Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy

Ravi, Rajani; Noonan, Kimberly; Pham, Vui; Bedi, Rishi; Zhavoronkov, Alex; Ozerov, Ivan V.; Makarev, Eugene; Av, Artemov; Wysocki, Piotr; Mehra, Ranee; Nimmagadda, Sridhar; Marchionni, Luigi; Sidransky, David; Borrello, Ivan; Izumchenko, Evgeny; Bedi, Atul

doi:10.1038/s41467-017-02696-6

Cited by 260 publications

(223 citation statements)

References 72 publications

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“…Consistent with these findings, previous studies involving preclinical models of advanced cancer with activation of TGFb-and EMT-relevant pathways, as well as fibroblast proliferation, demonstrated the inhibition of T cell-mediated tumor killing and a decrease in T-cell trafficking into tumors (13,61). In line with our findings, some preclinical studies have indicated that antibody-ligand traps (anti-CTLA4-TGFbRII and anti-PDL1-TGFbRII) exhibit a superior therapeutic index compared with those of their parent immune-checkpoint inhibitors, which are currently in clinical use (73,76).…”

Section: Discussionsupporting

confidence: 88%

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Zeng

Zhou

et al. 2019

Cancer Immunology Research

759

661

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Tumor microenvironment (TME) cells constitute a vital element of tumor tissue. Increasing evidence has elucidated their clinicopathologic significance in predicting outcomes and therapeutic efficacy. Nonetheless, no studies have reported a systematic analysis of cellular interactions in the TME. In this study, we comprehensively estimated the TME infiltration patterns of 1,524 gastric cancer patients and systematically correlated the TME phenotypes with genomic characteristics and clinicopathologic features of gastric cancer using two proposed computational algorithms. Three TME phenotypes were defined, and the TMEscore was constructed using principal component analysis algorithms. The high TMEscore subtype was characterized by immune activation and response to virus and IFNg. Activation of transforming growth factor b, epithelial-mesenchymal transition, and angiogenesis pathways were observed in the low TMEscore subtype, which are considered T-cell suppressive and may be responsible for significantly worse prognosis in gastric cancer [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.33-0.54; P < 0.001]. Multivariate analysis revealed that the TMEscore was an independent prognostic biomarker, and its value in predicting immunotherapeutic outcomes was also confirmed (IMvigor210 cohort: HR, 0.63; 95% CI, 0.46-0.89; P ¼ 0.008; GSE78220 cohort: HR, 0.25; 95% CI, 0.07-0.89; P ¼ 0.021). Depicting a comprehensive landscape of the TME characteristics of gastric cancer may, therefore, help to interpret the responses of gastric tumors to immunotherapies and provide new strategies for the treatment of cancers.

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Section: Discussionsupporting

confidence: 88%

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Zeng

Zhou

et al. 2019

Cancer Immunology Research

759

661

View full text Add to dashboard Cite

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“…These observations imply that additional immunosuppressive mechanisms such as those mediated by PD-1 whose expression was unaffected in tumor-infiltrating CD8 + T cells (Fig. 1b), may compensate for TGFβ signaling blockade for CTL repression as suggested by recent studies 20-23 .…”

Section: Textsupporting

confidence: 57%

TGFβ Suppresses Type 2 Immunity to Cancer

Liu

Kuo

Capistrano

et al. 2020

Preprint

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The immune system employs two distinct defense strategies against infections: pathogen elimination typified by type 1 immunity, and pathogen containment exemplified by type 2 immunity in association with tissue repair. Akin to infectious diseases, cancer progresses with cancer cell acquisition of microorganism-like behavior propagating at the expense of the host.While immunological mechanisms of cancer cell elimination are well defined, whether immunemediated cancer cell containment can be induced is poorly understood. Here we show that ablation of transforming growth factor-β receptor II (TGFβRII) in CD4 + T cells promotes tumor tissue healing and halts cancer progression. Notably, the restorative response is dependent on the T helper 2 cytokine IL-4 fortifying vasculature organization that spares only proximal layers of cancer cells from hypoxia, nutrient starvation and death. Thus, type 2 immunity represents an effective cancer defense mechanism, and TGFβ signaling in helper T cells may be targeted for novel cancer immunotherapy.3 TextIn response to invading pathogens, vertebrate immune system employs two discrete strategies of host defense: pathogen elimination typified by type 1 immunity following innate immune recognition of prokaryotic microorganisms 1 , and pathogen containment associated with tissue repair manifested by type 2 immunity following the invasion of metazoan parasites that inflict tissue damage 2 . Similar to infectious diseases, cancer imposes insults to the host with cancer cell acquisition of microorganism-like behavior of clonal expansion. Indeed, cancer cell-targeted type 1 immunity mediated by CD8 + cytotoxic T lymphocytes (CTLs), cytotoxic innate lymphocytes and innate-like T cells represent host protective mechanisms of cancer cell elimination 3-5 . Notwithstanding, the host impact of cancer cells is much more intimate than that of microbes, and cancer pathogenicity, in particular that of solid tumors, is dependent on cancer cell coercing a supportive environment that promotes tumor encroachments leading to the impairment of tissue function [6][7][8][9] . Notably, tumor tissues resemble active wounds, and are considered as "wounds that do not heal" 10 , implying that cancer microenvironment-targeted tissue repair responses could restrain tumor progression.Dissimilar from infectious diseases, cancer arises from malignant transformation of selfcells. Consequently, immunological self-tolerance can be maladapted to repress cancer-elicited immune responses. Indeed, multiple T cell self-tolerance regulators including Foxp3 + regulatory T (Treg) cells, co-inhibitory receptors PD-1 and CTLA-4, and the regulatory cytokine transforming growth factor-β (TGFβ) suppress immune control of tumor development [11][12][13][14][15] .Depletion of tumor-infiltrating Treg cells via genetic approaches or administration of anti-PD-1 and anti-CTLA-4 result in CTL-dependent cancer cell elimination in animal models and patients 16,17 . In transgenic mouse models of cancer, blockade of TGFβ signaling in T cells...

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“…Ongoing trials of the TGF‐β antibody galunisertib plus nivolumab and durvalumab are being explored in pancreatic cancer, NSCLC, hepatocellular carcinoma, and other solid tumors. Additionally, an extremely promising strategy to target TGF‐β involves using a bispecific antibody against PD‐L1 or CTLA‐4 with a TGF‐β trap . Dramatic responses were observed with this drug in cervical cancers and pancreatic cancers, with an ongoing study including multiple expansion cohorts .…”

Section: Sarcomas—a Framework For Approaching Modern Immunotherapymentioning

confidence: 99%

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

Wilky

2019

Immunological Reviews

163

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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Bifunctional immune checkpoint-targeted antibody-ligand traps that simultaneously disable TGFβ enhance the efficacy of cancer immunotherapy

Cited by 260 publications

References 72 publications

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

Tumor Microenvironment Characterization in Gastric Cancer Identifies Prognostic and Immunotherapeutically Relevant Gene Signatures

TGFβ Suppresses Type 2 Immunity to Cancer

Immune checkpoint inhibitors: The linchpins of modern immunotherapy

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