TY - JOUR A1 - Duell, Johannes A1 - Lammers, Philip E. A1 - Djuretic, Ivana A1 - Chunyk, Allison G. A1 - Alekar, Shilpa A1 - Jacobs, Ira A1 - Gill, Saar T1 - Bispecific Antibodies in the Treatment of Hematologic Malignancies JF - Clinical Pharmacology & Therapeutics N2 - Monoclonal antibody therapies are an important approach for the treatment of hematologic malignancies, but typically show low single-agent activity. Bispecific antibodies, however, redirect immune cells to the tumor for subsequent lysis, and preclinical and accruing clinical data support single-agent efficacy of these agents in hematologic malignancies, presaging an exciting era in the development of novel bispecific formats. This review discusses recent developments in this area, highlighting the challenges in delivering effective immunotherapies for patients. Y1 - 2019 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-226392 VL - 106 ER - TY - JOUR A1 - Liebers, Nora A1 - Duell, Johannes A1 - Fitzgerald, Donnacha A1 - Kerkhoff, Andrea A1 - Noerenberg, Daniel A1 - Kaebisch, Eva A1 - Acker, Fabian A1 - Fuhrmann, Stephan A1 - Leng, Corinna A1 - Welslau, Manfred A1 - Chemnitz, Jens A1 - Middeke, Jan-Moritz A1 - Weber, Thomas A1 - Holtick, Udo A1 - Trappe, Ralf A1 - Pfannes, Roald A1 - Liersch, Ruediger A1 - Spoer, Christian A1 - Fuxius, Stefan A1 - Gebauer, Niklas A1 - Caillé, Léandra A1 - Geer, Thomas A1 - Koenecke, Christian A1 - Keller, Ulrich A1 - Claus, Rainer A1 - Mougiakakos, Dimitrios A1 - Mayer, Stephanie A1 - Huettmann, Andreas A1 - Pott, Christiane A1 - Trummer, Arne A1 - Wulf, Gerald A1 - Brunnberg, Uta A1 - Bullinger, Lars A1 - Hess, Georg A1 - Mueller-Tidow, Carsten A1 - Glass, Bertram A1 - Lenz, Georg A1 - Dreger, Peter A1 - Dietrich, Sascha T1 - Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas JF - Blood Advances N2 - The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and bridging cohort had received a median of 3 prior treatment lines. In the salvage cohort, the best overall response rate was 48.1%. The 6-month progression-free survival and overall survival (OS) was 27.7% and 49.6%, respectively. In the bridging cohort, 51.2% of patients could be successfully bridged with pola to the intended CAR T-cell therapy. The combination of pola bridging and successful CAR T-cell therapy resulted in a 6-month OS of 77.9% calculated from pola initiation. Pola vedotin-rituximab without a chemotherapy backbone demonstrated encouraging overall response rates up to 40%, highlighting both an appropriate alternative for patients unsuitable for chemotherapy and a new treatment option for bridging before leukapheresis in patients intended for CAR T-cell therapy. Furthermore, 7 of 12 patients with previous failure of CAR T-cell therapy responded to a pola-containing regimen. These findings suggest that pola may serve as effective salvage and bridging treatment of r/r LBCL patients. Y1 - 2021 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-369173 VL - 5 ER - TY - JOUR A1 - Rasche, Leo A1 - Duell, Johannes A1 - Morgner, Charlotte A1 - Chatterjee, Manik A1 - Hensel, Frank A1 - Rosenwald, Andreas A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Brändlein, Stephanie T1 - The Natural Human IgM Antibody PAT-SM6 Induces Apoptosis in Primary Human Multiple Myeloma Cells by Targeting Heat Shock Protein GRP78 JF - PLoS ONE N2 - In contrast to other haematological malignancies, targeted immunotherapy has not entered standard treatment regimens for de novo or relapsed multiple myeloma (MM) yet. While a number of IgG-formatted monoclonal antibodies are currently being evaluated in clinical trials in MM, our study aimed to investigate whether the fully human IgM monoclonal antibody PAT-SM6 that targets a tumour-specific variant of the heat shock protein GRP78 might be an attractive candidate for future immunotherapeutic approaches. We here show that GRP78 is stably and consistently expressed on the surface on tumour cells from patients with de novo, but also relapsed MM and that binding of PAT-SM6 to MM cells can specifically exert cytotoxic effects on malignant plasma cells, whereas non-malignant cells are not targeted. We demonstrate that the induction of apoptosis and, to a lesser extent, complement dependent cytotoxicity is the main mode of action of PAT-SM6, whereas antibody dependent cellular cytotoxicity does not appear to contribute to the cytotoxic properties of this antibody. Given the favourable safety profile of PAT-SM6 in monkeys, but also in a recent phase I trial in patients with malignant melanoma, our results form the basis for a planned phase I study in patients with relapsed MM. KW - cytotoxicity KW - apoptosis KW - immunohistochemistry techniques KW - enzyme-linked immunoassays KW - multiple myeloma KW - cell staining KW - cell binding KW - complement system Y1 - 2013 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-130125 VL - 8 IS - 5 ER - TY - JOUR A1 - Steinhardt, Maximilian J. A1 - Krummenast, Franziska C. A1 - Rosenwald, Andreas A1 - Gerhard-Hartmann, Elena A1 - Heidemeier, Anke A1 - Einsele, Hermann A1 - Topp, Max S. A1 - Duell, Johannes T1 - R-CHOP intensification with mid-cycle methotrexate and consolidating AraC/TT with BCNU/aHSCT in primary aggressive lymphoma with CNS involvement JF - Journal of Cancer Research and Clinical Oncology N2 - Purpose Patients suffering from aggressive systemic peripheral lymphoma with primary central nervous system involvement (PCL) are a rare and sparsely investigated population. Recommended treatment regimens include a combination of intrathecal and systemic chemotherapy as well as whole brain radiotherapy while offering relatively poor survival. Methods We conducted a single-center retrospective study that analyzed safety and outcome of 4 + 4 cycles Rituximab (R)-CHOP and R-high-dose Methotrexate (HD-MTX) for newly diagnosed, transplant-eligible patients ("Ping-Pong"), followed by Cytarabine (AraC)/Thiotepa (TT), BCNU/TT, and autologous hematologic stem cell transplantation (aHSCT). We retrospectively analyzed a set of 16 patients with high-intermediate or high-risk IPI status. Results Overall response rate to Ping-Pong was 100% measured by CT/MRI, including 93.75% complete remissions after BCNU/TT followed by PBSCT. One patient failed to qualify for high-dose chemotherapy due to progression when receiving Cytarabine/TT. All patients experienced grade III adverse events, 3 of them a grade IV adverse event. Estimated progression-free survival is 93.75% after a 4.8-year follow-up currently. Conclusion Our study suggests high effectivity of R-CHOP with mid-cycle MTX with aHSCT consolidation towards acceptable OS results in this challenging patient population. KW - lymphoma KW - HD KW - MTX KW - R-CHOP Y1 - 2022 U6 - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-267731 SN - 1432-1335 VL - 148 IS - 1 ER -