The induction of immunogenic cell death by type II anti‐<scp>CD</scp>20 monoclonal antibodies has mechanistic differences compared with type I rituximab

Cheadle, Eleanor J.; Sidon, L.; Dovedi, Simon J.; Melis, Monique; Alduaij, Waleed; Illidge, Tim; Honeychurch, Jamie

doi:10.1111/bjh.12427

Cited by 21 publications

(12 citation statements)

References 10 publications

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“…Although obinutuzumab can induce immunogenic cell death, 12 in this model enhanced NK cell-mediated ADCC may eradicate tumor before establishment of a tumor-specific CD8-mediated T-cell response. However, although IFNγ secreting tumor-specific CD8 + T cells were not detected post therapy, depletion of CD8 + T cells during the course of therapy appeared critical for generation of immunological memory as over half of these mice were not protected from rechallenge, in agreement with a previous report.…”

Section: Discussionmentioning

confidence: 92%

“…11 Furthermore, we have demonstrated that obinutuzumab induces the release of damage-associated molecular pattern molecules, which can prime dendritic cell maturation and T-cell activation. 12 Recent data have demonstrated the importance of the tumor microenvironment in regulating T-cell responses, which has led to intense interest in manipulating the balance between positive immune-stimulatory signals and negative regulatory signals with immuno-modulatory agents. 13 …”

Section: Introductionmentioning

confidence: 99%

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A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

et al. 2016

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Anti-CD20 monoclonal antibodies (mAb) such as rituximab have been proven to be highly effective at improving outcome in B-cell malignancies. However, many patients ultimately relapse and become refractory to treatment. The glycoengineered anti-CD20 mAb obinutuzumab was developed to induce enhanced antibody-dependent cellular cytotoxicity, antibody-dependent phagocytosis and direct cell death and was shown to lead to improved outcomes in a randomized study in B-CLL. We hypothesized that immune stimulation through Toll-like receptor 7 (TLR7) agonism in combination with obinutuzumab would further enhance lymphoma clearance and the generation of long-term antitumor immune responses. Here we demonstrate, in syngeneic human CD20 (hCD20)-expressing models of lymphoma, that systemic administration of a TLR7 agonist (R848) increases responses when administered in combination with obinutuzumab and protects against disease recurrence. Depletion studies demonstrate that primary antitumor activity is dependent on both NK cells and CD4+ T cells but not on CD8+ T cells. However, both CD4+ and CD8+ T cells appear necessary for the generation of protective immunological memory. Importantly, increased tumor-free survival post obinutuzumab and R848 combination therapy was seen in hCD20 transgenic mice, which express hCD20 on normal B cells. These findings provide a rationale for clinical testing of obinutuzumab in combination with systemically administered TLR7 agonists to further improve outcome.

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Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

et al. 2016

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“…93 Moreover, few of these therapies can liberate co-stimulatory signals from cancer cells (required to make ADCP immunogenic), for example, rituximab causing release of the TLR agonist, HMGB1. 94,95 Overall, these results show that besides their targeted activities, ADCP can help antibody-based therapies to achieve the desirable 'off-target' induction of antitumour immunity (Figure 2). 93 This raises similar precedence for other immunotherapies targeted towards the cancer cells, that is, anti-PD-L1 antibodies.…”

Section: Regulated Necrosismentioning

confidence: 85%

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

et al. 2016

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Phagocytosis of dying cells is a major homeostatic process that represents the final stage of cell death in a tissue context. Under basal conditions, in a diseased tissue (such as cancer) or after treatment with cytotoxic therapies (such as anticancer therapies), phagocytosis has a major role in avoiding toxic accumulation of cellular corpses. Recognition and phagocytosis of dying cancer cells dictate the eventual immunological consequences (i.e., tolerogenic, inflammatory or immunogenic) depending on a series of factors, including the type of 'eat me' signals. Homeostatic clearance of dying cancer cells (i.e., tolerogenic phagocytosis) tends to facilitate pro-tumorigenic processes and actively suppress antitumour immunity. Conversely, cancer cells killed by immunogenic anticancer therapies may stimulate non-homeostatic clearance by antigen-presenting cells and drive cancer antigen-directed immunity. On the other hand, (a general) inflammatory clearance of dying cancer cells could have pro-tumorigenic or antitumorigenic consequences depending on the context. Interestingly, the immunosuppressive consequences that accompany tolerogenic phagocytosis can be reversed through immune-checkpoint therapies. In the present review, we discuss the pivotal role of phagocytosis in regulating responses to anticancer therapy. We give particular attention to the role of phagocytosis following treatment with immunogenic or immune-checkpoint therapies, the clinical prognostic and predictive significance of phagocytic signals for cancer patients and the therapeutic strategies that can be employed for direct targeting of phagocytic determinants.

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“…Emerging data suggest a ''vaccination'' effect with anti-CD20 antibodies, whereby cell death enhances dendritic cell maturation and T-cell activation to produce an antilymphoma immune response [67]. ''Proof-of-principle'' data have demonstrated an increased level of FL idiotype-specific T cells relative to baseline after rituximab treatment in five FL patients [68].…”

Section: Preclinical Observations With Obinutuzumabmentioning

confidence: 99%

Obinutuzumab in hematologic malignancies: Lessons learned to date

Illidge

Klein

Sehn

et al. 2015

Cancer Treatment Reviews

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The routine use of anti-CD20 monoclonal antibodies (mAbs) has improved patient outcomes in CD20-positive non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Despite the clinical success achieved with rituximab, relapses are still common with further improvements in anti-CD20 mAb efficacy required. Many novel anti-CD20 antibodies are in development, but obinutuzumab is currently the only type II glycoengineered anti-CD20 mAb in clinical testing. Obinutuzumab has increased antibody-dependent cell-mediated cytotoxicity, reduced complement-dependent cytotoxicity and enhanced direct non-apoptotic cell death. In preclinical models, obinutuzumab induced superior tumor remission compared with rituximab at the equivalent dose levels, and was active in rituximab-refractory tumors. Obinutuzumab exhibits encouraging efficacy as monotherapy in NHL, and combined with chemotherapy in relapsed/refractory NHL and treatment-naïve symptomatic CLL. In a recent randomized, phase III trial in patients with untreated comorbid CLL, overall response rate was significantly greater (78% vs. 65%, P<0.0001) and median progression-free survival was significantly prolonged (26.7 vs. 15.2months, P<0.0001) for obinutuzumab plus chlorambucil vs. rituximab plus chlorambucil. Obinutuzumab is a type II anti-CD20 antibody that utilizes distinct mechanisms of action relative to type I antibodies like rituximab and has led to significant clinical improvement over rituximab in a phase III trial in CLL. Further trials are ongoing to determine whether such improvements in outcome will be seen in CD20-positive B-cell malignancies.

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The induction of immunogenic cell death by type II anti‐CD20 monoclonal antibodies has mechanistic differences compared with type I rituximab

Abstract: These authors are joint senior authors.

Cited by 21 publications

References 10 publications

A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

A TLR7 agonist enhances the antitumor efficacy of obinutuzumab in murine lymphoma models via NK cells and CD4 T cells

Immunogenic versus tolerogenic phagocytosis during anticancer therapy: mechanisms and clinical translation

Obinutuzumab in hematologic malignancies: Lessons learned to date

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