmax was 15.8 d (range 9, 21 d) on DL1 and 11.5 d (range 9, 14 d) on DL2. Mean AUC was 3155 d*cells/µl (DL1) and 4339 d*cells/µl (DL2). Persistence of MB-CART2019.1 was observed in 12/12 patients until data cut-off. Altogether 9/12 patients (ORR 75%) responded to MB-CART2019.1 with 5/12 CRs. In DL1 3/6 patients responded (ORR 50%) and in DL2 6/6 patients (ORR 100%). The 3 patients without response to MB-CART2019.1 had a mean AUC0-28 of 870 d*cells/µl, whereas mean AUC0-28 in 9 responders was 4843 d*cells/µl reflecting the correlation between the pharmacodynamic parameters and the clinical response. Responses are ongoing in 5/9 patients, with a maximum duration of response of 330 days at data cut-off. Summary/Conclusions In this first-in-human dose finding study of MB-CART2019.1 no DLT and no severe (grade ≥3) CRS or neurotoxicity were observed. Feasibility and safety were very good in this cohort of elderly r/r B-NHL patients. The sustained expansion of tandem CAR T-cells was accompanied by efficacy: all patients (6/6) treated on DL2 responded and all 5 patients with CR (5/5) are in ongoing remission by the time of this report. Based on the promising risk-to-benefit ratio observed in our study, evaluation of MB-CART2019.1 at a dose of 2.5x106/kg body weight in clinical phase II and phase III trials for patients with relapsed aggressive B-NHL is underway. Disclosures Borchmann: Miltenyi Biotec B.V. & Co. KG: Honoraria. Balke-Want:Miltenyi Biotec B.V. & Co. KG: Honoraria. Ayuk:Celgene: Consultancy, Honoraria; Kite/Gilead: Honoraria; Therakos/Mallinckrodt: Honoraria, Research Funding; Neovii: Research Funding; Novartis: Honoraria. Holtkamp:Miltenyi Biomedicine GmbH: Current Employment. Preussner:Miltenyi Biomedicine GmbH: Ended employment in the past 24 months. Zadoyan:Miltenyi Biomedicine GmbH: Current Employment. Hanssens:Miltenyi Biomedicine GmbH: Current Employment. Kaiser:Miltenyi Biotec B.V. & Co. KG: Current Employment. Jurk:Miltenyi Biotec B.V. & Co. KG: Current Employment. Bürger:Miltenyi Biotec B.V. & Co. KG: Current Employment. Schneider:Lentigen Technology Inc., A Miltenyi Company: Current Employment, Patents & Royalties. Dropulic:Lentigen Technology Inc., A Miltenyi Company: Current Employment. Overstijns:Miltenyi Biomedicine GmbH: Current Employment, Membership on an entity's Board of Directors or advisory committees; Miltenyi Biotec B.V. & Co. KG: Current Employment, Membership on an entity's Board of Directors or advisory committees. Scheid:Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Amgen: Honoraria; Takeda: Honoraria, Research Funding. Holtick:Miltenyi Biotec B.V. & Co. KG: Honoraria. Miltenyi:Miltenyi Biomedicine GmbH: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Lentigen Technology Inc., A Miltenyi Company: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Miltenyi Biotec B.V. & Co. KG: Current Employment, Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.