Endothelial injury and dysfunction with emerging immunotherapies in multiple myeloma, the impact of COVID-19, and endothelial protection with a focus on the evolving role of defibrotide

Review

Author: Calabretta, Eleonora ; Mo, Clifton C ; Baron, Rebecca M ; Moraleda, José M ; Richardson, Paul G ; Díaz-Ricart, Maribel ; Kocoglu, Mehmet H ; Connors, Jean Marie ; Corrado, Francesco ; Richardson, Edward ; Rapoport, Aaron P ; Wei, Lee-Jen ; Carlo-Stella, Carmelo ; Iacobelli, Massimo

Patients with multiple myeloma (MM) were among the groups impacted more severely by the COVID-19 pandemic, with higher rates of severe disease and COVID-19-related mortality. MM and COVID-19, plus post-acute sequelae of SARS-CoV-2 infection, are associated with endothelial dysfunction and injury, with overlapping inflammatory pathways and coagulopathies. Existing treatment options for MM, notably high-dose therapy with autologous stem cell transplantation and novel chimeric antigen receptor (CAR) T-cell therapies and bispecific T-cell engaging antibodies, are also associated with endothelial cell injury and mechanism-related toxicities. These pathologies include cytokine release syndrome (CRS) and neurotoxicity that may be exacerbated by underlying endotheliopathies. In the context of these overlapping risks, prophylaxis and treatment approaches mitigating the inflammatory and pro-coagulant effects of endothelial injury are important considerations for patient management, including cytokine receptor antagonists, thromboprophylaxis with low-molecular-weight heparin and direct oral anticoagulants, and direct endothelial protection with defibrotide in the appropriate clinical settings.

01 Feb 2024·Leukemia

Combining venetoclax and azacytidine with T-cell bispecific antibodies for treatment of acute myeloid leukemia: a preclinical assessment

Letter

Author: Colombetti, Sara ; Eckmann, Jan ; Subklewe, Marion ; Klein, Christian ; Sponheimer, Monika ; Korfi, Koorosh ; Neumann, Anne-Sophie ; Emhardt, Alica-Joana ; Kramar, Vesna ; Magno, Giulia ; Dunshee, Diana ; Leutbecher, Alexandra ; Bücklein, Veit ; Umaña, Pablo ; Schönle, Anne ; Philipp, Nora ; Nixdorf, Daniel ; Hänel, Gerulf

In the current report, we investigate the immune modulating impact of Ven/Aza on the efficacy of a WT1-targeted TCB in AML in vitro and in vivo.Importantly, the clustering of the T-cell compartment remained largely unaffected in our anal. with the exception of CD8+ naive T cells that were partially depleted in response to Ven/Aza .Ten-fold higher concentrations of Ven further enhanced the reduction of CD8+ naive T cells and led to an overall reduction in viable T cells.A more detailed anal. revealed that the cytoreductive effect in this experiment was only mediated by Ven but not Aza.Next, we studied primary patient samples derived from Ven/ Aza- treated patients.T cells were extracted from peripheral blood on days 1-4, 5-7 and 14-16 post Ven/Aza treatment.We first evaluated the WT1-TCB mediated cytotoxicity against OCIAML3 cells in a co-culture with the extracted T cells and observed that WT1-TCB consistently and dose-dependently induced target cell lysis.

01 Feb 2021·Expert Opinion on Biological TherapyQ3 · MEDICINE

Anti-CD20 treatment for B-cell malignancies: current status and future directions

Q3 · MEDICINE

Review

Author: Jamois, Candice ; Klein, Christian ; Nielsen, Tina

INTRODUCTIONThe introduction of anti-CD20 monoclonal antibody therapy with rituximab in the 1990s greatly improved outcomes for patients with B-cell malignancies. Disease resistance or relapse after successful initial therapy and declining efficacy of subsequent rounds of treatment were the basis for the development of alternative anti-CD20-based antibody therapies.AREAS COVEREDThe novel anti-CD20 antibodies of atumumab, ublituximab, and obinutuzumab were developed to be differentiated via structural and mechanistic features over rituximab. We provide an overview of preclinical and clinical data, and demonstrate ways in which the pharmacodynamic properties of these novel agents translate into clinical benefit for patients.EXPERT OPINIONOf the novel anti-CD20 antibodies, only obinutuzumab has shown consistently improved efficacy over rituximab in randomized pivotal trials in indolent non-Hodgkin lymphoma and chronic lymphocytic leukemia. The Phase 3 GALLIUM trial demonstrated significant improvements in progression-free survival with obinutuzumab-based immunochemotherapy over rituximab-based immunochemotherapy. Novel combinations of obinutuzumab, including with chemotherapy-free options are being explored, such as with the newly approved combinations of obinutuzumab with venetoclax, ibrutinib, or acalabrutinib. The biggest unmet need remains in the treatment of diffuse large B-cell lymphoma; emerging options in this field include the use of CAR-T cells and T-cell bispecific antibodies.

100 Deals associated with Bispecific antibody T cell therapy (GlycoNex)

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Preclinical	TW	GlycoNex, Inc.	-

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