2021-01-05 | 文獻閱讀

CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b studyUsefulness of IL-21, IL-7, and IL-15 conditioned media for expansion of antigen-specific CD8+ T cells from healthy donor-PBMCs suitable for immunotherapyResolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the MicrobiotaPD-L1 Multiplex and Quantitative Image Analysis for Molecular DiagnosticsInterferon-α-Induced Dendritic Cells Generated with Human Platelet Lysate Exhibit Elevated Antigen Presenting Ability to Cytotoxic T LymphocytesIdentification of tumor‐associated macrophage subsets that are associated with breast cancer prognosisType I interferons in pancreatic cancer and development of new therapeutic approachesLandmark Series: Immunotherapy and Targeted Therapy for Pancreatic CancerNeoadjuvant and adjuvant immunotherapy in renal cell carcinomaReverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell TypesCD44, a marker of cancer stem cells, is positively correlated with PD-L1 expression and immune cells infiltration in lung adenocarcinoma
1 CD40激動性單克隆抗體APX005M（sotigalimab）和化學療法（含或不含nivolumab）用於治療轉移性胰腺癌：一項開放性，多中心，1b期研究
標題：CD40 agonistic monoclonal antibody APX005M (sotigalimab) and chemotherapy, with or without nivolumab, for the treatment of metastatic pancreatic adenocarcinoma: an open-label, multicentre, phase 1b study
期刊：The Lancet Oncology
時間：2020-12-30
DOI：http://dx.doi.org/10.1016/S1470-2045(20)30532-5
Abstract
Background
Standard chemotherapy remains inadequate in metastatic pancreatic adenocarcinoma. Combining an agonistic CD40 monoclonal antibody with chemotherapy induces T-cell-dependent tumour regression in mice and improves survival. In this study, we aimed to evaluate the safety of combining APX005M (sotigalimab) with gemcitabine plus nab-paclitaxel, with and without nivolumab, in patients with pancreatic adenocarcinoma to establish the recommended phase 2 dose.
Methods
This non-randomised, open-label, multicentre, four-cohort, phase 1b study was done at seven academic hospitals in the USA. Eligible patients were adults aged 18 years and older with untreated metastatic pancreatic adenocarcinoma, Eastern Cooperative Oncology Group performance status score of 0–1, and measurable disease by Response Evaluation Criteria in Solid Tumors version 1.1. All patients were treated with 1000 mg/m2 intravenous gemcitabine and 125 mg/m2 intravenous nab-paclitaxel. Patients received 0·1 mg/kg intravenous APX005M in cohorts B1 and C1 and 0·3 mg/kg in cohorts B2 and C2. In cohorts C1 and C2, patients also received 240 mg intravenous nivolumab. Primary endpoints comprised incidence of adverse events in all patients who received at least one dose of any study drug, incidence of dose-limiting toxicities (DLTs) in all patients who had a DLT or received at least two doses of gemcitabine plus nab-paclitaxel and one dose of APX005M during cycle 1, and establishing the recommended phase 2 dose of intravenous APX005M. Objective response rate in the DLT-evaluable population was a key secondary endpoint. This trial (PRINCE, PICI0002) is registered with ClinicalTrials.gov, NCT03214250 and is ongoing.
Findings
Between Aug 22, 2017, and July 10, 2018, of 42 patients screened, 30 patients were enrolled and received at least one dose of any study drug; 24 were DLT-evaluable with median follow-up 17·8 months (IQR 16·0–19·4; cohort B1 22·0 months [21·4–22·7], cohort B2 18·2 months [17·0–18·9], cohort C1 17·9 months [14·3–19·7], cohort C2 15·9 months [12·7–16·1]). Two DLTs, both febrile neutropenia, were observed, occurring in one patient each for cohorts B2 (grade 3) and C1 (grade 4). The most common grade 3–4 treatment-related adverse events were lymphocyte count decreased (20 [67%]; five in B1, seven in B2, four in C1, four in C2), anaemia (11 [37%]; two in B1, four in B2, four in C1, one in C2), and neutrophil count decreased (nine [30%]; three in B1, three in B2, one in C1, two in C2). 14 (47%) of 30 patients (four each in B1, B2, C1; two in C2) had a treatment-related serious adverse event. The most common serious adverse event was pyrexia (six [20%] of 30; one in B2, three in C1, two in C2). There were two chemotherapy-related deaths due to adverse events: one sepsis in B1 and one septic shock in C1. The recommended phase 2 dose of APX005M was 0·3 mg/kg. Responses were observed in 14 (58%) of 24 DLT-evaluable patients (four each in B1, C1, C2; two in B2).
Interpretation
APX005M and gemcitabine plus nab-paclitaxel, with or without nivolumab, is tolerable in metastatic pancreatic adenocarcinoma and shows clinical activity. If confirmed in later phase trials, this treatment regimen could replace chemotherapy-only standard of care in this population.
Table.1 劑量限制毒性可評估人群的基線特徵
Table.3 APX005M抗體組合在劑量限制毒性可評估人群中的臨床活性（n = 24）
Fig.1 聯合吉西他濱加納布紫杉醇聯合或不聯合nivolumab對APX005M的總體反應
Fig.2 外周血單個核細胞群體的藥效學
2 IL-21，IL-7和IL-15條件培養基可用於從適合免疫療法的健康供體PBMC擴增抗原特異性CD8 + T細胞
標題：Usefulness of IL-21, IL-7, and IL-15 conditioned media for expansion of antigen-specific CD8+ T cells from healthy donor-PBMCs suitable for immunotherapy
期刊：Cellular Immunology
時間：2020-12-14
DOI：http://dx.doi.org/10.1016/j.cellimm.2020.104257
Highlights
Peptide-pulsed PBMCs and moDCs drive strong expansion of Ag-specific CD8+ T cells.
IL-21, 7, 15 promote the expansion of CD8+ T cells with an early memory phenotype.
α1DCs and stDCs promote the expansion of non-exhausted antigen-specific CD8+ T cells.
Abstract
Clonal anergy and depletion of antigen-specific CD8+ T cells are characteristics of immunosuppressed patients such as cancer and post-transplant patients. This has promoted translational research on the adoptive transfer of T cells to restore the antigen-specific cellular immunity in these patients. In the present work, we compared the capability of PBMCs and two types of mature monocyte-derived DCs (moDCs) to prime and to expand ex-vivo antigen-specific CD8+ T cells using culture conditioned media supplemented with IL-7, IL-15, and IL-21. The data obtained suggest that protocols involving moDCs are as efficient as PBMCs-based cultures in expanding antigen-specific CD8+ T cell to ELA and CMV model epitopes. These three gamma common chain cytokines promote the expansion of naïve-like and central memory CD8+ T cells in PBMCs-based cultures and the expansion of effector memory T cells when moDCs were used. Our results provide new insights into the use of media supplemented with IL-7, IL-15, and IL-21 for the in-vitro expansion of early-differentiated antigen-specific CD8+ T cells for immunotherapy purposes.
3 通過遺傳學，免疫學和微生物群的整合解決結腸癌的悖論
標題：Resolving the Paradox of Colon Cancer Through the Integration of Genetics, Immunology, and the Microbiota
期刊：Frontiers in Immunology
時間：2020-12-14
DOI：http://dx.doi.org/10.3389/fimmu.2020.600886
Abstract
While colorectal cancers (CRC) are paradigmatic tumors invaded by effector memory lymphocytes, the mechanisms accounting for the relative resistance of MSI negative CRC to immunogenic cell death mediated by oxaliplatin and immune checkpoint inhibitors has remained an open conundrum. Here, we propose the viewpoint where its microenvironmental contexture could be explained -at least in part- by macroenvironmental cues constituted by the complex interplay between the epithelial barrier, its microbial ecosystem, and the local immune system. Taken together this dynamic ménage-à-trois offers novel coordinated actors of the humoral and cellular immune responses actionable to restore sensitivity to immune checkpoint inhibition. Solving this paradox involves breaking tolerance to crypt stem cells by inducing the immunogenic apoptosis of ileal cells in the context of an ileal microbiome shifted towards immunogenic bacteria using cytotoxicants. This manoeuver results in the elicitation of a productive Tfh and B cell dialogue in mesenteric lymph nodes culminating in tumor-specific memory CD8+ T cell responses sparing the normal epithelium.
Fig.2 原發性和轉移性結直腸癌（CRC）的免疫情況
Fig.3 免疫和微生物成分的地理分布突出了迴腸和結腸部分之間的特異性
Fig.4 腸道營養不良與結腸癌發生之間的工具聯繫
Fig.6 證據表明腸道菌群在免疫檢查點抑制劑（ICI）介導的抗癌作用中具有關鍵作用
Fig.7 Tfh和B細胞編排對ICI在具有免疫原性迴腸微生物組的TMB高乳腺腫瘤或MSS CRC中的作用4 PD-L1多重診斷和定量圖像分析，用於分子診斷
標題：PD-L1 Multiplex and Quantitative Image Analysis for Molecular Diagnostics
期刊：Cancers
時間：2020-12-24
DOI：http://dx.doi.org/10.3390/cancers13010029
Summary
Assessing some diagnostic tests can be extremely difficult, even for highly trained clinicians. We have shown in the past that by using an advanced computer software program (QuPath), applied to high resolution images of patient tissue samples, we can assist pathologists in their assessment of a routine test that determines immunotherapy treatment. We also showed that by using a different testing method in the laboratory, called multiplexing, which detects several proteins at once rather than just one alone, we are subjectively more confident in the patient’s reported score. Here, we show that multiplexing is comparable to the traditional method, and that we can also easily apply our computer software tools to extract very specific information from the patient samples, which we are unable to do using the traditional laboratory method. We believe these tools can support pathologists to triage patient cases for this important diagnostic test.
Abstract
Multiplex immunofluorescence (mIF) and digital image analysis (DIA) have transformed the ability to analyse multiple biomarkers. We aimed to validate a clinical workflow for quantifying PD-L1 in non-small cell lung cancer (NSCLC). NSCLC samples were stained with a validated mIF panel. Immunohistochemistry (IHC) was conducted and mIF slides were scanned on an Akoya Vectra Polaris. Scans underwent DIA using QuPath. Single channel immunofluorescence was concordant with single-plex IHC. DIA facilitated quantification of cell types expressing single or multiple phenotypic markers. Considerations for analysis included classifier accuracy, macrophage infiltration, spurious staining, threshold sensitivity by DIA, sensitivity of cell identification in the mIF. Alternative sequential detection of biomarkers by DIA potentially impacted final score. Strong concordance was observed between 3,3』-Diaminobenzidine (DAB) IHC slides and mIF slides (R2 = 0.7323). Comparatively, DIA on DAB IHC was seen to overestimate the PD-L1 score more frequently than on mIF slides. Overall, concordance between DIA on DAB IHC slides and mIF slides was 95%. DIA of mIF slides is rapid, highly comparable to DIA on DAB IHC slides, and enables comprehensive extraction of phenotypic data and specific microenvironmental detail intrinsic to the sample. Exploration of the clinical relevance of mIF in the context of immunotherapy treated cases is warranted.
5 人血小板裂解物產生的幹擾素-α誘導的樹突狀細胞表現出對細胞毒性T淋巴細胞的抗原提呈能力增強
標題：Interferon-α-Induced Dendritic Cells Generated with Human Platelet Lysate Exhibit Elevated Antigen Presenting Ability to Cytotoxic T Lymphocytes
期刊：Vaccines
時間：2020-12-24
DOI：http://dx.doi.org/10.3390/vaccines9010010
Abstract
Given the recent advancements of immune checkpoint inhibitors, there is considerable interest in cancer immunotherapy provided through dendritic cell (DC)-based vaccination. Although many studies have been conducted to determine the potency of DC vaccines against cancer, the clinical outcomes are not yet optimal, and further improvement is necessary. In this study, we evaluated the potential ability of human platelet lysate (HPL) to produce interferon-α-induced DCs (IFN-DCs). In the presence of HPL, IFN-DCs (HPL-IFN-DCs) displayed high viability, yield, and purity. Furthermore, HPL-IFN-DCs displayed increased CD14, CD56, and CCR7 expressions compared with IFN-DCs produced without HPL; HPL-IFN-DCs induced an extremely higher number of antigen-specific cytotoxic T lymphocytes (CTLs) than IFN-DCs, which was evaluated with a human leukocyte antigen (HLA)-restricted melanoma antigen recognized by T cells 1 (MART-1) peptide. Additionally, the endocytic and proteolytic activities of HPL-IFN-DCs were increased. Cytokine production of interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-α was also elevated in HPL-IFN-DCs, which may account for the enhanced CTL, endocytic, and proteolytic activities. Our findings suggest that ex-vivo-generated HPL-IFN-DCs are a novel monocyte-derived type of DC with high endocytic and proteolytic activities, thus highlighting a unique strategy for DC-based immunotherapies.
6 鑑定與乳腺癌預後相關的腫瘤相關巨噬細胞亞群
標題：Identification of tumor‐associated macrophage subsets that are associated with breast cancer prognosis
期刊：Clinical and Translational Medicine
時間：2020-12-06
DOI：https://doi.org/10.1002/ctm2.239
Abstract
Background
Breast cancer is the leading cause of cancer‐related deaths in women, demanding new treatment options. With the advent of immune checkpoint blockade, immunotherapy emerged as a treatment option. In addition to lymphocytes, tumor‐associated macrophages exert a significant, albeit controversial, impact on tumor development. Pro‐inflammatory macrophages are thought to hinder, whereas anti‐inflammatory macrophages promote tumor growth. However, molecular markers to identify prognostic macrophage populations remain elusive.
Methods
We isolated two macrophage subsets, from 48 primary human breast tumors, distinguished by the expression of CD206. Their transcriptomes were analyzed via RNA‐Seq, and potential prognostic macrophage markers were validated by PhenOptics in tissue microarrays of patients with invasive breast cancer.
Results
Normal human breast tissue contained mainly CD206+ macrophages, while increased relative amounts of CD206− macrophages were observed in tumors. The presence of CD206+ macrophages correlated with a pronounced lymphocyte infiltrate and subsets of CD206+ macrophages, expressing SERPINH1 and collagen 1, or MORC4, were unexpectedly associated with improved survival of breast cancer patients. In contrast, MHCIIhi CD206− macrophages were linked with a poor survival prognosis.
Conclusion
Our data highlight the heterogeneity of tumor‐infiltrating macrophages and suggest the use of multiple phenotypic markers to predict the impact of macrophage subpopulations on cancer prognosis. We identified novel macrophage markers that correlate with the survival of patients with invasive mammary carcinoma.
7 胰腺癌的I型幹擾素和新治療方法的發展
標題：Type I interferons in pancreatic cancer and development of new therapeutic approaches
期刊：Critical Reviews in Oncology/Hematology
時間：2020-12-30
DOI：http://dx.doi.org/10.1016/j.critrevonc.2020.103204
Abstract
Immunotherapy has emerged as a new treatment strategy for cancer. However, its promise in pancreatic cancer has not yet been realized. Understanding the immunosuppressive tumor microenvironment of pancreatic cancer, and identifying new therapeutic targets to increase tumor-specific immune responses, is necessary in order to improve clinical outcomes.
Type I interferons, e.g. IFN-α and –β, are considered as an important bridge between the innate and adaptive immune system. Thereby, type I IFNs induce a broad spectrum of anti-tumor effects, including immunologic, vascular, as well as direct anti-tumor effects.
While IFN therapies have been around for a while, new insights into exogenous and endogenous activation of the IFN pathway have resulted in new IFN-related cancer treatment strategies.
Here, we focus on the pre-clinical and clinical evidence of novel ways to take advantage of the type I IFN pathway, such as IFN based conjugates and activation of the STING and RIG-I pathways.
Fig.1 STING，RIG-I和I型IFN途徑之間的串擾
8 具有裡程碑意義的系列：胰腺癌的免疫治療和靶向治療
標題：Landmark Series: Immunotherapy and Targeted Therapy for Pancreatic Cancer
期刊：Annals of Surgical Oncology
時間：2020-12-30
DOI：http://dx.doi.org/10.1245/s10434-020-09367-9
Abstract
Pancreatic cancer is one of the most aggressive gastrointestinal malignancies despite multimodality therapy. In the last several years, genomic studies have revealed that carcinogenesis is driven largely by key driver mutations that can be targeted for oncologic therapy. In addition, advances in cancer immunology have identified receptors and monoclonal antibodies that can be manipulated into harnessing the power of the host’s immune system for antitumor treatment. These strategies have generated a paradigm shift in the management of several cancer types, including those in the gastrointestinal tract. However, there are several complicating factors when translating the results to pancreatic cancer, including the dense, fibrotic stroma unique to this disease that may shield the cancer cells from both cytotoxic and immunologic agents. Although the majority of trials have been performed in the metastatic setting, this review will focus on both the historic studies that have defined this field as well as the emerging data arising from ongoing efforts to exploit newly discovered mutations and their druggable targets.
Fig.3 Virginia Mason輔助幹擾素方案9 腎細胞癌的新輔助和輔助免疫治療
標題：Neoadjuvant and adjuvant immunotherapy in renal cell carcinoma
期刊：World Journal of Urology
時間：2021-01-01
DOI：https://doi.org/10.1007/s00345-020-03550-z
Abstract
Objective
The treatment landscape for renal cell carcinoma (RCC) is rapidly evolving. The aim of this review is to summarize the randomized-controlled trials evaluating the role of immunotherapy in neoadjuvant or adjuvant setting.
Materials and methods
We searched PubMed, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov for studies including neoadjuvant or adjuvant immunotherapy, and provided a brief overview of the pharmacodynamics of immunotherapy for RCC.
Results
Several drugs are currently under investigation. In the neoadjuvant setting, four studies are evaluating the role of single-agent immunotherapy, one of dual-agent immunotherapy, and four studies the role of immunotherapy in combination with tyrosine kinase inhibitors or anti-interleukin-1 beta. In the adjuvant setting, two studies are evaluating the role of single-agent immunotherapy and two of dual-agent immunotherapy.
Conclusions
The approval of immune checkpoint inhibition as a front-line therapeutic strategy for advanced RCC has also ultimately led to the investigation of these agents first in the adjuvant and then in the neoadjuvant setting. Currently, there are nine studies aimed to evaluate the role of immunotherapy in the neoadjuvant setting and four studies in the adjuvant setting.
10 MHC-I分子在免疫和非免疫細胞類型中的反向信號傳遞
標題：Reverse Signaling by MHC-I Molecules in Immune and Non-Immune Cell Types
期刊：Frontiers in Immunology
時間：2020-12-15
DOI：http://dx.doi.org/10.3389/fimmu.2020.605958
Abstract
Major histocompatibility complex (MHC) molecules are well-known for their role in antigen (cross-) presentation, thereby functioning as key players in the communication between immune cells, for example dendritic cells (DCs) and T cells, or immune cells and their targets, such as T cells and virus-infected or tumor cells. However, much less appreciated is the fact that MHC molecules can also act as signaling receptors. In this process, here referred to as reverse MHC class I (MHC-I) signaling, ligation of MHC molecules can lead to signal-transduction and cell regulatory effects in the antigen presenting cell. In the case of MHC-I, reverse signaling can have several outcomes, including apoptosis, migration, induced or reduced proliferation and cytotoxicity towards target cells. Here, we provide an overview of studies showing the signaling pathways and cell outcomes upon MHC-I stimulation in various immune and non-immune cells. Signaling molecules like RAC-alpha serine/threonine-protein kinase (Akt1), extracellular signal-regulated kinases 1/2 (ERK1/2), and nuclear factor-κB (NF-κB) were common signaling molecules activated upon MHC-I ligation in multiple cell types. For endothelial and smooth muscle cells, the in vivo relevance of reverse MHC-I signaling has been established, namely in the context of adverse effects after tissue transplantation. For other cell types, the role of reverse MHC-I signaling is less clear, since aspects like the in vivo relevance, natural MHC-I ligands and the extended downstream pathways are not fully known.The existing evidence, however, suggests that reverse MHC-I signaling is involved in the regulation of the defense against bacterial and viral infections and against malignancies. Thereby, reverse MHC-I signaling is a potential target for therapies against viral and bacterial infections, cancer immunotherapies and management of organ transplantation outcomes.
Fig.1 MHC I類分子的抗原呈遞作用及其結構
Fig.2 各種細胞類型中反向MHC-1信號通路的概述11 CD44是癌症幹細胞的標誌物，與肺腺癌中PD-L1表達和免疫細胞浸潤呈正相關
標題：CD44, a marker of cancer stem cells, is positively correlated with PD-L1 expression and immune cells infiltration in lung adenocarcinoma
期刊：Cancer Cell International
時間：2020-12-07
DOI：https://doi.org/10.1186/s12935-020-01671-4
Abstract
Background
PD-L1 inhibitors is widely applied in lung adenocarcinoma patients. Tumor cells with high PD-L1 expression could trigger immune evasion. Cancer stem cells (CSCs) can evade from immunesurveillance due to their immunomodulating effects. However, the correlation between CSC and PD-L1 and some immune-related markers is seldom reported in patients with lung adenocarcinoma. Therefore, we aimed to ascertain their association in lung adenocarcinoma patients.
Methods
We assessed CD44 expression and its association with PD-L1 in lung adenocarcinoma, using Tumor Immune Estimation Resource (TIMER), which was further validated in our patient cohort. The immune cells infiltration was depicted by CIBERSORT using GEO database. The correlation between CD44 and immune cells was also analyzed. We further evaluated the prognostic role of CD44 in patients with lung adenocarcinoma both using Kaplan–Meier plotter and validated in our patient cohort.
Results
Positive association between CD44 and PD-L1 were found in lung adenocarcinoma patients. T cells CD4 memory resting cells and mast cells resting cells varied significantly between patients with CD44 high and those with CD44 low. Furthermore, positive association could be found between CD44 expression and immune cells. Arm-level depletion of CD44 was linked with B cell, CD4+ T cell, neutrophil and dendritic cell infiltration. Patients with higher CD44 levels had worsened overall survival (OS).
Conclusions
In summary, these results demonstrate that CD44 was associated with PD-L1 and infiltration of immune cells, and was a negative prognostic factor for predicting worsened OS in lung adenocarcinoma.