Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Ragusa, Simone; Prat-Luri, Borja; González-Loyola, Alejandra; Nassiri, Sina; Squadrito, Mario Leonardo; Guichard, A; Cavin, Sabrina; Gjorevski, Nikolce; Barras, David; Marra, Giancarlo; Perentes, Jean Yannis; Corse, Emily; Bianchi, Roberta; Wetterwald, Laureline; Kim, Jae Hui; Oliver, Guillermo; Delorenzi, Mauro; Palma, Michele De; Petrova, Tatiana V.

doi:10.1172/jci129558

Cited by 50 publications

(39 citation statements)

References 81 publications

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“…In preclinical models, this therapy resulted in reprogramming of the vasculature, which promoted immune cell adhesion and engineered T cells' subsequent ability to enter the brain, thereby eliciting a robust antitumor response (290). Another intriguing study in mouse colorectal cancer models showed that adaptive resistance to chemotherapy (5-FU and cisplatin) is associated with a pronounced stromal response and T-cell exclusion (291). Combined targeting of the desmoplastic stroma along with the vasculature (VEGF-ANG2) and a CD40 agonist resulted in a conversion from fibrotic immune-excluded tumors to enable the unleashing of a CTL-mediated anticancer response (291).…”

Section: Discussionmentioning

confidence: 99%

“…Another intriguing study in mouse colorectal cancer models showed that adaptive resistance to chemotherapy (5-FU and cisplatin) is associated with a pronounced stromal response and T-cell exclusion (291). Combined targeting of the desmoplastic stroma along with the vasculature (VEGF-ANG2) and a CD40 agonist resulted in a conversion from fibrotic immune-excluded tumors to enable the unleashing of a CTL-mediated anticancer response (291). These brief illustrative examples demonstrate the potential for such complex multitargeting strategies to be evaluated in animal models as a means to identify and stratify combinations for potential translation to patients.…”

Section: Discussionmentioning

confidence: 99%

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Therapeutic Targeting of the Tumor Microenvironment

2021

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The importance of the tumor microenvironment (TME) in dynamically regulating cancer progression and influencing therapeutic outcome is now widely appreciated, and multiple therapies directed to various components of the TME have been developed in recent years. In this review, we will introduce the key cell types and features of the TME; discuss how these can be therapeutically targeted, with an emphasis on therapies that are under clinical evaluation or have been approved; highlight how the TME is altered by various interventions including standardof-care therapies; and conclude with an overview of the opportunities and potential challenges to consider in the coming years.The TME is defined as the complex and rich multicellular environment in which a tumor develops. The TME typically comprises immune cells, including T and B lymphocytes, tumor-associated macrophages (TAM), dendritic cells (DC), natural killer (NK) cells, neutrophils, and myeloid-derived suppressor cells (MDSC); stromal cells such as cancer-associated fibroblasts (CAF), pericytes, and mesenchymal stromal cells; the extracellular matrix (ECM) and other secreted molecules, such as growth factors, cytokines, chemokines, and extracel-absTRaCT Strategies to therapeutically target the tumor microenvironment (TME) have emerged as a promising approach for cancer treatment in recent years due to the critical roles of the TME in regulating tumor progression and modulating response to standard-of-care therapies. Here, we summarize the current knowledge regarding the most advanced TME-directed therapies, which have either been clinically approved or are currently being evaluated in trials, including immunotherapies, antiangiogenic drugs, and treatments directed against cancer-associated fibroblasts and the extracellular matrix. We also discuss some of the challenges associated with TME therapies, and future perspectives in this evolving field.Significance: This review provides a comprehensive analysis of the current therapies targeting the TME, combining a discussion of the underlying basic biology with clinical evaluation of different therapeutic approaches, and highlighting the challenges and future perspectives.Research.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Therapeutic Targeting of the Tumor Microenvironment

2021

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“… 95 , 96 , 97 Vanucizumab, as well as a mouse-specific surrogate bispecific, mediated potent anti-tumoral and anti-angiogenic efficacy in various preclinical models as monotherapy and in combination with chemotherapy, 81 , 98–101 as well as combined with PD-1 checkpoint inhibition 102–104 and CD40 agonism. 105 , 106 Vanucizumab was generally well tolerated as a monotherapy in a Phase 1 clinical trial and demonstrated promising anti-tumor efficacy, IgG-like pharmacokinetics and low immunogenicity, 107 as well as the anticipated pharmacodynamic mechanism of action. 108 Based on the negative outcome of the randomized McCAVE Phase 2 study, where it was compared to bevacizumab in combination with FOLFOX-6 chemotherapy in patients with untreated metastatic colorectal carcinoma, clinical development was discontinued.…”

Section: Applications In Targeted Cancer Therapy: Angiogenesis Receptor Tyrosine Kinases and Death Receptor Signalingmentioning

confidence: 99%

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

Surowka

Schaefer

Klein

2021

mAbs

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Bispecific antibodies have recently attracted intense interest. CrossMab technology was described in 2011 as novel approach enabling correct antibody light-chain association with their respective heavy chain in bispecific antibodies, together with methods enabling correct heavy-chain association using existing pairs of antibodies. Since the original description, CrossMab technology has evolved in the past decade into one of the most mature, versatile, and broadly applied technologies in the field, and nearly 20 bispecific antibodies based on CrossMab technology developed by Roche and others have entered clinical trials. The most advanced of these are the Ang-2/VEGF bispecific antibody faricimab, currently undergoing regulatory review, and the CD20/CD3 T cell bispecific antibody glofitamab, currently in pivotal Phase 3 trials. In this review, we introduce the principles of CrossMab technology, including its application for the generation of bi-/multispecific antibodies with different geometries and mechanisms of action, and provide an overview of CrossMab-based therapeutics in clinical trials.

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“…Moreover, recent studies targeting CD40 together with VEGF and ANG2 blockade demonstrated significant benefit in mouse tumor models. One study showed beneficial immune activation after the combined blockade of VEGF and ANG2 with CD40 agonistic antibodies in mice with desmoplastic and chemoresistant colorectal cancer [ 121 ]. Similarly, another study showed robust tumor regression associated with increased CD8 + T-cell infiltration when anti-CD40 was combined with dual ANG2 and VEGF blockade [ 122 ].…”

Section: Enhancing Cancer Immunotherapy By Targeting Ang2mentioning

confidence: 99%

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

Leong

Kim

2020

IJMS

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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.

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Antiangiogenic immunotherapy suppresses desmoplastic and chemoresistant intestinal tumors in mice

Cited by 50 publications

References 81 publications

Therapeutic Targeting of the Tumor Microenvironment

Therapeutic Targeting of the Tumor Microenvironment

Ten years in the making: application of CrossMab technology for the development of therapeutic bispecific antibodies and antibody fusion proteins

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

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