First-in-human dose escalation of monalizumab plus durvalumab, with expansion in patients with metastatic microsatellite-stable colorectal cancer.

Segal, Neil H.; Naidoo, Jarushka; Curigliano, Giuseppe; Patel, Sandip Pravin; Sahebjam, Solmaz; Papadopoulos, Kyriakos P.; Gordon, Michael; Wang, Ding; Rueda, A. Gómez; Song, Xuyang; Li, Xia; Marshall, Shannon; Abdullah, Shaad E.; Diamond, Jennifer R.

doi:10.1200/jco.2018.36.15_suppl.3540

Cited by 38 publications

(27 citation statements)

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“…In vitro and in vivo blocking of both NKG2A/HLA-E and PD-1/PD-L1 pathways with antibodies have shown complete response rate (124,135,136). A combination of monalizumab and durvalumab has shown clinical efficacy and a manageable toxicity profile, with no DTLs, as suggested by preliminary data in patients with heavily pretreated metastatic microsatellite colorectal cancer (137).…”

Section: Nkg2a and Cd94mentioning

confidence: 96%

NK Cell-Based Immune Checkpoint Inhibition

Arooj²,

2020

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Immunotherapy, with an increasing number of therapeutic dimensions, is becoming an important mode of treatment for cancer patients. The inhibition of immune checkpoints, which are the source of immune escape for various cancers, is one such immunotherapeutic dimension. It has mainly been aimed at T cells in the past, but NK cells are a newly emerging target. Simultaneously, the number of checkpoints identified has been increasing in recent times. In addition to the classical NK cell receptors KIRs, LIRs, and NKG2A, several other immune checkpoints have also been shown to cause dysfunction of NK cells in various cancers and chronic infections. These checkpoints include the revolutionized CTLA-4, PD-1, and recently identified B7-H3, as well as LAG-3, TIGIT & CD96, TIM-3, and the most recently acknowledged checkpoint-members of the Siglecs family (Siglec-7/9), CD200 and CD47. An interesting dimension of immune checkpoints is their candidacy for dual-checkpoint inhibition, resulting in therapeutic synergism. Furthermore, the combination of immune checkpoint inhibition with other NK cell cytotoxicity restoration strategies could also strengthen its efficacy as an antitumor therapy. Here, we have undertaken a comprehensive review of the literature to date regarding NK cell-based immune checkpoints.

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Section: Nkg2a and Cd94mentioning

confidence: 96%

NK Cell-Based Immune Checkpoint Inhibition

Arooj²,

2020

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“…Monalizumab increases NK and CD8 + antibody-dependent cellular cytotoxicity (ADCC) and synergizes with anti-PD-1/PD-L1 blockade and antiepidermal growth factor receptor (EGFR) (Cetuximab) treatment (46). Interim results from clinical studies of Monalizumab + Cetuximab/ Durvalumab (anti-PD-L1) appear well-tolerated, with encouraging efficacy profiles (NCT02643550, NCT02671435) (46,161).…”

Section: Kir/nkg2amentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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“…The antagonistic NKG2A antibody monalizumab (IPH2201) is currently under investigation both as a single agent and in combination with cetuximab (anti-EGFR) or durvalumab (anti-PD-L1). Interim results from both combination trials report encouraging safety profiles and signs of efficacy (121,127).…”

Section: Cytokine Therapy: Mobilizing Nk Cells In Cancermentioning

confidence: 95%

Killers 2.0: NK cell therapies at the forefront of cancer control

Hodgins

Khan

Park

et al. 2019

Journal of Clinical Investigation

166

127

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The existence of immune cells that mediate cellular cytotoxicity without prior activation was determined by multiple groups who reported the spontaneous killing of tumor cells by lymphocytes from unimmunized mice (1-3). We now know that these cells with natural cytotoxicity, or natural killer (NK) cells, are important mediators of cancer immunosurveillance. NK cells are a heterogeneous population, and in humans they have been historically divided into IFN-γ-producing CD56 hi CD16 + and cytotoxic CD56 lo CD16 hi (4), whereas in mice they are grouped according to their expression of CD27 and CD11b (5), although it is now clear that the complexity is much higher. Distinct NK cell subsets play different roles in tumor immunity and cancer immunotherapy, as reviewed in Stabile et al. (6). NK cells are equipped with many receptors that tightly regulate their activation and allow them to discriminate between "normal" and "dangerous" cells (7). In addition to regulating NK cell activation, signals coming from activating and inhibitory receptors also tune the steady-state responsiveness of NK cells to future stimuli, in a process called NK cell education (reviewed in refs. 8, 9). Inhibitory receptors, such as killer-cell immunoglobulinlike receptors (KIRs), deliver negative signals that prevent NK cell autoreactivity. KIRs and other inhibitory receptors recognize MHC I molecules, whose absence may result in NK activation, the so-called "missing-self recognition" (10, 11). Later studies showed that lack of MHC expression was not sufficient or necessary to induce NK activation; rather, signaling from activating receptors was required. Broadly speaking, activating receptors, including NKG2D, provide activating signals upon binding to stress-induced ligands on target cells, which is referred to as "induced-self recognition" (12, 13). Ultimately, NK activation depends on the balance between activating and inhibitory signals triggered by these receptors binding their ligands. When activating signals prevail, NK cells respond, whereas when inhibitory signaling is stronger, NK cells do not respond. Healthy cells, with some exceptions (14-16), express low levels of activating ligands and an abundance of inhibitory ligands and therefore are not attacked by NK cells. On the other hand, tumor cells often acquire expression of NK cellactivating ligands and/or lose expression of MHC molecules. NK cells sense and respond to changes in the repertoire of molecules expressed on the surface of healthy cells during cellular transformation. This positions NK cells as important sentinels against cancer and as prime targets for cancer immunotherapy (17).

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First-in-human dose escalation of monalizumab plus durvalumab, with expansion in patients with metastatic microsatellite-stable colorectal cancer.

Abstract: #3540Copy of this poster obtained through QR code is for personal use only and may not be reproduced without permission from the author of the poster.

Cited by 38 publications

References 0 publications

NK Cell-Based Immune Checkpoint Inhibition

NK Cell-Based Immune Checkpoint Inhibition

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Killers 2.0: NK cell therapies at the forefront of cancer control

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