Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

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Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials


Characteristics and outcomes of patients with advanced sarcoma enrolled in early phase immunotherapy trials

Roman Groisberg, David S. Hong, […]Vivek Subbiah
Journal for ImmunoTherapy of Cancer volume 5, Article number: 100 (2017) Cite this article
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Abstract
Background
Immunotherapies, specifically those based on immune checkpoint inhibitors, have shown promising activity in multiple tumor types. Other than mifamurtide (MEPACT®) for osteosarcoma approved by European Medicines Agency, there are no approved immunotherapies for sarcomas.


Methods
We analyzed medical records of patients with advanced sarcoma who were referred to Phase 1 clinic at MD Anderson and received an immunotherapy (checkpoint inhibitors, vaccines, or cytokine based therapies). Clinical parameters including demographics, clinical history, toxicity, and response were abstracted.

Results
Among 50 patients enrolled in immunotherapy trials (Bone 10; Soft-tissue 40) we found 14 different subtypes of sarcomas. Royal Marsden Hospital (RMH) prognostic score was <2 (86%). Performance status (PS) was 0–1 in 48 patients (96%); median number of prior therapies was 3 (0–12). Immunotherapy consisted of checkpoint inhibitors (82%: PD1 = 7, PD-L1 = 11, CTLA4 = 22, other = 1) of which 42% were combinations, as well as vaccines (14%), and cytokines (4%). Median overall survival (OS) was 13.4 months (11.2 months: not reached). Median progression free survival (PFS) was 2.4 months (95% CI = 1.9–3.2 months). Best response was partial response (PR) in 2 patients with alveolar soft part sarcoma (ASPS) and stable disease (SD) in 11 patients (3 GIST, 3 liposarcomas (2 DDLS, 1 WDLS), 2 ASPS, 2 leiomyo, 1 osteo). PFS was 34% (23%, at 50%) at 3 months, 16% (8%, 30%) at 6 months, and 6% (2%, 20%) at 1 year. Pseudo-progression followed by stable disease was observed in 2 patients (4%). Grade 3/4 adverse events included rash (10%), fever (6%), fatigue (6%), and nausea/vomiting (6%).

Conclusion
Immunotherapies were well tolerated in advanced sarcoma patients enrolled in trials. All four ASPS patients had clinical benefit with checkpoint inhibitors and this was the only subtype experiencing partial response. Further evaluation of checkpoint inhibitors in ASPS is warranted.


https://jitc.biomedcentral.com/articles ... 017-0301-y

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The most remarkable response was that of alveolar soft part sarcomas (ASPS) to immunotherapy. Even with a limited sample of four patients, half had a strong partial response bordering on complete response. The other two patients had stable disease. This is far outside the normal behavior for a biologically indolent but relentless tumor [27] and raises the question of mechanism. Is this a question of PD-L1 blockade and cytotoxic T-cell activation? We know that most tumors with FDA approved anti-PD-1 immunotherapy have response rates in the 10–20% range. This would imply that either our four patients are unusual responders such as those seen in prior interferon trials, or that other mechanisms exist. Tanaka et al. [28] created a mouse model of alveolar soft part sarcoma based on the characteristic ASPSCR1-TFE3 fusion protein. The model demonstrated a highly vascular tumor with genes expressed in transendothelial migration. This vascularity is key to the early metastatic potential of this tumor. Additionally, ASPS lines these new blood vessels with hemangiopericytes that prevent leakage of nutrients and oxygen out of the blood vessels. We know that chemokines and their ligands are often involved in vascular recognition and targeting of microvascular endothelial cells [29]. Perhaps chemokines play an important role in the action of immunotherapy in ASPS; our group is undertaking further studies to elucidate this mechanism. Alternatively, the TFE3 fusion may be immunogenic itself or act via TGF-β or CD40 ligand to stimulate T-cells and antigen presenting cells [30]. Others have reported that mismatch repair pathway aberrations may be responsible for ASPS response to immunotherapy [31].

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Abstract

Neither the innate nor adaptive immune system “responds” unless leukocytes cross blood vessels. This process occurs through diapedesis, in which the leukocyte moves in an ameboid fashion through tightly apposed endothelial borders and, in some cases, through the endothelial cell itself. This review focuses on the active role of the endothelial cell in diapedesis. Several mechanisms play a critical role in transendothelial migration, including signals derived from clustering of apically disposed intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, disruption or loosening of adherens junctions, and targeted recycling of platelet/endothelial cell adhesion molecule and other molecules from the recently described lateral border recycling compartment. Surprisingly, many of the same molecules and mechanisms that regulate paracellular migration also control transcellular migration. A hypothesis that integrates the various known mechanisms of transmigration is proposed.

Keywords: inflammation, lateral border recycling compartment (LBRC), endothelial cell, diapedesis, platelet/endothelial cell adhesion molecule (PECAM), cell junctions

di·a·pe·de·sis
/ˌdīəpəˈdēsis/
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nounMEDICINE
the passage of blood cells through the intact walls of the capillaries, typically accompanying inflammation.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628537/

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Organ-Specific Mechanisms of Transendothelial Neutrophil Migration in the Lung, Liver, Kidney, and Aorta

Immune responses are dependent on the recruitment of leukocytes to the site of inflammation. The classical leukocyte recruitment cascade, consisting of capture, rolling, arrest, adhesion, crawling, and transendothelial migration, is thoroughly studied but mostly in model systems, such as the cremasteric microcirculation. This cascade paradigm, which is widely accepted, might be applicable to many tissues, however recruitment mechanisms might substantially vary in different organs. Over the last decade, several studies shed light on organ-specific mechanisms of leukocyte recruitment. An improved awareness of this matter opens new therapeutic windows and allows targeting inflammation in a tissue-specific manner. The aim of this review is to summarize the current understanding of the leukocyte recruitment in general and how this varies in different organs. In particular we focus on neutrophils, as these are the first circulating leukocytes to reach the site of inflammation. Specifically, the recruitment mechanism in large arteries, as well as vessels in the lungs, liver, and kidney will be addressed.

https://www.frontiersin.org/articles/10 ... 02739/full

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Neutrophils are the most abundant leukocytes in human blood and comprise the first line of defense in the innate immune system.

https://jlb.onlinelibrary.wiley.com/doi ... U1216-521R

Neutrophils in the activation and regulation of innate and adaptive immunity

Key Points
Neutrophils have long been viewed as short-lived effector cells of the innate immune system, with a primary role in resistance against extracellular pathogens and in acute inflammation.

Neutrophils express a vast repertoire of pattern recognition receptors and in response to signals undergo functional reprogramming. In addition to classical antimicrobial molecules (such as reactive oxygen intermediates), the effector repertoire of neutrophils includes an array of cytokines and chemokines, components of the humoral arm of innate immunity (such as pentraxin 3) and the formation of neutrophil extracellular traps. Thus, the participation of these 'unsung heroes' to mechanisms of innate resistance goes well beyond the production of microorganism- and tissue-damaging molecules, to include a diverse, highly regulated, customized production of cytokines and antibody-like soluble pattern recognition molecules, as well as the release of neutrophil extracellular traps.

Once recruited into tissues, neutrophils engage in complex bidirectional interactions with macrophages, mesenchymal stem cells, dendritic cells, natural killer cells, and B and T cells.

In particular, neutrophils contribute to the activation, orientation and expression of adaptive immune responses.

Given their role as a component of innate and adaptive responses, it is not surprising that neutrophils have emerged as important players in the pathogenesis of numerous disorders, including infection caused by intracellular pathogens, autoimmunity, chronic inflammation and cancer.

“These new perspectives raise the issue of targeting neutrophils as a therapeutic strategy in immunopathology.”