Immune-related adverse events and anti-tumor efficacy of immune checkpoint inhibitors

AbstractAlthough immune checkpoint inhibitors (ICIs) have transformed the treatment landscape for patients with many advanced malignancies, only 15 –60% of patients respond, leaving a broad swath of patients who do not derive benefit. Identifying biomarkers to optimally identify patients who will benefit from ICIs is a major research focus for the oncology community. Thus far, predictive biomarker research has focused on tumor signatures such as microsatellite instability, programmed death-ligand 1 (PD-L1) expression and tumor mutational burden; clinical biomarkers have been far less studied. One potential clinical biomarker for ICI response in patients is immune-related adverse event (IRAE) onset.IRAEs are thought to represent bystander effects from activated T-cells and it is plausible that patients responding to ICIs would have greater likelihood of autoimmune toxicities (e.g. due to a more competent/treatment-responsive immune system, or cross-reactivity between tumor and host tissue). Earlier studies in melanoma patients however, suggested no association between IRAE onset and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody efficacy. In contrast, a growing body of literature suggests IRAE onset is predictive of anti-programmed cell death protein 1 (PD-1) and anti-PD-L1 antibody response across a variety of solid tumors. Most of these studies report that patients who experienced IRAEs demonstrate marked improvements in progression-free survival, o...
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research

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This article summarizes the rationale for, and development of CDK inhibitors in melanoma, with their evolution from pan-CDK inhibitors to highly specific agents, throughout clinical trials and finally their potential future use. EXPERT OPINION: Whilst CDK inhibitors have been practice changing in breast cancer management, their efficacy is yet to be proven in melanoma. Combination with BRAF/MEK inhibitors has been hindered by dose-limiting toxicities, but their role may yet to be found within the spectrum of biomarker-derived personalized melanoma management. The effect that CDK inhibitors can have as an adjunct to imm...
Source: Expert Opinion on Pharmacotherapy - Category: Drugs & Pharmacology Tags: Expert Opin Pharmacother Source Type: research
In this study, we modeled an alternative strategy to amplify tumor antigen-specific TCR transgenic CD8+ T cells through limited application of a long-acting IL-2 fusion protein, mIL-2/mCD25, which selectively targets the high-affinity IL-2R. Here, mice were vaccinated with a tumor antigen and high-dose mIL-2/mCD25 was applied to coincide with the induction of the high affinity IL-2R on tumor-specific T cells. A single high dose of mIL-2/mCD25, but not an equivalent amount of IL-2, amplified the frequency and function of tumor-reactive CD8+ T effector (Teff) and memory cells. These mIL-2/mCD25-dependent effects relied on di...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research
Abstract Despite the depth of knowledge concerning the pathogenesis of melanoma, the most aggressive type of skin cancer, the prognosis and survival of patients still remain a challenge. In addition, responses to chemotherapy and immunotherapy are still poor, which underscore an urgent need in the development of new therapeutic strategies for the treatment of melanoma. Recently, the dynamic role of autophagy has gained considerable interest in the pathogenesis and treatment of melanoma. Whereas a decrease in autophagy activity promotes melanoma formation by increasing oncogene-induced tumorigenesis and DNA damage ...
Source: Molecular Biology Reports - Category: Molecular Biology Authors: Tags: Mol Biol Rep Source Type: research
chele Milella Antitumor therapies have made great strides in recent decades. Chemotherapy, aggressive and unable to discriminate cancer from healthy cells, has given way to personalized treatments that, recognizing and blocking specific molecular targets, have paved the way for targeted and effective therapies. Melanoma was one of the first tumor types to benefit from this new care frontier by introducing specific inhibitors for v-Raf murine sarcoma viral oncogene homolog B (BRAF), mitogen-activated protein kinase (MEK), v-kit Hardy–Zuckerman 4 feline sarcoma viral oncogene homolog (KIT), and, recently, immun...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
SAN CARLOS, Calif., Oct. 05, 2020 (GLOBE NEWSWIRE) -- Iovance Biotherapeutics, Inc. (NASDAQ: IOVA), a late-stage biotechnology company developing novel T cell-based cancer immunotherapies, today provided a regulatory update for...
Source: Drugs.com - Clinical Trials - Category: Pharmaceuticals Source Type: clinical trials
The metabolic properties of tumor microenvironment (TME) are dynamically dysregulated to achieve immune escape and promote cancer cell survival. However, in vivo properties of glucose metabolism in cancer and immune cells are poorly understood and their clinical application to development of a biomarker reflecting immune functionality is still lacking.Methods: We analyzed RNA-seq and fluorodeoxyglucose (FDG) positron emission tomography profiles of 63 lung squamous cell carcinoma (LUSC) specimens to correlate FDG uptake, expression of glucose transporters (GLUT) by RNA-seq and immune cell enrichment score (ImmuneScore). Si...
Source: Theranostics - Category: Molecular Biology Authors: Tags: Research Paper Source Type: research
omen-Heravi Extracellular vesicles (EVs), including exosomes and microvesicles, are membrane-bound vesicles secreted by most cell types during both physiologic conditions as well in response to cellular stress. EVs play an important role in intercellular communication and are emerging as key players in tumor immunology. Tumor-derived EVs (TDEs) harbor a diverse array of tumor neoantigens and contain unique molecular signature that is reflective of tumor’s underlying genetic complexity. As such they offer a glimpse into the immune tumor microenvironment (TME) and have the potential to be a novel, minimally inv...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
UCLA researchers have received a $13 million grant from the National Institutes of Health to find new ways to overcome melanoma resistance to some of the most promising targeted therapies and immunotherapies.There have been significant advancements in the past decade using targeted therapies and immunotherapies for treating people withadvanced forms of this deadliest type of skin cancer, but the treatments still only work in some people. Tumors can — and oftendo— become resistant to these drugs.“While these therapies have transformed the way people with melanoma are treated, only about 40% to 50% of peopl...
Source: UCLA Newsroom: Health Sciences - Category: Universities & Medical Training Source Type: news
(University of California - Los Angeles Health Sciences) UCLA researchers have received a $13 million grant from the National Institutes of Health to find new ways to overcome melanoma resistance to some of the most promising targeted therapies and immunotherapies.
Source: EurekAlert! - Cancer - Category: Cancer & Oncology Source Type: news
ConclusionsOur study unraveled novel molecular mechanisms regarding the regulation of tumor PD-L1 and provided a novel combination therapeutic strategy of SB-3CT and ICB therapy to enhance the efficacy of immunotherapy.
Source: Genome Medicine - Category: Genetics & Stem Cells Source Type: research
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