Blocking the CD47-Sirpa Axis Enhances Tafasitamab-Mediated Phagocytosis

Biedermann, Alexander; Mangelberger-Eberl, Doris; Mougiakakos, Dimitrios; Büttner‐Herold, Maike; Flamann, Cindy; Kellner, Christian; Altmeyer, Sarah; Bittenbring, Jörg; Augsberger, Christian; Patra-Kneuer, Maria; Landgraf, Karin; Ilieva-Babinsky, Kristina; Haskamp, Stefan; Beier, Fabian; Voelkl, Simon; Pallasch, Christian P.; Jacobs, Bénédikt; Steidl, Stefan; Heitmüller, Christina; Mackensen, Andréas; Bruns, Heiko

doi:10.1182/blood-2022-159955

Cited by 2 publications

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“…There might be additional factors, negatively or positively influencing antibody-induced antitumor effects. For instance, ADCC and ADCP can be modulated by differential expression of regulatory molecules by the target and the effector cells (45)(46)(47)(48). Further studies are required to address the relative role of antigen expression in the context of antibodymediated effects.…”

Section: Discussionmentioning

confidence: 99%

Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma

Patra-Kneuer,

Chang,

et al. 2023

Front. Immunol.

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BackgroundDespite recent advances in the treatment of aggressive lymphomas, a significant fraction of patients still succumbs to their disease. Thus, novel therapies are urgently needed. As the anti-CD20 antibody rituximab and the CD19-targeting antibody tafasitamab share distinct modes of actions, we investigated if dual-targeting of aggressive lymphoma B-cells by combining rituximab and tafasitamab might increase cytotoxic effects.MethodsAntibody single and combination efficacy was determined investigating different modes of action including direct cytotoxicity, antibody-dependent cell-mediated cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP) in in vitro and in vivo models of aggressive B-cell lymphoma comprising diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma (BL).ResultsThree different sensitivity profiles to antibody monotherapy or combination treatment were observed in in vitro models: while 1/11 cell lines was primarily sensitive to tafasitamab and 2/11 to rituximab, the combination resulted in enhanced cell death in 8/11 cell lines in at least one mode of action. Treatment with either antibody or the combination resulted in decreased expression of the oncogenic transcription factor MYC and inhibition of AKT signaling, which mirrored the cell line-specific sensitivities to direct cytotoxicity. At last, the combination resulted in a synergistic survival benefit in a PBMC-humanized Ramos NOD/SCID mouse model.ConclusionThis study demonstrates that the combination of tafasitamab and rituximab improves efficacy compared to single-agent treatments in models of aggressive B-cell lymphoma in vitro and in vivo.

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Section: Discussionmentioning

confidence: 99%

Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma

Patra-Kneuer,

Chang,

et al. 2023

Front. Immunol.

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The future of immunotherapy for diffuse large B‐cell lymphoma

Duell,

Westin

2024

Intl Journal of Cancer

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With the introduction of anti‐CD19 chimeric antigen receptor (CAR) T‐cell (CAR T) therapies, bispecific CD3/CD20 antibodies and anti‐CD19 antibodies, immunotherapy continues to transform the treatment of diffuse large B‐cell lymphoma (DLBCL). A number of novel immunotherapeutic strategies are under investigation to build upon current clinical benefit and offer further options to those patients who cannot tolerate conventional intensive therapies due to their age and/or state of health. Alongside immunotherapies that leverage the adaptive immune response, natural killer (NK) cell and myeloid cell‐engaging therapies can utilize the innate immune system. Monoclonal antibodies engineered for greater recognition by the patient's immune system can enhance antitumor cytotoxic mechanisms mediated by NK cells and macrophages. In addition, CAR technology is extending into NK cells and macrophages and investigational immune checkpoint inhibitors targeting macrophage/myeloid cell checkpoints via the CD47/SIRPα axis are in development. Regimens that engage both innate and adaptive immune responses may help to overcome resistance to current immunotherapies. Furthermore, combinations of immunotherapy and oncogenic pathway inhibitors to reprogram the immunosuppressive tumor microenvironment of DLBCL may also potentiate antitumor responses. As immunotherapy treatment options continue to expand, both in the first‐line setting and further lines of therapy, understanding how to harness these immunotherapies and the potential for combination approaches will be important for the development of future DLBCL treatment approaches.

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Blocking the CD47-Sirpa Axis Enhances Tafasitamab-Mediated Phagocytosis

Cited by 2 publications

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Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma

Activity of tafasitamab in combination with rituximab in subtypes of aggressive lymphoma

The future of immunotherapy for diffuse large B‐cell lymphoma

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