Following a similar report on multiple myeloma, Ghione and colleagues report the expected observation that patients with non-Hodgkin lymphoma (NHL) receiving anti-B cell therapies have markedly ...reduced antibody responses to COVID-19 immunization. Although there is no information regarding T-cell immunity, this suggests that while vaccination is certainly still recommended for this population, patients should be strongly encouraged to maintain social distancing precautions and should be revaccinated after an appropriate interval from the end of their antilymphoma therapy.
Upregulation of the anti-apoptotic protein MCL-1 has been implicated in chemotherapy resistance and poor clinical outcomes in B-cell lymphoma (BCL). We report the activity of AMG176, a direct, ...selective MCL-1 inhibitor, in preclinical models of BCL. A panel of cell lines representing diffuse large B-cell lymphoma (DLBCL), double-hit lymphoma (DHL) and Burkitt's lymphoma (BL) was selected. AMG176 induced apoptotic cell death in a dose- and time-dependent manner in all BCL cell lines. Baseline MCL-1 expression was not predictive of response. AMG176 exhibited impressive synergy with venetoclax and chemotherapeutic agents, less so with proteasomal inhibitors, and antagonism with anti-CD20 monoclonal antibodies. The activity of AMG176 could not be confirmed in murine models of BCL. Combination therapy targeting MCL-1 and BCL-2 may provide an alternative therapeutic approach in BCL, however optimal patient selection will remain the key to obtaining high response rates and tolerability.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Veltuzumab is a humanized anti-CD20 monoclonal antibody with complementarity-determining regions (CDRs) identical to rituximab, except for one residue at the 101st position (Kabat numbering) in CDR3 ...of the variable heavy chain (VH), having aspartic acid (Asp) instead of asparagine (Asn), with framework regions of epratuzumab, a humanized anti-CD22 antibody. When compared with rituximab, veltuzumab has significantly reduced off-rates in 3 human lymphoma cell lines tested, aswell as increased complement-dependent cytotoxicity in 1 of 3 cell lines, but no other in vitro differences. Mutation studies confirmed that the differentiation of the off-rate between veltuzumab and rituximab is related to the single amino acid change in CDR3-VH. Studies of intraperitoneal and subcutaneous doses in mouse models of human lymphoma and in normal cynomolgus monkeys disclosed that low doses of veltuzumab control tumor growth or deplete circulating or sessile B cells. Low- and high-dose veltuzumab were significantly more effective in vivo than rituximab in 3 lymphoma models. These findings are consistent with activity in patients with non-Hodgkin lymphoma given low intravenous or subcutaneous doses of veltuzumab. Thus, changing Asn101 to Asp101 in CDR3-VH of rituximab is responsible for veltuzumab's lower off-rate and apparent improved potency in preclinical models that could translate into advantages in patients.
Summary
The immunomodulatory drugs (IMiDs) lenalidomide and actimid (also known as CC‐4047) are thalidomide analogues which are more potent than their parental compound. In combination with ...rituximab, we have previously demonstrated that IMiDs have synergistic in vivo anti‐tumour activity in preclinical studies in a human lymphoma severe combined immunodeficiency mouse model. This report further explored the mechanisms by which IMiDs exert their anti‐lymphoma effects. Following exposure of subcutaneous lymphoma tumours in murine models to IMiDs, there was a significant increase in the recruitment of natural killer (NK) cells to tumour sites. This increase in NK cells was mediated via stimulation of dendritic cells and modification of the cytokine microenvironment associated with an increase in monocyte chemotactic protein‐1, tumour necrosis factor‐α and interferon‐γ and probably augmented rituximab‐associated antibody‐dependent cellular cytotoxicity. IMiDs also had significant anti‐angiogenic effects in our B‐cell lymphoma models. Thus, by modulation of the immune system mediated via dendritic cells and NK cells, changing the cytokine milieu, as well as by their anti‐angiogenic effects, IMiDs in combination with rituximab resulted in augmented in vivo anti‐tumour effects against B‐cell lymphoma. Our positive preclinical data adds additional support for the evaluation of IMiDs plus rituximab in patients with relapsed/refractory B‐cell lymphoma.
Background
Ofatumumab is a humanized type 1 anti‐CD20 monoclonal antibody. Preclinical studies show improved complement‐mediated cytotoxicity (CMC) compared to rituximab in mantle cell lymphoma ...(MCL). This study evaluates the safety and efficacy of combining ofatumumab with HyperCVAD/MA (O‐HyperCVAD) in newly diagnosed MCL.
Methods
In this single‐arm phase 2 study, 37 patients were treated with the combination of O‐HyperCVAD for 4 or 6 cycles, followed by high dose chemotherapy and autologous stem cell transplant. Primary objectives were overall response rate (ORR) and complete response (CR) rate at the end of therapy. Secondary objectives included minimal residual disease (MRD) negativity, progression‐free survival (PFS), and overall survival (OS).
Results
Median age was 60 years; ORR was 86% and 73% achieved a CR by modified Cheson criteria. The MRD negativity rate was 78% after 2 cycles of therapy, increasing to 96% at the end of induction; median PFS and OS were 45.5 months and 56 months, respectively. Achieving a post‐induction CR by both imaging and flow cytometry was associated with improved PFS and OS. Early MRD negativity (post‐2 cycles) was also associated with an improved PFS but not OS. There were 3 deaths while on therapy, and grades 3 and 4 adverse events (AEs) were observed in 22% and 68% of the patients.
Conclusion
The addition of ofatumumab to HyperCVAD/HD‐MA led to high rates of MRD negativity by flow cytometry in patients with newly diagnosed MCL. Achieving a CR post‐induction by both imaging and flow cytometry is associated with improved overall survival.
Ofatumumab combined with HyperCVAD/MA results in high response rates and minimal residual disease negativity in patients with newly diagnosed mantle cell lymphoma. Achieving a post‐induction complete response by both imaging and flow cytometry was associated with improved survival rates.
New thalidomide derivatives CC-5013 and CC-4047 (immunomodulatory drugs, IMiD) are up to 10,000 times more potent than Thalidomide.
The biological effects of IMiDs are presumed to be mediated by (a) ...activation of some components of the innate natural killer
(NK) cells or adoptive immune system (T cells), (b) modification of cytokine microenvironment in the tumor bed, or by (c)
inhibition of angiogenesis. In this article, we tested an innovative combination strategy involving rituximab and IMiDs in
aggressive lymphoma cell lines and human lymphoma xenografts. Treatment of non-Hodgkin's lymphoma cells with CC-5013 resulted
in a 40% to 70% growth inhibition when compared with controls ( P < 0.05). Exposure of lymphoma cells to CC-4047 resulted in a lesser degree of growth inhibition. Induction of apoptosis was
shown in 10% to 26% of lymphoma cells 24 hours following exposure to either IMiD. In vivo studies in severe combined immunodeficient mice showed synergistic activity between CC-4047 (and to a lesser degree, CC-5013)
plus rituximab. Animals treated with the CC-4047/rituximab combination had a median survival of 74 days ( P = 0.0012) compared with 58 days ( P = 0.167) in CC-5013/rituximab-treated animals compared with 45 days in rituximab monotherapy–treated animals. The synergistic
effect between IMiDs and rituximab in our mouse model was attributed to NK cell expansion. The enhancement of rituximab activity
by IMiDs was abrogated by in vivo depletion of NK cells. Augmenting NK cell function by CC-4047 or CC-5013 exposure may increase the antitumor effects of rituximab
against B-cell lymphomas and warrants further exploration in the context of a clinical trial.
Acquirement of resistance to rituximab has been observed in lymphoma patients. To define mechanisms associated with rituximab
resistance, we developed various rituximab-resistant cell lines (RRCL) ...and studied changes in CD20 expression/structure, lipid
raft domain (LRD) reorganization, calcium mobilization, antibody-dependent cellular cytotoxicity, and complement-mediated
cytotoxicity (CMC) between parental and RRCL. Significant changes in surface CD20 antigen expression were shown in RRCL. Decreased
calcium mobilization and redistribution of CD20 into LRD were found in RRCL. Western blotting identified a unique 35 kDa protein
band in RRCL, which was not seen in parental cells and was secondary to an increase in surface and cytoplasmic expression
of IgM light chains. CD20 gene expression was decreased in RRCL. In vitro exposure to PS341 increased CD20 expression in RRCL and minimally improved the sensitivity to rituximab-associated CMC. Our
data strongly suggest that the acquisition of rituximab resistance is associated with global gene and protein down-regulation
of the CD20 antigen affecting LRD organization and downstream signaling. CD20 expression seems to be regulated at the pretranscriptional
and posttranscriptional levels. Proteasome inhibition partially reversed rituximab resistance, suggesting the existence of
additional mediators of rituximab resistance. Future research is geared to identify drugs and/or biological agents that are
effective against RRCL.
Mantle cell lymphoma (MCL) is a mature B-cell lymphoma considered to be incurable with current treatments, including first-line rituximab in combination with multiagent chemotherapy and for those ...eligible, high-dose chemotherapy and stem cell support or rituximab maintenance. On the other hand, achieving a complete remission by high-sensitive flow cytometry is associated with prolonged duration of remission, stressing the need to develop and/or incorporate novel agents into the management of MCL. To this end, we examined the activity of ofatumumab, an anti-CD20 monoclonal antibody with distinct binding and immunologic properties compared to rituximab, in MCL preclinical models.
MCL cells were labeled with (51)Cr before incubation with rituximab or ofatumumab (10 μg/mL) plus human serum or effector cells. (51)Cr-release was measured and the percentage of lysis was calculated. Surface CD20, CD55, and CD59 were measured by Imagestream analysis. SCID mice inoculated subcutaneously with Z138 cells were assigned to control versus four doses of ofatumumab or rituximab (10 mg/kg/dose).
Ofatumumab exhibited enhanced in vitro complement-dependent cytotoxicity activity compared with rituximab in MCL cell lines, despite a high degree of in vitro resistance to rituximab associated with low CD20 levels and/or high expression of complement inhibitory proteins. Ofatumumab also delayed tumor progression and prolonged survival in a murine model of MCL.
Our results demonstrate that ofatumumab is more effective than rituximab in MCL preclinical models, including in the presence of rituximab resistance, and support the clinical investigation of ofatumumab in combination with standard systemic chemotherapy in MCL (NCT01527149).
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