Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Waight, Jeremy D.; Chand, Dhan; Dietrich, Sylvia; Gombos, Randi; Horn, Thomas; González, Ana María; Manrique, Mariana; Swiech, Lukasz; Morin, Benjamin; Brittsan, Christine; Tanne, Antoine; Akpeng, Belinda; Croker, Ben A.; Buell, Jennifer; Stein, Robert B.; Savitsky, David; Wilson, Nicholas S.

doi:10.1016/j.ccell.2018.05.005

Cited by 79 publications

(74 citation statements)

References 67 publications

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“…It is thought that the IgG2 subtypes preferentially bind to activating human fragment crystallizable gamma receptors (FcγRs) expressed by phagocytic cells and natural killer (NK) cells, signaling for destruction of T regs via antibody‐dependent cell‐mediated cytotoxicity and phagocytotosis . Activity and specificity of FcγR interactions with IgG subsets has been shown to play critical roles in a variety of antibodies targeting CTLA‐4 and other immune checkpoint proteins …”

Section: Development and Early Establishment Of Immune Checkpoint Inhmentioning

confidence: 99%

“…18 Activity and specificity of FcγR interactions with IgG subsets has been shown to play critical roles in a variety of antibodies targeting CTLA-4 and other immune checkpoint proteins. 19 CTLA-4 monotherapy can produce meaningful and durable responses in melanoma, with the first clinical trials showing 22% 3-year overall survival (OS) and durable responses extending beyond 10 years. 20 Durable responses to CTLA-4 monotherapy are rare (<10%) but occasionally reported in other solid tumors including pancreatic adenocarcinoma, renal cell carcinoma, B-cell lymphoma, prostate cancer, refractory colorectal cancer, hepatocellular carcinoma, and malignant mesothelioma, reviewed in.…”

Section: Introductionmentioning

confidence: 99%

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Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

166

113

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Immune checkpoint inhibitors (ICIs) have revolutionized our approach to cancer treatment in the past decade. While monoclonal antibodies to CTLA‐4 and PD‐1/PD‐L1 have produced remarkable and durable responses in a subset of patients, the majority of patients will still develop primary or adaptive resistance. With complex mechanisms of resistance limiting the efficacy of checkpoint inhibitor monotherapy, it is critical to develop combination approaches to allow more patients to benefit from immunotherapy. In this review, I approach the current landscape of ICI research from the perspective of sarcomas, a rare group of bone and soft tissue cancers that have had limited benefit from checkpoint inhibitor monotherapy, and little investigation of biomarkers to predict responses. By surveying the various mechanisms of resistance and treatment modalities being explored in other solid tumors, I outline how ICIs will undoubtedly serve as the critical foundation for future directions in modern immunotherapy.

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Section: Development and Early Establishment Of Immune Checkpoint Inhmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

166

113

View full text Add to dashboard Cite

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“…Response to CD8 + T cell epitopes was tested in the context of depletion of tumor-infiltrating T regulatory cells (Tregs). E.G7 tumor-bearing C57BL/6J mice were treated with 9D9 (IgG2a), an anti-CTLA-4 monoclonal antibody, which inhibits the CTLA-4/B7 interaction but also depletes Tregs from the tumor microenvironment (14,15). The tumors underwent complete regression in mice treated with this antibody ( Figure 4B).…”

Section: Resultsmentioning

confidence: 99%

Identification of epitopes in ovalbumin that provide insights for cancer neoepitopes

et al. 2019

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“…Therefore, it is expected that ICOS Low cells (e.g. CD8 + T Eff cells) will be less sensitive to depletion than ICOS High T Reg but yet could be sensitive to co-stimulatory potential via ICOS signalling if the antibody also harbours agonistic properties (via clustering through Fc γ R receptors) ( 28, 29 ). With this in mind, we identified an antibody called KY1044.…”

Section: Resultsmentioning

confidence: 99%

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression

Sainson

Thotakura

Kosmač

et al. 2019

Preprint

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25The immunosuppressive tumour microenvironment constitutes a significant hurdle to the 26 response to immune checkpoint inhibitors. Both soluble factors and specialised immune cells 27 such as regulatory T cells (TReg) are key components of active intratumoural 28 immunosuppression. Previous studies have shown that Inducible Co-Stimulatory receptor 29 (ICOS) is highly expressed in the tumour microenvironment, especially on TReg, suggesting that 30 it represents a relevant target for preferential depletion of these cells. Here, we used immune 31 profiling of samples from tumour bearing mice and cancer patients to characterise the 32 expression of ICOS in different tissues and solid tumours. By immunizing an Icos knockout 33 transgenic mouse line expressing antibodies with human variable domains, we selected a fully 34 human IgG1 antibody called KY1044 that binds ICOS from different species. Using KY1044, we 35 demonstrated that we can exploit the differential expression of ICOS on T cell subtypes to 36 modify the tumour microenvironment and thereby improve the anti-tumour immune 37 response. We showed that KY1044 induces sustained depletion of ICOS high TReg cells in mouse 38 tumours and depletion of ICOS high T cells in the blood of non-human primates, but was also 39 associated with secretion of pro-inflammatory cytokines from ICOS low TEFF cells. Altogether, 40 KY1044 improved the intratumoural TEFF:TReg ratio and increased activation of TEFF cells, 41 resulting in monotherapy efficacy or in synergistic combinatorial efficacy when administered 42 with the immune checkpoint blocker anti-PD-L1. In summary, our data demonstrate that 43 targeting ICOS with KY1044 can favourably alter the intratumoural immune contexture, 44 promoting an anti-tumour response. 45 46 48 targeting immune checkpoints (e.g. CTLA-4, PD-1 and PD-L1). These immune checkpoint 49 inhibitors (ICIs) are associated with strong and durable responses in patients suffering from 50 advanced malignancies, including but not limited to metastatic melanoma, non-small cell lung 51 cancer (NSCLC), head and neck cancer, renal and bladder cancer (1). However, within all these 52 indications, there are still a high proportion of patients who exhibit intrinsic or acquired 53 resistance to ICIs. These patients represent a population with high unmet medical needs who 54 may benefit from novel combinatory approaches with ICIs. 55 Multiple molecular and cellular mechanisms have been associated with the lack of response to 56 immunotherapies (2). Accumulating evidence has shown that a low incidence of cytotoxic T 57 cells and the presence of immunosuppressive cells represent major barriers to establishing a 58 response to ICIs. One such class of immunosuppressive cells are regulatory T cells (TReg), which 59 are characterised by the expression of the transcription factor FOXP3 and function by blocking 60 the activation and cytotoxic potential of effector T-cells (TEff) through multiple mechanisms (3, 61 4). In fact, numbers of intratumoural TReg cells neg...

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Selective FcγR Co-engagement on APCs Modulates the Activity of Therapeutic Antibodies Targeting T Cell Antigens

Cited by 79 publications

References 67 publications

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Identification of epitopes in ovalbumin that provide insights for cancer neoepitopes

A novel antibody targeting ICOS increases intratumoural cytotoxic to regulatory T cell ratio and induces tumour regression

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