BACKGROUND: Despite 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. METHODS: Antibody 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). RESULTS: Three 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. CONCLUSION: This 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.

• Klíčová slova
• CD19, CD20, antibody therapy, lymphoma, rituximab, tafasitamab, tumor immunology,
• MeSH
• Burkittův lymfom * farmakoterapie   MeSH
• difúzní velkobuněčný B-lymfom * farmakoterapie   MeSH
• humanizované monoklonální protilátky MeSH
• leukocyty mononukleární MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• rituximab farmakologie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• humanizované monoklonální protilátky MeSH
• rituximab MeSH
• tafasitamab MeSH Prohlížeč

The approval of BTK and PI3K inhibitors (ibrutinib, idelalisib) represents a revolution in the therapy of B cell malignancies such as chronic lymphocytic leukemia (CLL), mantle-cell lymphoma (MCL), diffuse large B cell lymphoma (DLBCL), follicular lymphoma (FL), or Waldenström's macroglobulinemia (WM). However, these "BCR inhibitors" function by interfering with B cell pathophysiology in a more complex way than anticipated, and resistance develops through multiple mechanisms. In ibrutinib treated patients, the most commonly described resistance-mechanism is a mutation in BTK itself, which prevents the covalent binding of ibrutinib, or a mutation in PLCG2, which acts to bypass the dependency on BTK at the BCR signalosome. However, additional genetic aberrations leading to resistance are being described (such as mutations in the CARD11, CCND1, BIRC3, TRAF2, TRAF3, TNFAIP3, loss of chromosomal region 6q or 8p, a gain of Toll-like receptor (TLR)/MYD88 signaling or gain of 2p chromosomal region). Furthermore, relative resistance to BTK inhibitors can be caused by non-genetic adaptive mechanisms leading to compensatory pro-survival pathway activation. For instance, PI3K/mTOR/Akt, NFkB and MAPK activation, BCL2, MYC, and XPO1 upregulation or PTEN downregulation lead to B cell survival despite BTK inhibition. Resistance could also arise from activating microenvironmental pathways such as chemokine or integrin signaling via CXCR4 or VLA4 upregulation, respectively. Defining these compensatory pro-survival mechanisms can help to develop novel therapeutic combinations of BTK inhibitors with other inhibitors (such as BH3-mimetic venetoclax, XPO1 inhibitor selinexor, mTOR, or MEK inhibitors). The mechanisms of resistance to PI3K inhibitors remain relatively unclear, but some studies point to MAPK signaling upregulation via both genetic and non-genetic changes, which could be co-targeted therapeutically. Alternatively, drugs mimicking the BTK/PI3K inhibition effect can be used to prevent adhesion and/or malignant B cell migration (chemokine and integrin inhibitors) or to block the pro-proliferative T cell signals in the microenvironment (such as IL4/STAT signaling inhibitors). Here we review the genetic and non-genetic mechanisms of resistance and adaptation to the first generation of BTK and PI3K inhibitors (ibrutinib and idelalisib, respectively), and discuss possible combinatorial therapeutic strategies to overcome resistance or to increase clinical efficacy.

• Klíčová slova
• B cell malignancies, B cell receptor, BCR inhibitor, adaptation, ibrutinib, resistance, targeted therapy,
• Publikační typ
• časopisecké články MeSH

Mantle cell lymphoma (MCL) is a heterogeneous malignancy with a broad spectrum of clinical behavior from indolent to highly aggressive cases. Despite the fact that MCL remains in most cases incurable by currently applied immunochemotherapy, our increasing knowledge on the biology of MCL in the last two decades has led to the design, testing, and approval of several innovative agents that dramatically changed the treatment landscape for MCL patients. Most importantly, the implementation of new drugs and novel treatment algorithms into clinical practice has successfully translated into improved outcomes of MCL patients not only in the clinical trials, but also in real life. This review focuses on recent advances in our understanding of the pathogenesis of MCL, and provides a brief survey of currently used treatment options with special focus on mode of action of selected innovative anti-lymphoma molecules. Finally, it outlines future perspectives of patient management with progressive shift from generally applied immunotherapy toward risk-stratified, patient-tailored protocols that would implement innovative agents and/or procedures with the ultimate goal to eradicate the lymphoma and cure the patient.

• Klíčová slova
• B-cell receptor signaling, cell cycle, mantle cell lymphoma,
• MeSH
• buněčný cyklus účinky léků   genetika   MeSH
• chemorezistence MeSH
• cílená molekulární terapie * metody   MeSH
• genetická variace MeSH
• klonální evoluce účinky léků   genetika   MeSH
• kombinovaná terapie MeSH
• lidé MeSH
• lymfom z plášťových buněk farmakoterapie   etiologie   metabolismus   mortalita   MeSH
• náchylnost k nemoci MeSH
• nádorové biomarkery antagonisté a inhibitory   MeSH
• prognóza MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• receptory antigenů B-buněk metabolismus   MeSH
• recidiva MeSH
• regulace genové exprese u nádorů účinky léků   MeSH
• signální transdukce účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• nádorové biomarkery MeSH
• protinádorové látky MeSH
• receptory antigenů B-buněk MeSH