N- acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner

AbstractTherapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol of human TIL13838I TCR-transduced T cells that are under evaluation in a Phase I clinical trial, demonstrated that findings in murine cells extend to human cells. Expansion of TIL13838I TCR-transduced T cells in NAC also increased their ability to kill target cells in vitro. Interestingly, NAC did not affect memory subsets, but diminished up-regulation of senescence (CD57) and exhaustion  (PD-1) markers and significantly decreased expression of the transcription factors EOMES and Foxo1. Pharmacological inhibition of the PI3K/Akt pathway ablates the decrease in Foxo1 induced by NAC treatment of activated T cells. This suggests a model in which NAC through PI3K/Akt activation suppres ses Foxo1 expression, thereby impacting its transcriptional targets EOMES, PD-1, and granzyme B. Taken together, our results indicate that NAC exerts pleiotropic effects that ...
Source: Cancer Immunology, Immunotherapy - Category: Cancer & Oncology Source Type: research

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ConclusionsImmune checkpoint inhibition can trigger inflammation in virtually any organ in the body, leading to diverse clinical manifestations. To our knowledge, this is the first case report of eosinophilic enteritis due to ipilimumab plus nivolumab.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
ConclusionsAnalysis of the spatially constrained distribution of CD8+ and CD163+ cells, representative of the opposite circuits of antitumor vs protumor immunity, respectively, may assist in identifying melanoma patients with improved response and better outcome upon treatment with MAPK inhibitors. These data underline the role of endogenous immune microenvironment in predisposing metastatic melanoma patients to benefit from therapies targeting driver-oncogenic pathways.
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
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 b...
Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
This article is protected by copyright. All rights reserved. PMID: 31729751 [PubMed - as supplied by publisher]
Source: European Journal of Immunology - Category: Allergy & Immunology Authors: Tags: Eur J Immunol Source Type: research
We examined publication bias and excess significance bias. 63 articles corresponding to 247 meta-analyses were eligible. Nine meta-analyses were classified to have convincing evidence, and 75 were classified as suggestive evidence. The clinical benefit of immunotherapy was supported by convincing evidence in the following settings: anti-PD-1/PD-L1 monoclonal antibody (mAb) therapy for treating advanced melanoma and non-small cell lung cancer (NSCLC), the combination of rituximab and chemotherapy for treating chronic lymphocytic leukemia and B-cell non-Hodgkin’s lymphoma, adoptive cell immunotherapy for NSCLC, and...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Article Source Type: research
Domenico Mallardo, MD, Istituto Nazionale Tumori " Fondazione Pascale " in Naples, discusses results from his trial – designed to evaluate anti-CTLA4 agents in patients with melanoma who relapsed on treatment with ipilimumab (Yervoy), which was presented at the 34th Annual Meeting&Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2019).
Source: CancerNetwork - Category: Cancer & Oncology Authors: Source Type: news
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Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
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Source: Journal for Immunotherapy of Cancer - Category: Cancer & Oncology Source Type: research
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Source: The Oncologist - Category: Cancer & Oncology Authors: Tags: Melanoma and Cutaneous Malignancies Source Type: research
Yicheng Ni Cancer remains a major cause of death globally. Given its relapsing and fatal features, curing cancer seems to be something hardly possible for the majority of patients. In view of the development in cancer therapies, this article summarizes currently available cancer therapeutics and cure potential by cancer type and stage at diagnosis, based on literature and database reviews. Currently common cancer therapeutics include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, treatment with curative intent by these methods are mainly eligible for patients with localized diseas...
Source: Cancers - Category: Cancer & Oncology Authors: Tags: Review Source Type: research
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