Dual angiopoietin-2 and VEGFA inhibition elicits antitumor immunity that is enhanced by PD-1 checkpoint blockade

2017 ◽  
Vol 9 (385) ◽  
pp. eaak9670 ◽  
Author(s):  
Martina Schmittnaegel ◽  
Nicolò Rigamonti ◽  
Ece Kadioglu ◽  
Antonino Cassará ◽  
Céline Wyser Rmili ◽  
...  
Keyword(s):  
Antitumor Immunity ◽  
Antiangiogenic Therapy ◽  
Metastatic Breast ◽  
Pancreatic Neuroendocrine Tumor ◽  
Genetically Engineered ◽  
Immune Checkpoints ◽  
Tumor Control ◽  
Antitumoral Activity ◽  
Therapeutic Benefits ◽  
Angiopoietin 2

Pathological angiogenesis is a hallmark of cancer and a therapeutic target. Vascular endothelial growth factor A (VEGFA) and angiopoietin-2 (ANGPT2; also known as ANG2) are proangiogenic cytokines that sustain tumor angiogenesis and limit antitumor immunity. We show that combined ANGPT2 and VEGFA blockade by a bispecific antibody (A2V) provided superior therapeutic benefits, as compared to the single agents, in both genetically engineered and transplant tumor models, including metastatic breast cancer (MMTV-PyMT), pancreatic neuroendocrine tumor (RIP1-Tag2), and melanoma. Mechanistically, A2V promoted vascular regression, tumor necrosis, and antigen presentation by intratumoral phagocytes. A2V also normalized the remaining blood vessels and facilitated the extravasation and perivascular accumulation of activated, interferon-γ (IFNγ)–expressing CD8+ cytotoxic T lymphocytes (CTLs). Whereas the antitumoral activity of A2V was, at least partly, CTL-dependent, perivascular T cells concurrently up-regulated the expression of the immune checkpoint ligand programmed cell death ligand 1 (PD-L1) in tumor endothelial cells. IFNγ neutralization blunted this adaptive response, and PD-1 blockade improved tumor control by A2V in different cancer models. These findings position immune cells as key effectors of antiangiogenic therapy and support the rationale for cotargeting angiogenesis and immune checkpoints in cancer therapy.

scholarly journals O4 Mechanisms of lung cancer hyper-progression promoted by PD-1 immune checkpoint blockade

2020 ◽  
Vol 8 (Suppl 2) ◽  
pp. A5.1-A5
Author(s):  
A Martinez-Usatorre ◽  
E Kadioglu ◽  
C Cianciaruso ◽  
B Torchia ◽  
J Faget ◽  
...  
Keyword(s):  
Lung Cancer ◽  
T Cells ◽  
Regulatory T Cells ◽  
Immune Checkpoint ◽  
Immune Cell ◽  
Immune Checkpoint Blockade ◽  
Genetically Engineered ◽  
Checkpoint Blockade ◽  
Therapeutic Benefits ◽  
Angiopoietin 2

BackgroundImmune checkpoint blockade (ICB) with antibodies against PD-1 or PD-L1 may provide therapeutic benefits in patients with non-small cell lung cancer (NSCLC). However, most tumours are resistant and cases of disease hyper-progression have also been reported.Materials and MethodsGenetically engineered mouse models of KrasG12Dp53null NSCLC were treated with cisplatin along with antibodies against angiopoietin-2/VEGFA, PD-1 and CSF1R. Tumour growth was monitored by micro-computed tomography and the tumour vasculature and immune cell infiltrates were assessed by immunofluorescence staining and flow cytometry.ResultsCombined angiopoietin-2/VEGFA blockade by a bispecific antibody (A2V) modulated the vasculature and abated immunosuppressive macrophages while increasing CD8+effector T cells in the tumours, achieving disease stabilization comparable or superior to cisplatin-based chemotherapy. However, these immunological responses were unexpectedly limited by the addition of a PD-1 antibody, which paradoxically enhanced progression of a fraction of the tumours through a mechanism involving regulatory T cells and macrophages. Elimination of tumour-associated macrophages with a CSF1R-blocking antibody induced NSCLC regression in combination with PD-1 blockade and cisplatin.ConclusionsThe immune cell composition of the tumour determines the outcome of PD-1 blockade. In NSCLC, high infiltration of regulatory T cells and immunosuppressive macrophages may account for tumour hyper-progression upon ICB.Disclosure InformationA. Martinez-Usatorre: None. E. Kadioglu: None. C. Cianciaruso: None. B. Torchia: None. J. Faget: None. E. Meylan: None. M. Schmittnaegel: None. I. Keklikoglou: None. M. De Palma: None.

scholarly journals Recent advances in understanding antitumor immunity

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 2545 ◽  
Author(s):  
Rodrigo Ramella Munhoz ◽  
Michael Andrew Postow
Keyword(s):  
Immune Responses ◽  
Antitumor Immunity ◽  
Adoptive Cell Therapy ◽  
Immune Checkpoints ◽  
Tumor Control ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Recent Advances ◽  
Open Questions

The term “antitumor immunity” refers to innate and adaptive immune responses which lead to tumor control. Turning the immune system into a destructive force against tumors has been achieved in a broad range of human cancers with the use of non-specific immunotherapies, vaccines, adoptive-cell therapy, and, more recently with significant success, through blockade of immune checkpoints. Nevertheless, the efficacy of these approaches is not universal, and tools to identify long-term responders and primarily refractory patients are warranted. In this article, we review recent advances in understanding the complex mechanisms of antitumor immunity and how these developments can be used to address open questions in a setting of growing clinical indications for the use of immunotherapy.

A highly stable multifunctional aptamer for enhancing antitumor immunity against hepatocellular carcinoma by blocking dual immune checkpoints

2021 ◽  
Author(s):  
Yanlin Du ◽  
Da Zhang ◽  
Yiru Wang ◽  
Ming Wu ◽  
Cuilin Zhang ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Checkpoint ◽  
Antitumor Immunity ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Immune Checkpoints

A highly stable multifunctional aptamer was prepared for strengthening antitumor immunity through a dual immune checkpoint blockade of CTLA-4 and PD-L1.

Therapeutic Effects of Matrine on Primary and Metastatic Breast Cancer

2010 ◽  
Vol 38 (06) ◽  
pp. 1115-1130 ◽  
Author(s):  
Hali Li ◽  
Gang Tan ◽  
Xian Jiang ◽  
Haiquan Qiao ◽  
Shangha Pan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Cancer Cells ◽  
Metastatic Breast ◽  
Proliferation Index ◽  
Therapeutic Effects ◽  
Dependent Manner ◽  
Therapeutic Benefits ◽  
4T1 Breast Cancer ◽  
Dose Dependent

Matrine, one of the main components extracted from a traditional Chinese herb, Sophora flavescens Ait, has displayed anti-cancer activity in several types of cancer cells. This study aims to evaluate the therapeutic benefits of matrine on primary and metastatic breast cancer. Matrine inhibited the viability of and induced apoptosis in human MCF-7 and mouse 4T1 breast cancer cells in a dose-dependent manner in vitro as shown by MTT assay, flow cytometry and laser scanning confocal microscopy. Administration of matrine inhibited the growth of primary tumors and their metastases to lungs and livers, in a dose-dependent manner, in a highly metastatic model of 4T1 breast cancer established in syngeneic Balb/c mice. Tumors from matrine-treated mice had a smaller proliferation index, shown by immunostaining with an anti-Ki-67 antibody, a greater apoptosis index, shown by TUNEL-staining, and a less microvessel density, shown by immunostaining with an anti-CD31 A antibody, compared to the controls. Western blot analysis of tumoral homogenates indicated that matrine therapy reduced the ratio of Bcl-2/Bax, downregulated the expressions of VEGF and VEGFR-2, and increased the activation of caspase-3 and caspase-9. This study suggests matrine may be a potent agent, from a natural resource, for treating metastatic breast cancer because of its anti-apoptotic, anti-proliferative and anti-angiogenic activities.

scholarly journals The Angiopoietin-2 and TIE Pathway as a Therapeutic Target for Enhancing Antiangiogenic Therapy and Immunotherapy in Patients with Advanced Cancer

2020 ◽  
Vol 21 (22) ◽  
pp. 8689
Author(s):  
Alessandra Leong ◽  
Minah Kim
Keyword(s):  
Cancer Treatment ◽  
Treatment Efficacy ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Vascular Changes ◽  
Therapeutic Success ◽  
Tumor Immune Evasion ◽  
Vegf Signaling ◽  
Antiangiogenic Drugs ◽  
Angiopoietin 2

Despite significant advances made in cancer treatment, the development of therapeutic resistance to anticancer drugs represents a major clinical problem that limits treatment efficacy for cancer patients. Herein, we focus on the response and resistance to current antiangiogenic drugs and immunotherapies and describe potential strategies for improved treatment outcomes. Antiangiogenic treatments that mainly target vascular endothelial growth factor (VEGF) signaling have shown efficacy in many types of cancer. However, drug resistance, characterized by disease recurrence, has limited therapeutic success and thus increased our urgency to better understand the mechanism of resistance to inhibitors of VEGF signaling. Moreover, cancer immunotherapies including immune checkpoint inhibitors (ICIs), which stimulate antitumor immunity, have also demonstrated a remarkable clinical benefit in the treatment of many aggressive malignancies. Nevertheless, the emergence of resistance to immunotherapies associated with an immunosuppressive tumor microenvironment has restricted therapeutic response, necessitating the development of better therapeutic strategies to increase treatment efficacy in patients. Angiopoietin-2 (ANG2), which binds to the receptor tyrosine kinase TIE2 in endothelial cells, is a cooperative driver of angiogenesis and vascular destabilization along with VEGF. It has been suggested in multiple preclinical studies that ANG2-mediated vascular changes contribute to the development and persistence of resistance to anti-VEGF therapy. Further, emerging evidence suggests a fundamental link between vascular abnormalities and tumor immune evasion, supporting the rationale for combination strategies of immunotherapy with antiangiogenic drugs. In this review, we discuss the recent mechanistic and clinical advances in targeting angiopoietin signaling, focusing on ANG2 inhibition, to enhance therapeutic efficacy of antiangiogenic and ICI therapies. In short, we propose that a better mechanistic understanding of ANG2-mediated vascular changes will provide insight into the significance of ANG2 in treatment response and resistance to current antiangiogenic and ICI therapies. These advances will ultimately improve therapeutic modalities for cancer treatment.

scholarly journals The GM-CSF–IRF5 signaling axis in eosinophils promotes antitumor immunity through activation of type 1 T cell responses

2020 ◽  
Vol 217 (12) ◽  
Author(s):  
Isabelle C. Arnold ◽  
Mariela Artola-Boran ◽  
Alessandra Gurtner ◽  
Katrin Bertram ◽  
Michael Bauer ◽  
...  
Keyword(s):  
T Cell ◽  
Antitumor Immunity ◽  
Critical Role ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
Gm Csf ◽  
Cell Responses

The depletion of eosinophils represents an efficient strategy to alleviate allergic asthma, but the consequences of prolonged eosinophil deficiency for human health remain poorly understood. We show here that the ablation of eosinophils severely compromises antitumor immunity in syngeneic and genetic models of colorectal cancer (CRC), which can be attributed to defective Th1 and CD8+ T cell responses. The specific loss of GM-CSF signaling or IRF5 expression in the eosinophil compartment phenocopies the loss of the entire lineage. GM-CSF activates IRF5 in vitro and in vivo and can be administered recombinantly to improve tumor immunity. IL-10 counterregulates IRF5 activation by GM-CSF. CRC patients whose tumors are infiltrated by large numbers of eosinophils also exhibit robust CD8 T cell infiltrates and have a better prognosis than patients with eosinophillow tumors. The combined results demonstrate a critical role of eosinophils in tumor control in CRC and introduce the GM-CSF–IRF5 axis as a critical driver of the antitumor activities of this versatile cell type.

Changes in circulating endothelial cells (CEL) in patients receiving trastuzumab for metastatic breast cancer predict response to treatment

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 579-579
Author(s):  
P. Spadaro ◽  
M. Ingemi ◽  
G. Dottore ◽  
G. Toscano ◽  
R. Maisano
Keyword(s):  
Breast Cancer ◽  
Endothelial Cells ◽  
Metastatic Breast Cancer ◽  
Performance Status ◽  
Antiangiogenic Therapy ◽  
Metastatic Breast ◽  
Circulating Endothelial Cells ◽  
Response To Treatment ◽  
Breast Cancer Patients ◽  
Her 2

579 Background: Amplification or overexpression of HER-2/neu has been identified in 10–20% of invasive breast cancers and is associated with shorter overall survival times; furthermore HER-2/neu is a predictive factor with regard to monoclonal antibody therapy with Trastuzumab. The observed association between the overexpression of HER-2/neu and higher VEGF expression indicates that HER-2/neu is involved, at least partly, in the regulation of angiogenesis in human breast cancer. Recently circulating endothelial cells (CECs) have been proposed as a marker of tumor progression and/or a response to antiangiogenic therapy; thus, we have performed a phase II study to explore the correlation between CECs and treatment with Trastuzumab in metastatic breast cancer Methods: 22 women aged ≥ 18 years with histologically proven Her-2-positive, ECOG performance status 0 to 2 who were not eligible for, or who wished to delay receiving chemotherapy received a standard loading dose of Trastuzumab 4 mg/Kg followed by 2 mg/Kg weekly. The weekly maintenance dose was continued until disease progression. A panel of monoclonal antibodies including anti CD45 to exclude hematopoietic cells, anti CD31, CD34, CD36, CD105, CD106, CD133, and KDR and appropriate analysis gates were used to enumerate resting and activated circulating endothelial cells Results: The overall response rate (RC + RP) to treatment was 25% (2 RC + 3RP). In healthy controls (N° 20) mean values of resting and activated CECs were 7.6/μL (4.6 - 11.2/μL) and 1.3/μL (0.1 - 2.4 /μL) respectively. Before treatment with Trastuzuamb the mean resting and activated CECs were 41.1/μL (16.4 - 60.5/μL) and 6.9/μL (5.1 - 8.7/μL). At a first assessment (6 wks) a significant decrease in CECs (p<0.001)was found in patients responding to treatment but not in the patients who did not achieve a remission Conclusions: Our finding has shown that resting and activated CECs are increased in metastatic breast cancer patients and decline during treatment in responding patients, furthermore, these data underline the crucial role of angiogenesis in this setting and support the rationale for a combination of Bevacizumab with Trastuzumab. No significant financial relationships to disclose.

Phase Ib study of cediranib in combination with daily temozolomide and radiation in patients with newly diagnosed glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e13010-e13010
Author(s):  
A. S. Chi ◽  
E. R. Gerstner ◽  
A. F. Eichler ◽  
H. K. Chea ◽  
J. Drappatz ◽  
...  
Keyword(s):  
Dose Level ◽  
Kinase Inhibitor ◽  
Antiangiogenic Therapy ◽  
Tumor Control ◽  
Vegf Receptor ◽  
Newly Diagnosed ◽  
Tumor Biopsy ◽  
Phase Ib ◽  
Post Radiation ◽  
Grade 3

e13010 Background: Pre-clinical evidence suggests antiangiogenic therapy combined with radiation therapy (RT) and chemotherapy may improve tumor control in patients with glioblastoma (GBM). We conducted a phase Ib study to evaluate the safety and maximum tolerated dose (MTD) of the combination of cediranib, a potent pan-VEGF receptor tyrosine kinase inhibitor, standard RT, and temozolomide (TMZ) in patients with newly diagnosed GBM who were not taking enzyme-inducing antiepileptic drugs (EIAED). Methods: After undergoing tumor biopsy or resection, six patients with pathologically confirmed GBM were treated with concurrent TMZ (75mg/m2/day), RT (60 Gy) and cediranib (dose level 1 = 20mg/day; dose level 2 = 30mg/day) followed by post-radiation TMZ (150–200 mg/m2 on days 1–5 of each 28 day cycle) and cediranib (45mg/day) for up to 6 monthly cycles. Cediranib was started concurrently with RT and TMZ 14–21 days after surgery. Results: Six patients were treated (cediranib 20mg = 3 patients; cediranib 30mg = 3 patients). No patients experienced a DLT, establishing the MTD for cediranib in combination with RT and TMZ as 30mg/day in this patient population. Expected toxicities of hypertension, fatigue, and palmar/plantar erythema were observed. During combined cediranib and TMZ therapy in the post-radiation setting, one patient discontinued cediranib because of toxicity (grade 3 transaminase elevation) and one patient required dose reduction to 15mg/day due to grade 3 proteinuria. No intratumoral or intracerebral hemorrhages were observed during the course of cediranib treatment. No cases of wound infection or wound dehiscence were observed. All patients are alive with a median follow-up of 156 days. Conclusions: Cediranib given in combination with standard RT and TMZ for newly diagnosed GBM patients not on EIAEDs is well tolerated and the MTD is 30mg/day. The phase II component of this trial is underway and will include correlative biomarker and MRI studies. [Table: see text]

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