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Background: The peritoneum is one of the most frequent sites of recurrent gastric carcinoma after curative treatment, despite the administration of pre- and/or postoperative systemic chemotherapy. Indeed, the prognosis of peritoneal carcinomatosis from gastric carcinoma continues to be poor, with a median survival of less than one year with systemic chemotherapy. Whereas the prognosis of peritoneal carcinomatosis from colorectal cancer has changed with the development of locally administered hyperthermic intraperitoneal chemotherapy (HIPEC), survival results following carcinomatosis from gastric cancer remain disappointing, yielding a 5-year survival rate of less than 20%. Innovative surgical therapies such as intraperitoneal immunotherapy therefore need to be developed for the immediate postoperative period after complete cytoreductive surgery. In a recent randomised study, a clinical effect was obtained after intraperitoneal infusion of catumaxomab in patients with malignant ascites, notably from gastric carcinoma. Catumaxomab, a nonhumanized chimeric antibody, is characterized by its unique ability to bind to three different types of cells: tumour cells expressing the epithelial cell adhesion molecule (EpCAM), T lymphocytes (CD3) and also accessory cells (Fcγ receptor). Because the peritoneum is an immunocompetent organ and up to 90% of gastric carcinomas express EpCAM, intraperitoneal infusion of catumaxomab after complete resection of all macroscopic disease (as defined in the treatment of carcinomatosis from colorectal cancer) could therefore efficiently treat microscopic residual disease. Methods/design: The aim of this randomized phase II study is to assess 2-year overall survival after complete resection of limited carcinomatosis synchronous with gastric carcinoma, followed by an intraperitoneal infusion of catumaxomab with different total doses administered in each of the 2 arms. Close monitoring of peri-opertive mortality, morbidity and early surgical re-intervention will be done with stopping rules. Besides this analysis, translational research will be conducted to determine immunological markers of catumaxomab efficacy and to correlate these markers with clinical efficacy. [ABSTRACT FROM AUTHOR]

Background The peritoneum is one of the most frequent sites of recurrent gastric carcinoma after curative treatment, despite the administration of pre- and/or postoperative systemic chemotherapy. Indeed, the prognosis of peritoneal carcinomatosis from gastric carcinoma continues to be poor, with a median survival of less than one year with systemic chemotherapy. Whereas the prognosis of peritoneal carcinomatosis from colorectal cancer has changed with the development of locally administered hyperthermic intraperitoneal chemotherapy (HIPEC), survival results following carcinomatosis from gastric cancer remain disappointing, yielding a 5-year survival rate of less than 20%. Innovative surgical therapies such as intraperitoneal immunotherapy therefore need to be developed for the immediate postoperative period after complete cytoreductive surgery. In a recent randomised study, a clinical effect was obtained after intraperitoneal infusion of catumaxomab in patients with malignant ascites, notably from gastric carcinoma. Catumaxomab, a nonhumanized chimeric antibody, is characterized by its unique ability to bind to three different types of cells: tumour cells expressing the epithelial cell adhesion molecule (EpCAM), T lymphocytes (CD3) and also accessory cells (Fcγ receptor). Because the peritoneum is an immunocompetent organ and up to 90% of gastric carcinomas express EpCAM, intraperitoneal infusion of catumaxomab after complete resection of all macroscopic disease (as defined in the treatment of carcinomatosis from colorectal cancer) could therefore efficiently treat microscopic residual disease. Methods/design The aim of this randomized phase II study is to assess 2-year overall survival after complete resection of limited carcinomatosis synchronous with gastric carcinoma, followed by an intraperitoneal infusion of catumaxomab with different total doses administered in each of the 2 arms. Close monitoring of peri-opertive mortality, morbidity and early surgical re- intervention will be done with stopping rules. Besides this analysis, translational research will be conducted to determine immunological markers of catumaxomab efficacy and to correlate these markers with clinical efficacy. [ABSTRACT FROM AUTHOR]

Beyond cancer-cell intrinsic factors, the immune status of the host has a prognostic impact on patients with cancer and influences the effects of conventional chemotherapies. Metastatic melanoma is intrinsically immunogenic, thereby facilitating the search for immune biomarkers of clinical responses to cytotoxic agents. Here, we show that a multi-tyrosine kinase inhibitor, sorafenib, upregulates interleukin (IL)-15Ra in vitro and in vivo in patients with melanoma, and in conjunction with natural killer (NK) group 2D (NKG2D) ligands, contributes to the Th1 polarization and accumulation of peripheral CD4+NKG2D+ T cells. Hence, the increase of blood CD4+NKG2D+ T cells after two cycles of sorafenib (combined with temozolomide) was associated with prolonged survival in a prospective phase I/II trial enrolling 63 patients with metastatic melanoma who did not receive vemurafenib nor immune checkpoint--blocking antibodies. In contrast, in metastatic melanoma patients treated with classical treatment modalities, this CD4+NKG2D+ subset failed to correlate with prognosis. These findings indicate that sorafenib may be used as an "adjuvant" molecule capable of inducing or restoring IL-15Rα/ IL-15 in tumors expressing MHCclass I--related chain A/B (MICA/B) and on circulating monocytes of responding patients, hereby contributing to the bioactivity of NKG2D+ Th1 cells. [ABSTRACT FROM AUTHOR]

We performed a Phase I clinical trial from October 2007 to October 2009, enrolling patients affected by refractory solid tumors, to determine the maximum tolerated dose (MTD) of interleukin (IL)-2 combined with low dose cyclophosphamide (CTX) and imatinib mesylate (IM). In a companion paper published in this issue of OncoImmunology, we show that the MTD of IL-2 is 6 MIU/day for 5 consecutive days, and that IL-2 increases the impregnation of both IM and of its main metabolite, CGP74588. Among the secondary objectives, we wanted to determine immunological markers that might be associated with progression-free survival (PFS) and/or overall survival (OS). The combination therapy markedly reduced the absolute counts of B, CD4+ T and CD8+ T cells in a manner that was proportional to IL-2 dose. There was a slight (less than 2-fold) increase in the proportion of regulatory T cells (Tregs) among CD4+ T cells in response to IM plus IL-2. The natural killer (NK)-cell compartment was activated, exhibiting a significant upregulation of HLA-DR, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and CD56. The abundance of HLA-DR+ NK cells after one course of combination therapy positively correlated with both PFS and OS. The IL-2-induced rise of the CD4+:CD8+ T-cell ratio calculated after the first cycle of treatment was also positively associated with OS. Overall, the combination of IM and IL-2 promoted the rapid expansion of HLA-DR+ NK cells and increased the CD4+:CD8+ T-cell ratio, both being associated with clinical benefits. This combinatorial regimen warrants further investigation in Phase II clinical trials, possibly in patients affected by gastrointestinal stromal tumors, a setting in which T and NK cells may play an important therapeutic role. [ABSTRACT FROM AUTHOR]

To communicate, cells are known to release in their environment proteins which bind to receptors on surrounding cells. But cells also secrete more complex structures, called membrane vesicles, composed of a lipid bilayer with inserted transmembrane proteins, enclosing an internal content of hydrophilic components. Exosomes represent a specific subclass of such secreted membrane vesicles, which, despite having been described more than 20 years ago by two groups studying reticulocyte maturation, have only recently received attention from the scientific community. This renewed interest originated first from the description of exosome secretion by antigen-presenting cells, suggesting a potential role in immune responses, and very recently by the identification of the presence of RNA (both messenger and microRNA) in exosomes, suggesting a potential transfer of genetic information between cells. In this review, we will describe the conclusions of 20 years of studies on the immune properties of exosomes and the most recent advances on their roles and potential uses as markers or as therapeutic tools during pathologies, especially in cancer. [ABSTRACT FROM AUTHOR]

The treatment of cancer by chemotherapy causes tumour cell death, mostly by apoptosis. This tumour cell death may or may not elicit an immune response. At least in some cases, the efficacy of chemotherapy critically depends on the induction of immunogenic cell death that is a type of cell demise that stimulates the activation of an adaptative anti-tumour immune response, which in turn helps to eradicate residual cancer (stem) cells. Indeed, anthracyclins care more efficient in curing tumours in immunocompetent than in T cell-deficient mice. The molecular mechanism implicated in this anti-tumour T cell activation was recently discovered. Anthracyclins cause immunogenic cell death due to their specific capacity to stimulate the translocation of calreticulin to the cell surface. Calreticulin then acts as an “eat me” signal for dendritic cells, allowing them to phagocytose tumour cells and to prime tumour antigen-specific cytotoxic T cells. Importantly, non-immunogenic chemotherapy can be rendered immunogenic by adsorbing recombinant calreticulin to tumour cells or by enforcing the translocation of endogenous calreticulin to the cell surface by means of PP1/GADD34 inhibitors. This strategy could have major implications for the treatment of human cancer. Indeed, in vivo treatments with anthracyclins can cause the translocation of calreticulin to the surface of circulating tumour cells, in patients with acute myeloid leukaemia (AML). The challenge will be to determine whether the exposure of calreticulin translocation on the tumour cell surface is linked to chemotherapy-induced anti-tumour immune responses and therapeutic efficacy in human cancer. [ABSTRACT FROM AUTHOR]

The interferon (IFN)-γ–induced TRAIL effector mechanism is a vital component of cancer immunosurveillance by natural killer (NK) cells in mice. Here we show that the main source of IFN-γ is not the conventional NK cell but a subset of B220+Ly6C− dendritic cells, which are atypical insofar as they express NK cell-surface molecules. Upon contact with a variety of tumor cells that are poorly recognized by NK cells, B220+NK1.1+ dendritic cells secrete high levels of IFN-γ and mediate TRAIL-dependent lysis of tumor cells. Adoptive transfer of these IFN-producing killer dendritic cells (IKDCs) into tumor-bearing Rag2−/−Il2rg−/− mice prevented tumor outgrowth, whereas transfer of conventional NK cells did not. In conclusion, we identified IKDCs as pivotal sensors and effectors of the innate antitumor immune response. [ABSTRACT FROM AUTHOR]

Abstract: Dendritic-cell-derived exosomes (DEX) secreted after dendritic cell loading with tumor peptides were found to mediate tumor rejection in mice. This observation prompted us to demonstrate that MHC class I/peptide complexes harbored onto exosomal membranes were capable of priming cytotoxic T cells and to mediate rejection of tumors expressing the relevant antigens. Moreover, DEX also promote NK cell activation in immunocompetent mice and NK cell-dependent antitumor effects. The first Phase I trial using DEX to immunize melanoma patients revealed the feasibility of DEX production in stage IV melanoma, their safety in long-term follow up and their bioactivity in vivo. [Copyright &y& Elsevier]

Exosomes are small membrane vesicles originating from late endosomes and secreted by hematopoietic and epithelial cells in culture. Exosome proteic and lipid composition is unique and might shed some light into exosome biogenesis and function. Exosomes secreted from professional antigen-presenting cells (i.e., B lymphocytes and dendritic cells) are enriched in MHC class I and II complexes, costimulatory molecules, and hsp70–90 chaperones, and have therefore been more extensively studied for their immunomodulatory capacities in vitro and in vivo. This review will present the main biological features pertaining to tumor or DC-derived exosomes, will emphasize their immunostimulatory function, and will discuss their implementation in cancer immunotherapy. [ABSTRACT FROM AUTHOR]

PURPOSE: With liquid biopsy's widespread adoption in oncology, an increased number of clonal hematopoiesis–associated mutations (CHm) have been identified in patients with solid tumors. However, its impact on patient outcomes remains unclear. This study aimed to analyze and describe CHm in a cohort of phase I patients. METHODS: Retrospective data collection from medical records and molecular profiles (Foundation One Liquid CDx Assay) was performed before first study drug administration at the Drug Development Department of Gustave Roussy (France) within the STING trial (ClinicalTrials.gov identifier: NCT04932525). CHm prevalence was assessed using any and ≥1% variant allele frequency (VAF) in epigenetic modifier genes (DNMT3A , TET2 , and ASXL1). RESULTS: From January 2021 to December 2022, 255 patients were enrolled in a phase I clinical trial. A total of 55% were male, with a median age of 62 years (24-86). Principal tumor locations were GI (27%) and genitourinary (21%). Overall, 104 patients (41%) had at least one CHm in liquid biopsy, with 55 patients (22%) having a VAF of ≥ 1%. The most frequent mutation was DNMT3A 73% at any VAF (n = 76) and 22% at 1% VAF (n = 23). Median progression-free survival (PFS) and overall survival were 3.8 months (m) for the CHm group versus 3.2 m for nonclonal hematopoiesis (CH; P =.08) and 18.26 m CHm versus 15.8 m non-CH (P =.9), respectively. PFS increased in the CHm population treated with targeted therapy (hazard ratio, 0.6 [95% CI, 0.42 to 0.84]; P =.004). CONCLUSION: CHm was commonly found in patients with solid tumors treated in phase I trials, with a prevalence of 41% in our cohort. The most frequently mutated gene was DNMT3A. The presence of CHm had no impact on the population of patients treated in the phase I trials. [ABSTRACT FROM AUTHOR]

Anti-CTLA-4 and anti-PD-1/PD-L1 immune checkpoint inhibitors are therapeutic monoclonal antibodies that do not target cancer cells but are designed to reactivate or promote antitumor immunity. Dosing and scheduling of these biologics were established according to conventional drug development models, even though the determination of a maximum tolerated dose in the clinic could only be defined for anti-CTLA-4. Given the pharmacology of these monoclonal antibodies, their high interpatient pharmacokinetic variability, the actual clinical benefit as monotherapy that is observed only in a specific subset of patients, and the substantial cost of these treatments, a number of questions arise regarding the selected dose and the dosing interval. This review aims to outline the development of these immunotherapies and considers optimization options that could be used in clinical practice. [ABSTRACT FROM AUTHOR]

Immunotherapy with immune-checkpoint inhibitors (ICIs) targeting programmed cell death 1 or programmed death-ligand 1 has revolutionised the treatment of advanced non-small cell lung cancer (NSCLC) and has been investigated in early NSCLC, alone or in combination with chemotherapy, anti-CTLA-4 antibodies and radiotherapy. Although more mature data are needed before setting a change of paradigm in early stages, reports of pathological response rates and disease-free survival are promising, especially with neoadjuvant multimodality approaches. Nevertheless, major pathological response rates for neoadjuvant anti-PD-(L)1 monotherapy rarely exceed 40%, and biomarkers for characterising patients who may benefit the most from ICIs are lacking. These biomarkers have a distinct value from the metastatic setting, with highly different tumour biologies. Among the most investigated so far in this context, programmed death-ligand 1 expression and, to a lesser extent, tumour mutational burden seem to correlate better with higher pathological response rates and survival. Epidermal growth factor receptor , Serine/Threonine Kinase 11 and Kelch-like ECH-associated protein 1 mutations rise as essential determinations for the treatment selection in early-stage NSCLC. Emerging and promising approaches comprise evaluation of blood-based ratios, microbiota, and baseline intratumoural TCR clonality. Circulating tumour DNA will be of great help in the near future when selecting best candidates for adjuvant ICIs, monitoring the tumour response to the neoadjuvant treatment in order to improve the rates of complete resections in the early stage. • Immune-checkpoint inhibitors (ICIs)are becoming a standard in early non-small cell lung cancer but do not benefit all patients. • Programmed death-ligand 1 expression and tumour mutational burden are the better-documented biomarkers. • Patients with epidermal growth factor receptor , Serine/Threonine Kinase 11 or Kelch-like ECH-associated protein 1 alterations yield poor benefit from ICIs. • Emerging biomarkers include TCR clonality, microbiota and blood-based ratios. • Circulating tumour DNA is a reliable tool to evaluate disease burden following surgery or ICIs. [ABSTRACT FROM AUTHOR]

Background: The peritoneum is one of the most frequent sites of recurrent gastric carcinoma after curative treatment, despite the administration of pre- and/or postoperative systemic chemotherapy. Indeed, the prognosis of peritoneal carcinomatosis from gastric carcinoma continues to be poor, with a median survival of less than one year with systemic chemotherapy. Whereas the prognosis of peritoneal carcinomatosis from colorectal cancer has changed with the development of locally administered hyperthermic intraperitoneal chemotherapy (HIPEC), survival results following carcinomatosis from gastric cancer remain disappointing, yielding a 5-year survival rate of less than 20%. Innovative surgical therapies such as intraperitoneal immunotherapy therefore need to be developed for the immediate postoperative period after complete cytoreductive surgery. In a recent randomised study, a clinical effect was obtained after intraperitoneal infusion of catumaxomab in patients with malignant ascites, notably from gastric carcinoma. Catumaxomab, a nonhumanized chimeric antibody, is characterized by its unique ability to bind to three different types of cells: tumour cells expressing the epithelial cell adhesion molecule (EpCAM), T lymphocytes (CD3) and also accessory cells (Fcγ receptor). Because the peritoneum is an immunocompetent organ and up to 90% of gastric carcinomas express EpCAM, intraperitoneal infusion of catumaxomab after complete resection of all macroscopic disease (as defined in the treatment of carcinomatosis from colorectal cancer) could therefore efficiently treat microscopic residual disease.Methods/design: The aim of this randomized phase II study is to assess 2-year overall survival after complete resection of limited carcinomatosis synchronous with gastric carcinoma, followed by an intraperitoneal infusion of catumaxomab with different total doses administered in each of the 2 arms. Close monitoring of peri-opertive mortality, morbidity and early surgical re-intervention will be done with stopping rules. Besides this analysis, translational research will be conducted to determine immunological markers of catumaxomab efficacy and to correlate these markers with clinical efficacy. [ABSTRACT FROM AUTHOR]

We aimed to determine whether immune checkpoint inhibitors (ICI) time-of-day infusion might influence the survival of patients with advanced non-small cell lung cancer (NSCLC). We retrospectively analysed patients who received single-agent anti-PD-(L)1 therapy in any line between 2016 and 2021. We calculated by Cox regression models the association between the proportion of ICI infusions received after 16:30h and overall survival (OS) and progression-free survival (PFS). 180 patients were included, 77% received ICI as second- or further-line (median of 12 infusions/patient). The median age was 65 years (IQR 57–70), 112 patients (62%) were male, 165 (92%) were current or former tobacco smokers, 140 (78%) had performance status (PS) 0 or 1, 26 (14%) were on steroid therapy at ICI initiation. Histology was non-squamous for 139 (77%), the median number of metastatic sites was 3, and 33% had brain metastases. Patients who received at least 20% of ICI infusions after 16:30h (65 out of 180, 36%) had a statistically significant shorter median PFS as compared with patients receiving less than 20% of infusions in the evening (4.9 vs 9.4 months, log-rank p = 0.020), while numerical but not statistical shorter OS was observed (14.0 vs 26.2 months, log-rank p = 0.090). In the multivariate analysis, receiving at least 20% of evening infusions did not significantly increase the risk of death, while PS and line of treatment were significantly correlated with the OS. On the contrary, a proportion of ICI administration after 16:30h ≥20% conferred an HR for the PFS of 1.44 (95% CI: 1.01–2.05, p = 0.043), but this prognostic effect was not found when including in the model the total number of ICI infusions received (HR 1.20, 95% CI: 0.83–1.75, p = 0.329). Time-of-day infusion of ICI may impact the survival of patients with advanced NSCLC. Underlying prognostic characteristics and the number of infusions received could represent conceivable confounding factors, linked to increased variance related to ICI infusion timing. Nonetheless, further studies may unravel chronobiological mechanisms modulating ICI efficacy. • Does immune checkpoint inhibitors (ICI) time-of-day infusion impact on survival? • Retrospective study, advanced NSCLC patients receiving single-agent ICI in any line. • Non-significant shorter OS in patients receiving ≥20% ICI infusions in the evening. • Significant shorter PFS in patients receiving ≥20% ICI infusion in the evening. • Chronobiological mechanisms modulating ICI efficacy should be investigated. [ABSTRACT FROM AUTHOR]

Immunotherapy has gained great interest in thoracic malignancies in the last decade, first in non-small cell lung cancer (NSCLC), but also more recently in small-cell lung cancer (SCLC) and malignant pleural mesothelioma (MPM). However, while 15–20% of patients will greatly benefit from immune checkpoint blockers (ICBs), a vast majority will rapidly exhibit resistance. Reasons for this are multiple: non-immunogenic tumors, immunosuppressive tumor microenvironment or defects in immune cells trafficking to the tumor sites being some of the most frequent. Current progress in adoptive cell therapies could offer a way to overcome these hurdles and bring effective immune cells to the tumor site. In this review, we discuss advantages, limits and future perspectives of adoptive cell therapy (ACT) in thoracic malignancies from lymphokine-activated killer cells (LAK), cytokine-induced killer cells (CIK), natural killer cells (NK), dendritic cells (DC) vaccines and tumor-infiltrating lymphocytes (TILs) to TCR engineering and CARs. Trials are still in their early phases, and while there may still be many limitations to overcome, a combination of these different approaches with ICBs, chemotherapy and/or radiotherapy could vastly improve the way we treat thoracic cancers. [ABSTRACT FROM AUTHOR]

• GEFTREM evaluates tremelimumab plus gefitinib in refractory EGFR -mutant NSCLC • Grade 3 TRAEs occurred in 81% patients, mostly diarrhoea and ALT/AST increase • SD was the best overall response in 72% patients, with a median PFS of 2.2 months • GEFTREM is the only study combining a first-generation EGFR-TKI with an anti-CTLA-4 • Toxicity and limited efficacy prevented further evaluation of tremelimumab plus gefitinib A phase I open-label multicentre study was initiated to evaluate the association of tremelimumab with gefitinib in EGFR -mutant NSCLC patients who progressed after first-generation EGFR-TKI. Here we provide the efficacy data from the entire cohort. Patients with advanced EGFR- mutant NSCLC with progression after response to EGFR-TKI were enrolled. Study treatment was gefitinib 250 mg daily and tremelimumab at 3 dose levels: 3, 6 and 10 mg/kg IV Q4W for 6 cycles followed by Q12W until progression or unacceptable toxicity. The primary objective was safety and tolerability, and to establish a RP2D. Between January 2014 and July 2015, 27 patients (21 in the escalating dose cohort and 6 in expansion cohort) received at least one dose of tremelimumab. DLTs occurred in 4 patients: 1 at 3 mg/kg (one grade 3 diarrhoea), 1 at 6 mg/kg (one grade 3 diarrhoea) and 2 at 10 mg/kg (one grade 3 diarrhoea and one grade 3 AST/ALT increase) of tremelimumab. Grade 3 TRAE occurred in 22 patients (81%), most frequently diarrhoea (30%) and ALT/AST increase (15%). Stable disease was the best overall response in 72% patients, with median PFS of 2.2 months (95% CI, 1.8–4.2). All patients discontinued treatment, most frequently due to disease progression (63% of patients). The recommended dose of tremelimumab in combination with gefitinib in EGFR -mutant NSCLC patients was 3 mg/kg. The gastrointestinal toxicity and the limited efficacy data prevented further evaluation of this combination. (GEFTREM; clinical trial number NCT02040064) [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are standard of care in metastatic renal cell carcinoma but their activity and safety in elderly patients is insufficiently explored. We evaluated outcomes of elderly patients with mRCC treated with nivolumab in the GETUG-AFU 26 NIVOREN phase 2 trial (NCT03013335) and conducted exploratory circulating biomarker analyses. Patients with mRCC were treated with nivolumab after at least one antiangiogenic therapy. The main endpoint of this analysis was safety in patients ≥ 70 years old (y.o), as per the rate of treatment-related grade 3–5 events (TRAE). Secondary endpoints included overall response rate (ORR), progression-free survival (PFS), overall survival. Exploration of candidate biomarkers associated with aging included baseline circulating cytokines involved in inflammation, adhesion, immune checkpoints, angiogenesis (IL6, IL7, IL8, BAFF, CXCL13, VCAM-1, 4–1BB, VEGF). Of 720 patients, 515 were < 70 y.o and 205 ≥ 70 y.o. Patients ≥ 70 y.o exhibited numerically less IMDC poor risk disease (21.0% vs 26.9%), sarcomatoid component (4.9% vs 9.8%) or brain metastases (5.9% vs. 14.7%), but more previous treatment lines (≥ 2 in 54.1% vs 48.5%). TRAE were higher in patients ≥ 70 y.o (24.9% vs. 17.9%, p = 0.033). Respective ORR (19.2% vs. 22.1%) and median PFS (4.5 versus 3.0 months, HR 0.97 [95%CI 0.81–1.15]) were similar. Overall survival was shorter in patients ≥ 70 y.o (19.3 versus 26.9 months, HR 1.26 [95%CI 1.04–1.51]), but not significantly in a competitive risk model. Only V-CAM1 and 4–1BB were found to be increased in patients ≥ 70 y.o. Nivolumab displayed higher grade 3/4 TRAE but manageable toxicity in elderly patients, with sustained activity. Elderly patients did not display specific inflammatory or angiogenic circulating profiles. • Nivolumab displays a favorable safety profile in elderly patients with renal cell carcinoma. • Activity of nivolumab is similar across age groups in the NIVOREN - GETUG AFU 26 trial. • Age alone is not associated with an adverse inflammatory immune landscape. [ABSTRACT FROM AUTHOR]

Drug repositioning refers to the utilization of a known compound in a novel indication underscoring a new mode of action that predicts innovative therapeutic options. Since 1959, alkylating agents, such as the lead compound cyclophosphamide (CTX), have always been conceived, at high dosages, as potent cytotoxic and lymphoablative drugs, indispensable for dose intensity and immunosuppressive regimen in the oncological and internal medicine armamentarium. However, more recent work highlighted the immunostimulatory and/or antiangiogenic effects of low dosing CTX (also called 'metronomic CTX') opening up novel indications in the field of cancer immunotherapy. CTX markedly influences dendritic cell homeostasis and promotes IFN type I secretion, contributing to the induction of antitumor cytotoxic T lymphocytes and/or the proliferation of adoptively transferred T cells, to the polarization of CD4 T cells into TH1 and/or TH17 lymphocytes eventually affecting the Treg/Teffector ratio in favor of tumor regression. Moreover, CTX has intrinsic 'pro-immunogenic' activities on tumor cells, inducing the hallmarks of immunogenic cell death on a variety of tumor types. Fifty years after its Food and Drug Administration approval, CTX remains a safe and affordable compound endowed with multifaceted properties and plethora of clinical indications. Here we review its immunomodulatory effects and advocate why low dosing CTX could be successfully combined to new-generation cancer vaccines. [ABSTRACT FROM AUTHOR]

Background: DC derived-exosomes are nanomeric vesicles harboring functional MHC/peptide complexes capable of promoting T cell immune responses and tumor rejection. Here we report the feasability and safety of the first Phase I clinical trial using autologous exosomes pulsed with MAGE 3 peptides for the immunization of stage III/IV melanoma patients. Secondary endpoints were the monitoring of T cell responses and the clinical outcome. Patients and methods: Exosomes were purified from day 7 autologous monocyte derived-DC cultures. Fifteen patients fullfilling the inclusion criteria (stage IIIB and IV, HLA-A1+, or -B35+ and HLA-DPO4+ leukocyte phenotype, tumor expressing MAGE3 antigen) were enrolled from 2000 to 2002 and received four exosome vaccinations. Two dose levels of either MHC class II molecules (0.13 versus 0.40 × 1014 molecules) or peptides (10 versus 100 μg/ml) were tested. Evaluationswere performed before and 2 weeks after immunization. A continuation treatment was performed in 4 cases of non progression. Results: The GMP process allowed to harvest about 5 × 1014 exosomal MHC class II molecules allowing inclusion of all 15 patients. There was no grade II toxicity and the maximal tolerated dose was not achieved. One patient exhibited a partial response according to the RECIST criteria. This HLA-B35+/A2+ patient vaccinated with A1/B35 defined CTL epitopes developed halo of depigmentation around naevi, a MART1-specific HLA-A2 restricted T cell response in the tumor bed associated with progressive loss of HLA-A2 and HLA-BC molecules on tumor cells during therapy with exosomes. In addition, one minor, two stable and one mixed responses were observed in skin and lymph node sites. MAGE3 specific CD4+ and CD8+ T cell responses could not be detected in peripheral blood. Conclusion: The first exosome Phase I trial highlighted the feasibility of large scale exosome production and the safety of exosome administration. [ABSTRACT FROM AUTHOR]

Human microbiota plays a key role in preserving homeostasis; therefore, alteration in its composition is associated with susceptibility to various diseases. Recent findings suggest that gut microbiota may influence response to cancer treatment, especially immune checkpoint blockers (ICBs). The development of ICBs has changed outcomes of patients with cancer and has allowed sustained recovery. Unfortunately, some patients do not respond to ICBs, and microbiota may be a promising new biomarker to identify patients who will have benefit from ICBs. This review presents relationship between microbiome composition or microbiota-derived metabolites and response to ICBs or immune-related adverse events. Furthermore, we will present different strategies to modulate microbiota composition in patients to enhance ICB efficacy or dampen their toxicities which could lead to the emergence of interesting complementary treatments. • Gut microbiome composition influences response to immune checkpoint blockers (ICBs) • Diversity of gut microbiome associated with better outcomes when treated with ICBs • Microbiota-derived metabolites influence immunity and response to ICBs • Human microbiome as a novel therapeutic target improves outcomes to ICBs [ABSTRACT FROM AUTHOR]

Objective: Primary Sjögren's syndrome (SS) is characterized by a lymphocytic infiltration of salivary glands (SGs) and the presence of an interferon (IFN) signature. SG epithelial cells (SGECs) play an active role in primary SS pathophysiology. We undertook this study to examine the interactions between SGECs and T cells in primary SS and the role of the interleukin‐7 (IL‐7)/IFN axis. Methods: Primary cultured SGECs from control subjects and patients with primary SS were stimulated with poly(I‐C), IFNα, or IFNγ. T cells were sorted from blood and stimulated with IL‐7. CD25 expression was assessed by flow cytometry. SG explants were cultured for 4 days with anti–IL‐7 receptor (IL‐7R) antagonist antibody (OSE‐127), and transcriptomic analysis was performed using the NanoString platform. Results: Serum IL‐7 level was increased in patients with primary SS compared to controls and was associated with B cell biomarkers. IL7R expression was decreased in T cells from patients with primary SS compared to controls. SGECs stimulated with poly(I‐C), IFNα, or IFNγ secreted IL‐7. IL‐7 stimulation increased the activation of T cells, as well as IFNγ secretion. Transcriptomic analysis of SG explants showed a correlation between IL7 and IFN expression. Finally, explants cultured with anti–IL‐7R antibody showed decreased IFN‐stimulated gene expression. Conclusion: These results suggest the presence of an IL‐7/IFNγ amplification loop involving SGECs and T cells in primary SS. IL‐7 was secreted by SGECs stimulated with type I or type II IFN and, in turn, activated T cells that secrete type II IFN. An anti–IL‐7R antibody decreased the IFN signature in T cells in primary SS and could be of therapeutic interest. [ABSTRACT FROM AUTHOR]

More than 25 therapeutic monoclonal antibodies (mAbs) used in oncology have been approved since 1997. Their nature has been largely modified through the last 20 years, from the chimeric IgG1 rituximab with pharmacokinetic parameters specific of murin or chimeric mAbs to humanized or human mAbs. Doses and administration frequency have been chosen based on this nature. More recently, the developed and registered mAbs are mostly IgG1, IgG2, IgG3 or IgG4 humanized or 100% human. Therefore, their behavior is different from the first mAbs authorized leading to lower systemic clearance and shorter half-life due to higher cellular uptake balanced by FcRn recognition with recirculation. The complexity of the pharmacokinetics and the pharmacokinetics/pharmacodynamics relation are increased for antibody-drug conjugates or bispecific T-cell engagers. However, significant number of studies reported pharmacokinetics/pharmacodynamics relations, with positive exposure-response link justifying the exploration of the pharmacokinetics in routine clinical practice of these therapeutic mAbs to prevent treatment failures and to limit their toxicities. • Most of the monoclonal antibodies (mAbs) used in oncology have a pharmacokinetic/pharmacodynamic (PK/PD) relationship. • Antibody–drug conjugates also have a PK/PD relationship. • PK/PD relation is complex as it includes PK of the cytotoxic, the mAb and the ADC. • PK/PD data regarding bispecific antibodies are still lacking. • Therapeutic drug monitoring and dose-adjustment may be of interest for some of these drugs. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies in oncology, used as targeted molecular therapy, linked to cytotoxic compound or directed against immune checkpoints, feature complex PKs essentially determined by their physicochemical characteristics. The increasing number of studies shows the existence of Pharmacokinetics/Pharmacodynamic (PK/PD) relationships for many of them. Although more studies, especially conducted in early clinical phases, are needed, existing studies highlight the need to integrate PK data for monoclonal antibodies in all phases of their development and the therapeutic management of patients with cancer. The current challenge is to identify non-responders as soon as possible. The use of monoclonal antibody dosage to determine the patient's PK profile and, as a result, the disease activity profile could therefore be an early predictive marker to help physicians optimise the strategy to be pursued, including dose adjustment, prolongation of the dose interval or even discontinuation of treatment. • PKs of monoclonal antibodies (mAbs) differ significantly from small molecules. • Distribution is limited to the blood and lymph. • Elimination is mainly due to cellular uptake depending on binding and targets. • Target-mediated drug disposition gives an inherent relationship between PK and PD. • Patient's PK profiles and parameters could be efficient predictive marker of efficacy. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors are monoclonal antibodies (mAbs) directed against negative immunologic regulators that are used to restore the immune response against cancer. Approved drugs include anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4), anti-programmed cell death 1 (PD-1) and anti-programmed cell death-ligand 1 (PD-L1) antibodies exhibiting pharmacokinetic (PK) characteristics typical of mAbs. Most factors such as age, sex, ethnicity, tumour burden, performance status and immunogenicity, but not body weight, do not seem to affect drug clearance clinically. However, an exposure-response relation has been described for both the efficacy and toxicity of anti-CTLA-4 and anti-PD-1 agents. The change in clearance over time is associated with overall response at least for nivolumab and pembrolizumab. Few PK/pharmacodynamic (PD) data are available for anti-PD-L1 mAbs, but time-varying clearance has been described for these drugs, and the high immunogenicity rate observed with atezolizumab may affect PK parameters and should be further studied. These data suggest the need for additional PK/PD studies. In this review, we summarise studies of the PKs of immune checkpoint inhibitors, exploring possible interactions with PD considerations. • A dose and exposure-response relation is evidenced for cytotoxic T-lymphocyte antigen 4. • No dose-response relation is evidenced for anti-programmed cell death 1 (PD1) and anti-programmed cell death-ligand 1(PD-L1). • Combined data suggest an exposure-response relations for these monoclonal antibodies. • An association between time-varying clearance and patient response is evidenced for anti-PD1 and anti-PD-L1. • Studies should be conducted to further understand the pharmacokinetic/pharmacodynamic relations of these drugs. [ABSTRACT FROM AUTHOR]

Résumé: Les anticorps monoclonaux utilisés en cancérologie, qu'ils soient de thérapie moléculaire ciblée, couplés à des cytotoxiques ou dirigés contre les checkpoints immunitaires, présentent une pharmacocinétique complexe essentiellement déterminée par leurs caractéristiques physico-chimiques. Des études démontrent l'existence de relations pharmacocinétiques-pharmacodynamiques pour nombre d'entre eux. Même si celles-ci mériteraient d'être plus nombreuses et d'être menées dès les phases cliniques précoces de manière prospective, elles indiquent la nécessité d'intégrer les données pharmacocinétiques des biothérapies dans la prise en charge thérapeutique des patients atteints de cancer pour en optimiser l'utilisation Monoclonal antibodies in oncology, used as targeted molecular therapy, coupled with cytotoxic or directed against immune checkpoints, present a complex pharmacokinetics essentially determined by their physic-chemical characteristic. Further, an increasing number of studies show the existence of pharmacokinetic-pharmacodynamic relationship for many of them. Although they should be more frequent and should be conducted prospectively in the early clinical phases, these studies point out the need to integrate pharmacokinetic data of these biologics in the therapeutic management of cancer patients to optimize their use. [ABSTRACT FROM AUTHOR]

Abstract Immune checkpoint blockade has been a pivotal development in the management of advanced non–small-cell lung cancer (NSCLC). Although durable antitumour activity and improved survival have been observed in a subset of patients, there is a need for additional predictive biomarkers to improve patient selection and avoid toxicity in potential non-responders. This review will address the use and limitations of tumour programmed death-ligand 1 expression as a predictive biomarker and review emerging biomarker strategies specifically related to NSCLC including genetic alterations (tumour mutation burden, loss and gain activated mutations), tumour-related factors (tumour microenvironment) and factors related to the host immune system. Novel approaches in biomarker detection such as peripheral blood monitoring will also be reviewed. Highlights • At present, tumour PD-L1 expression is the only approved biomarker, albeit imperfect, used in clinical practice for PD-(L)1 blockade in NSCLC. • Tumour Mutational Burden may enter clinical practice as a biomarker to select patients who are potential candidates for dual immune blockade. • Several biomarker strategies specifically related to NSCLC are under investigation. • Tumour-related factors such as genetic alterations and tumour microenvironment play a crucial role and are relevant for a prediction role. • Factors related to the host immune system (peripheral blood biomarkers etc.) and their combination with other biomarkers will be the next future. [ABSTRACT FROM AUTHOR]

Abstract Background Immune checkpoint inhibitors (ICIs), such as anti–CTLA-4 and anti–PD-1 antibodies, are effective against several malignancies. They are associated with gastrointestinal immune-related adverse events (GI-IrAEs), which may be severe and lead to ICI discontinuation. We assessed the risk of evolution of GI-IrAEs to chronic GI inflammation and the risk of recurrence after a second line of ICI. Patients and methods This was a single-centre study. Included patients had a GI-IrAE due to ICIs between September 2010 and July 2017. We assessed the persistence of symptoms, endoscopic and/or histological inflammation, and the risk of recurrent GI-IrAEs after the second line of ICIs. Results Eighty patients were included. The median follow-up was 8.4 months (0.36–72.3). The median duration of GI symptoms was 1.5 months (5 days–10.3 months): 1.4 months (7 days–4.9 months) with anti–CTLA-4, 2.0 months (5 days–10.3 months) with anti–PD-1 and 1.0 month (8 days–3.4 months) with combination therapy (log-rank test: p = 0.02). Three and 6 months after the beginning of GI-IrAEs, 22% (95% confidence interval: 14%–33%) and 5.4% (2.0%–14.7%) of patients had persistent symptoms, respectively. After a median of 6 months, 20/27 patients had endoscopic and/or histological inflammation, of whom, seven were symptom free. After the first episode, 6/26 patients relapsed after receiving another course of ICIs. Among these 26, 89% (77%–100%) had no recurrence after 3 months, 71% or 95% if the second line was anti–CTLA-4 or anti–PD-1, respectively. Conclusion GI-IrAEs seem to be acute or subacute, not chronic. Reintroduction of ICIs is possible in patients who had GI-IrAE. Highlights • Gastrointestinal immune-related adverse events (GI-IrAEs) due to immune checkpoint inhibitors (ICIs) appear time limited: • Seventy-eight percent of patients with GI-IrAEs are symptom free 3 months after the first symptoms. • Symptoms persist longer in those treated with anti–PD-1 than with anti–CTLA-4. • The risk of recurrent GI-IrAEs after ICI reintroduction seems limited: • Eighty-nine percent of patients have no recurrence after 3 months. [ABSTRACT FROM AUTHOR]

Background: Recently, the intervention calculus when the DAG is absent (IDA) method was developed to estimate lower bounds of causal effects from observational high-dimensional data. Originally it was introduced to assess the effect of baseline biomarkers which do not vary over time. However, in many clinical settings, measurements of biomarkers are repeated at fixed time points during treatment and, therefore, this method needs to be extended. The purpose of this paper is to extend the first step of the IDA, the Peter Clarks (PC)-algorithm, to a time-dependent exposure in the context of a binary outcome.Methods: We generalised the so-called "PC-algorithm" to take into account the chronological order of repeated measurements of the exposure and proposed to apply the IDA with our new version, the chronologically ordered PC-algorithm (COPC-algorithm). The extension includes Firth's correction. A simulation study has been performed before applying the method for estimating causal effects of time-dependent immunological biomarkers on toxicity, death and progression in patients with metastatic melanoma.Results: The simulation study showed that the completed partially directed acyclic graphs (CPDAGs) obtained using COPC-algorithm were structurally closer to the true CPDAG than CPDAGs obtained using PC-algorithm. Also, causal effects were more accurate when they were estimated based on CPDAGs obtained using COPC-algorithm. Moreover, CPDAGs obtained by COPC-algorithm allowed removing non-chronological arrows with a variable measured at a time t pointing to a variable measured at a time t´ where t´ < t. Bidirected edges were less present in CPDAGs obtained with the COPC-algorithm, supporting the fact that there was less variability in causal effects estimated from these CPDAGs. In the example, a threshold of the per-comparison error rate of 0.5% led to the selection of an interpretable set of biomarkers.Conclusions: The COPC-algorithm provided CPDAGs that keep the chronological structure present in the data and thus allowed to estimate lower bounds of the causal effect of time-dependent immunological biomarkers on early toxicity, premature death and progression. [ABSTRACT FROM AUTHOR]

Immunotherapy targeting and blocking immune checkpoint, such as anti-CTLA- 4 (ipilimumab), anti-PD-1 (nivolumab, pembrolizumab) and anti-PD-L-1 (avelumab, atezolizumab) monoclonal mAbs are new immunotherapies in the treatment of patients with cancer. Nevertheless, these drugs can induce immune-related adverse events similar to auto-immune and inflammatory diseases. Enterocolitis is a frequent toxicity induced by these treatments. This adverse event may be severe, and may require immunosuppressive therapy as well as discontinuation of immunotherapy. Currently, the number of patients receiving these molecules is increasing and therapeutic combinations are in development. Gastroenterologists will be increasingly faced with the diagnosis and treatment of this type of enterocolitis. The purpose of this review is to help to recognize and manage enterocolitis induced by immune checkpoint blockers and to discuss current research issues in this field. [ABSTRACT FROM AUTHOR]

Immune checkpoint inhibitors have demonstrated unprecedented clinical activity in a wide range of cancers. Significant therapeutic responses have recently been observed in patients presenting mismatch repair-deficient (MMRD) tumours. MMRD cancers exhibit a remarkably high rate of mutations, which can result in the formation of neoantigens, hypothesised to enhance the antitumour immune response. In addition to MMRD tumours, cancers mutated in the exonuclease domain of the catalytic subunit of the DNA polymerase epsilon ( POLE ) also exhibit an ultramutated genome and are thus likely to benefit from immunotherapy. In this review, we provide an overview of recent data on hypermutated tumours, including MMRD and POLE -mutated cancers, with a focus on their distinctive clinicopathological and molecular characteristics as well as their immune environment. We also discuss the emergence of immune therapy to treat these hypermutated cancers, and we comment on the recent Food and Drug Administration approval of an immune checkpoint inhibitor, the programmed cell death 1 antibody (pembrolizumab, Keytruda), for the treatment of patients with metastatic MMRD cancers regardless of the tumour type. This breakthrough represents a turning point in the management of these hypermutated tumours and paves the way for broader strategies in immunoprecision medicine. [ABSTRACT FROM AUTHOR]

Introduction The class I human leucocyte antigen (HLA) molecules play a critical role as an escape mechanism of antitumoral immunity. HLA-A2 status has been evaluated as a prognostic factor in lung cancer, mostly in localized disease and with inconsistent findings. We evaluated the role of HLA-A2 status as a prognostic factor in a large and homogeneus cohort of advanced NSCLC patients. Methods Advanced NSCLC patients eligible for platinum-based chemotherapy were consecutively included in a single center between October 2009 and July 2015 in the prospective MSN study (NCT02105168). HLA-A2 status was analysed by flow cytometry. Clinical, pathological and molecular data were collected. A Cox model was used for prognostic analyses. Results Of 545 stage IIIB/IV NSCLC patients included, 344 (63%) were male, 466 (85%) were smokers, 447 (83%) had PS 0–1, 508 (93%) had stage IV, 407 (75%) had an adenocarcinoma and median age was 61 years (range, 21–84). Incidence of patients with EGFRmut , ALK -positive and KRASmut was 14% (49/361), 9% (29/333) and 31% (107/350), respectively. The overall rate of HLA-A2 positivity was 48%. No association was observed between HLA-A2 status and any patient or tumor characteristics analyzed. With a median follow-up of 27.1 months, median OS was 12.8 months [95%CI 11.0–14.6] in HLA-A2+ vs. 12.5 months [95%CI 10.4–15.3] in HLA-A2- patients (HR 1.05 [95%CI 0.86–1.29], p = 0.61). Median progression-free survival was similar in the two cohorts. Conclusion HLA-A2 status was not identified as prognostic for benefit in a large advanced NSCLC population treated with platinum-based chemotherapy. [ABSTRACT FROM AUTHOR]

Checkpoint inhibitors blocking CTLA-4 (ipilimumab) and PD-1 (nivolumab, pembrolizumab) have transfigured our cancer treatment paradigm. However, these drugs can induce immune-related adverse events that share clinical and pathological characteristics with immune-mediated diseases. One of the most severe immune-related adverse event observed with anti-CTLA-4 is an enterocolitis that mirrors naturally occurring inflammatory bowel disease. This paper reviews the clinical, immunological, and microbiota data associated with the immune-related enterocolitis induced by the cancer immunotherapy blocking CTLA-4, ipilimumab. A parallel analysis of the mechanisms underlying inflammatory bowel diseases on the one hand, and anti-CTLA-4-induced colitis on the other hand, stresses the crucial role of the gut microbiota and of resident T in the genesis of both iatrogenic and spontaneous inflammatory bowel diseases. [ABSTRACT FROM AUTHOR]

NK cells are critical for innate immunity-mediated protection. The main roles of NK cells rely on their cytotoxic functions or depend on the tuning of Th1 adaptive immunity by IFN-γ. However, the precise influence of inflammatory cytokines on NK cell and CD4 T lymphocyte interactions was never investigated. In this study, we provide evidence that IL-21, a cytokine produced during chronic inflammation or infectious diseases, promotes the differentiation of a specific subset of NK cells coexpressing CD86 and HLA-DR and lacking NKp44. More importantly, IL-21-propagated HLA-DR+ NK cells produce macrophage migration inhibitory factor and provide costimulatory signaling during naive CD4+ T cell priming inducing the differentiation of uncommitted central memory T cells. Central memory T cells expanded in the presence of HLA-DR+ NK cells are CXCR3+CCR62 CCR42CXCR52 and produce IL-2, as well as low levels of TNF-α. Costimulation of CD4+ T cells by HLA-DR+ NK cells prevents the acquisition of effector memory phenotype induced by IL-2. Moreover, we identified this population of NK HLA-DR+ macrophage migration inhibitory factor+ cells in inflammatory human appendix. Collectively, these results demonstrate a novel function for IL-21 in tuning NK and CD4+ T cell interactions promoting a specific expansion of central memory lymphocytes. [ABSTRACT FROM AUTHOR]

Tumors with the help of the surrounding environment facilitate the immune suppression in patients, and immunotherapy can counteract this inhibition. Among immunotherapeutic strategies, the immunostimulatory cytokine IL-15 could represent a serious candidate for the reactivation of antitumor immunity. However, exogenous IL-15 may have a limited impact on patients with cancer due to its dependency on IL-15Ra frequently downregulated in cancer patients. In this work, we studied the antitumor activity of the IL-15 superagonist receptor-linker-IL-15 (RLI), designed to bypass the need of endogenous IL-15Ra. RLI consists of human IL-15 covalently linked to the human IL-15Ra sushi+ domain. In a mouse model of colorectal carcinoma, RLI as a stand-alone treatment could limit tumor outgrowth only when initiated at an early time of tumor development. At a later time, RLI was not effective, coinciding with the strong accumulation of terminally exhausted programmed cell death-1 (PD-1)high T cell Ig mucin-3+ CD8+ T cells, suggesting that RLI was not able to reactivate terminally exhausted CD8+ T cells. Combination with PD-1 blocking Ab showed synergistic activity with RLI, but not with IL-15. RLI could induce a greater accumulation of memory CD8+ T cells and a stronger effector function in comparison with IL-15. Ex vivo stimulation of tumor-infiltrated lymphocytes from 16 patients with renal cell carcinoma demonstrated 56% of a strong tumor-infiltrated lymphocyte reactivation with the combination anti-PD-1/RLI compared with 43 and 6% with RLI or anti-PD-1, respectively. Altogether, this work provides evidence that the sushi-IL-15Ra/IL-15 fusion protein RLI enhances antitumor activity of anti-PD-1 treatment and is a promising approach to stimulate host immunity. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs), such as exosomes and microvesicles, are released by different cell types and participate in physiological and pathophysiological processes. EVs mediate intercellular communication as cell-derived extracellular signalling organelles that transmit specific information from their cell of origin to their target cells. As a result of these properties, EVs of defined cell types may serve as novel tools for various therapeutic approaches, including (a) anti-tumour therapy, (b) pathogen vaccination, (c) immune-modulatory and regenerative therapies and (d) drug delivery. The translation of EVs into clinical therapies requires the categorization of EV-based therapeutics in compliance with existing regulatory frameworks. As the classification defines subsequent requirements for manufacturing, quality control and clinical investigation, it is of major importance to define whether EVs are considered the active drug components or primarily serve as drug delivery vehicles. For an effective and particularly safe translation of EV-based therapies into clinical practice, a high level of cooperation between researchers, clinicians and competent authorities is essential. In this position statement, basic and clinical scientists, as members of the International Society for Extracellular Vesicles (ISEV) and of the European Cooperation in Science and Technology (COST) program of the European Union, namely European Network on Microvesicles and Exosomes in Health and Disease (ME-HaD), summarize recent developments and the current knowledge of EV-based therapies. Aspects of safety and regulatory requirements that must be considered for pharmaceutical manufacturing and clinical application are highlighted. Production and quality control processes are discussed. Strategies to promote the therapeutic application of EVs in future clinical studies are addressed. [ABSTRACT FROM AUTHOR]

Exosomes are nanometric membrane vesicles of late endosomal origin released by most, if not all, cell types as a means of sophisticated intercellular communication. A multitude of studies showed how exosomes can mediate and regulate immune responses against tumors. Dendritic cell-derived exosomes (Dex) have received much attention as immunotherapeutic anticancer agents since the discovery that they harbor functional MHC-peptide complexes, in addition to various other immune-stimulating components, that together facilitate immune cell-dependent tumor rejection. The therapeutic potential of Dex has been substantiated with their development and clinical testing in the treatment of cancer. This review focuses on mechanisms by which Dex interact with and influence immune cells and describes how they can be engineered to promote their immunogenic capacity as novel and dynamic anticancer agents. [ABSTRACT FROM AUTHOR]

Catumaxomab (CatmAb), a trifunctional bispecific antibody directed against the epithelial cell adhesion molecule (EpCAM) and the T-cell antigen CD3, is approved as intraperitoneal therapy for the treatment of malignant ascites in patients with EpCAM-positive carcinomas. The immunomonitoring results of a phase II/III study using CatmAb revealed a tumoricidal effect associated with reduced VEGF levels, CD69-expressing T cells, and the release of T-helper cell (TH)-1 cytokines. We comprehensively dissected the immunomodulatory effects of the CatmAb on the major subsets of malignant ascites-infiltrating leukocytes and the molecular fingerprint of tumor cell death. Herein we show that in the presence of EpCAM-positive tumor targets, CatmAb markedly enhanced T-cell activation [CD69, CD107A (LAMP1), HLA-DR and PD-1(PDCD1) expression] and stimulated inflammatory CD4 + TH1 and CD8 + TH1 to release IFN-Υ but failed to trigger TH17 cells. Engagement of CD16-expressing cells caused upregulation of TRAIL (TNFSF10) and costimulatory CD40 and CD80 molecules. CatmAb promoted tumor cell death associated with ATP release and strongly synergized with oxaliplatin for the exposure of the three hallmarks of immunogenic cell death (calreticulin, HMGB1, and ATP). These findings warrant validation as potential biomarkers of efficacy of CatmAb. [ABSTRACT FROM AUTHOR]

Imatinib mesylate (IM) is a small molecule inhibitor of protein tyrosine kinases. In addition to its direct effect on malignant cells, it has been suggested IM may activate of natural killer (NK) cells, hence exerting immunomodulatory functions. In preclinical settings, improved antitumor responses have been observed when IM and interleukin-2 (IL-2), a cytokine that enhances NK cells functions, were combined. The goals of this study were to determine the maximum tolerated dose (MTD) of IL-2 combined with IM at a constant dose of 400 mg, the pharmacokinetics of IM and IL-2, as well as toxicity and clinical efficacy of this immunotherapeutic regimen in patients affected by advanced tumors. The treatment consisted in 50 mg/day cyclophosphamide from 21 d before the initiation of IM throughout the first IM cycle (from D-21 to D14), 400 mg/day IM for 14 d (D1 to D14) combined with escalating doses of IL-2 (3, 6, 9 and 12 MIU/day) from days 10 to 14. This treatment was administered at three week intervals to 17 patients. Common side effects of the combination were mild to moderate, including fever, chills, fatigue, nausea and hepatic enzyme elevation. IL-2 dose level II, 6 MIU/day, was determined as the MTD with the following dose-limiting toxicities: systemic capillary leak syndrome, fatigue and anorexia. Pharmacokinetic studies revealed that the area under the curve and the maximum concentration of IM and its main metabolite CGP74588 increased significantly when IM was concomitantly administered with IL-2. In contrast, IM did not modulate IL-2 pharmacokinetics. No objective responses were observed. The best response obtained was stable disease in 8/17 (median duration: 12 weeks). Finally, IL-2 augmented the impregnation of IM and its metabolite. The combination of IM (400 mg/day) and IL-2 (6 MIU/day) in tumors that express IM targets warrants further investigation. [ABSTRACT FROM AUTHOR]

During cancer development, a number of regulatory cell subsets and immunosuppressive cytokines subvert adaptive immune responses. Although it has been shown that tumor-derived interleukin (IL)-18 participates in the PD-1--dependent tumor progression in NK cell--controlled cancers, the mechanistic cues underlying this immunosuppression remain unknown. Here, we show that IL-18 converts a subset of Kit- (CD11b-) into Kit+ natural killer (NK) cells, which accumulate in all lymphoid organs of tumor bearers and mediate immunoablative functions. Kit+ NK cells overexpressed B7-H1/PD-L1, a ligand for PD-1. The adoptive transfer of Kit+ NK cells promoted tumor growth in two pulmonary metastases tumor models and significantly reduced the dendritic and NK cell pools residing in lymphoid organs in a B7-H1--dependent manner. Neutralization of IL-18 by RNA interference in tumors or systemically by IL-18--binding protein dramatically reduced the accumulation of Kit+CD11b-NK cells in tumor bearers. Together, our findings show that IL-18 produced by tumor cells elicits Kit+CD11b-NK cells endowed with B7-H1--dependent immunoablative functions in mice. [ABSTRACT FROM AUTHOR]

By revisiting CD90, a GPI-anchored glycoprotein, we show that CD90 is expressed by a subset of CD4+ and CD8+ human T cells. CD4+CD90+ cells share similarities with Th17 cells because they express the Th17-specific transcription factor RORC2 and produce IL-17A. CD4+CD90+ cells are activated memory T cells that express the gut mucosal markers CCR6, CD161, and the α(4) and β(7) integrins. Compared with CD90-depleted CCR6+ memory Th17 cells, CD4+CD90+ cells express higher levels of IL-22 and proinflammatory cytokines (IL-6, TNF-α and GM-CSF), but they produce lower levels of IL-21 and no IL-9. Analyses of CD8+CD90+ cells reveal that they express RORC2 and are able to produce higher levels of IL-17A, IL-22, and CCL20 compared with CD90-depleted CD8+ cells. These data show that CD90 identifies Th17 and Tc17 cells with a peculiar cytokine profile. Studies of circulating CD90+ cells in HIV patients show that CD90+ cells are decreased with an imbalance of the CD4+CD90+/regulatory T cell ratio in nontreated patients compared with treated patients and healthy donors. Overall, human CD90 identifies a subset of Th17 and Tc17 cells within CD4+ and CD8+ T cells, respectively, which are depleted during HIV infection. [ABSTRACT FROM AUTHOR]

Detection of human Ag-specific T cells is limited by sensitivity and blood requirements. As dendritic cells (DCs) can potently stimulate T cells, we hypothesized that their induction in PBMCs in situ could link Ag processing and presentation to Ag-specific T-cell activation. To this end, unfractionated PBMCs (fresh or frozen) or whole blood were incubated for 48 hours with protein or peptide Ag together with different DC-activating agents to rapidly and sequentially induce, pulse, and mature DCs. DC activation was therefore lined up with Ag recognition by neighboring T cells, thus telescoping the sequential steps of T-cell activation. Efficient processing of protein Ags made prior knowledge of epitopes and HLA restrictions dispensable. While reducing stimulation time, manipulation and blood requirements, in situ DC induction specifically amplified Ag-specific T-cell responses (cytokine secretion, proliferation, CD137/CD154 up-regulation, and binding of peptide-HLA multimers). IL-1β, although released by DCs, was also secreted in an Ag-specific fashion, thus providing an indirect biomarker of T-cell responses. These accelerated cocultured DC (acDC) assays offered a sensitive means with which to evaluate T-cell responses to viral and melanoma Ag vaccination, and may therefore find application for immune monitoring in viral, tumor, autoimmune, and transplantation settings. [ABSTRACT FROM AUTHOR]

Immunosuppressive cytokines subvert innate and adaptive immune responses during cancer progression. The inflammatory cytokine interleukin-18 (IL-18) is known to accumulate in cancer patients, but its pathophysiological role remains unclear. In this study, we show that low levels of circulating IL-18, either exogenous or tumor derived, act to suppress the NK cell arm of tumor immunosurveillance. IL-18 produced by tumor cells promotes the development of NK-controlled metastases in a PD-1-dependent manner. Accordingly, PD-1 is expressed by activated mature NK cells in lymphoid organs of tumor bearers and is upregulated by IL-18. RNAi-mediated knockdown of IL-18 in tumors, or its systemic depletion by IL-18-binding protein, are sufficient to stimulate NK cell-dependent immunosurveillance in various tumor models. Together, these results define IL-18 as an immunosuppressive cytokine in cancer. Our findings suggest novel clinical implementations of anti-PD-1 antibodies in human malignancies that produce IL-18. Cancer Res; 71(16); 5393-9. ©2011 AACR. [ABSTRACT FROM AUTHOR]

The natural killer (NK) cell receptor NKp30 is involved in the recognition of tumor and dendritic cells (DCs). Here we describe the influence of three NKp30 splice variants on the prognosis of gastrointestinal sarcoma (GIST), a malignancy that expresses NKp30 ligands and that is treated with NK-stimulatory KIT tyrosine kinase inhibitors. Healthy individuals and those with GIST show distinct patterns of transcription of functionally different NKp30 isoforms. In a retrospective analysis of 80 individuals with GIST, predominant expression of the immunosuppressive NKp30c isoform (over the immunostimulatory NKp30a and NKp30b isoforms) was associated with reduced survival of subjects, decreased NKp30-dependent tumor necrosis factor-α (TNF-α) and CD107a release, and defective interferon-γ (IFN-γ) and interleukin-12 (IL-12) secretion in the NK-DC cross-talk that could be restored by blocking of IL-10. Preferential NKp30c expression resulted partly from a single-nucleotide polymorphism at position 3790 in the 3′ untranslated region of the gene encoding NKp30. The genetically determined NKp30 status predicts the clinical outcomes of individuals with GIST independently from KIT mutation. [ABSTRACT FROM AUTHOR]

Dendritic cell (DC) derived-exosomes (Dex) are nanomeric vesicles harboring functional MHC/peptide complexes promoting T cell-dependent tumor rejection. In the first Phase I trial using peptide-pulsed Dex, the observation of clinical regressions in the absence of T cell responses prompted the search for alternate effector mechanisms. Mouse studies unraveled the bioactivity of Dex on NK cells. Indeed, Dex promoted an IL-15Ra- and NKG2D-dependent NK cell proliferation and activation respectively, resulting in anti-metastatic effects mediated by NK1.1+ cells. In humans, Dex express functional IL-15Rα which allow proliferation and IFNγ secretion by NK cells. In contrast to immature DC, human Dex harbor NKG2D ligands on their surface leading to a direct engagement of NKG2D and NK cell activation ex vivo. In our phase I clinical trial, we highlight the capacity of Dex based-vaccines to restore the number and NKG2D-dependent function of NK cells in 7/14 patients. Altogether, these data provide a mechanistic explanation on how Dex may stimulate non MHC restricted-anti-tumor effectors and induce tumor regression in vivo. [ABSTRACT FROM AUTHOR]

Tumors can regress as a result of invading myeloid and lymphoid cells that act in concert. Although the myeloid cells are widely recognized as antigen presenters and lymphoid cells as classical effectors, recent evidence revealed the capacity of dendritic cells (DC) to kill tumor cells. The functional concept of ‘natural killer (NK) myeloid DC’ is supported by mouse and human in vitro data that may be clinically relevant because human killer DC can contribute to tumor shrinking during topical therapy with toll-like receptor (TLR) agonists. Whether tumor killing by DC is a ‘catalyzing’ step for efficient crosspresentation and/or a promoting step for an immunogenic cell death pathway remains an open question. We also discuss how interferon-producing killer DC (IKDC) may participate in the control of tumor progression. [Copyright &y& Elsevier]

Natural killer (NK) cells influence innate and adaptive immune host defenses. Existing data indicate that manipulating the balance between inhibitory and activating NK receptor signals, the sensitivity of target cells to NK cell-mediated apoptosis, and NK cell cross-talk with dendritic cells might hold therapeutic promise. Efforts to modulate NK cell trafficking into inflamed tissues and/or lymph nodes, and to counteract NK cell suppressors, might also prove fruitful in the clinic. However, deeper investigation into the benefits of combination therapy, greater understanding of the functional distinctions between NK cell subsets, and design of new tools to monitor NK cell activity are needed to strengthen our ability to harness the power of NK cells for therapeutic aims. [ABSTRACT FROM AUTHOR]

Abstract: Tumor growth results from a delicate balance between intrinsic dysregulation of oncogenes, tumor suppressor and stability genes counteracted by extrinsic defenses composed of immune cells shaping tumor immunogenicity. Although immune subversion might be the ultimate outcome of this process, a complex network of cellular interactions take place eventually leading to tumor specific cognate immune responses. The links between innate and cognate antitumor immunity eliciting protective T cell responses are instigated by cytokines, chemokines and damage associated molecular patterns. The intricate differentiation pathway whereby dendritic cells could undergo an efficient maturation program in the tumor microenvironment appears crucial. We will discuss the role of innate effectors and cancer therapies in the process of defense against tumor cells. [Copyright &y& Elsevier]

The conventional treatment of cancer relies upon radiotherapy and chemotherapy. Such treatments supposedly mediate their effects via the direct elimination of tumor cells. Nonetheless, there are circumstances in which conventional anti-cancer therapy can induce a modality of cellular demise that elicits innate and cognate immune responses, which in turn mediate part of the anti-tumor effect. Although different chemotherapeutic agents may kill tumor cells through an apparently homogeneous apoptotic pathway, they differ in their capacity to stimulate immunogenic cell death. We discovered that the pre-apoptotic translocation of intracellular calreticulin (endo-CRT) to the plasma membrane surface (ecto-CRT) is critical for the recognition and engulfment of dying tumor cells by dendritic cells. Thus, anthracyclines and γ-irradiation that induce ecto-CRT cause immunogenic cell death, while other pro-apoptotic agents (such as mitomycin C and etoposide) induce neither ecto-CRT nor immunogenic cell death. Depletion of CRT abolishes the immunogenicity of cell death elicited by anthracyclines, while exogenous supply of CRT or enforcement of CRT exposure by pharmacological agents that favor CRT translocation can enhance the immunogenicity of cell death. For optimal anti-tumor vaccination and immunogenic chemotherapy, the same cells have to expose ecto-CRT and to succumb to apoptosis; if these events affect different cells, no anti-tumor immune response is elicited. These results may have far reaching implications for tumor immunology because (i) ecto-CRT exposure by tumor cells allows for the prediction of therapeutic outcome and because (ii) the re-establishment of ecto-CRT may ameliorate the efficacy of chemotherapy. [ABSTRACT FROM AUTHOR]

For the last four decades, the treatment of cancer has relied on four treatment modalities, namely surgery, radiotherapy, cytotoxic chemotherapy, and hormonotherapy. Most of these therapies are believed to directly attack and eradicate tumor cells. The emerging concept that cancer is not just a disease of a tissue or an organ but also a host disease relies on evidence of tumor-induced immunosuppression and polymorphisms in genes involved in host protection against tumors. This theory is now gaining new impetus, based on our recent data showing that optimal therapeutic effects require the immunoadjuvant effect of tumor cell death induced by cytotoxic anticancer agents. Here, we show that the release of the high mobility group box 1 protein (HMGB1) by dying tumor cells is mandatory to license host dendritic cells (DCs) to process and present tumor antigens. HMGB1 interacts with Toll-like receptor 4 (TLR4) on DCs, which are selectively involved in the cross-priming of anti-tumor T lymphocytes in vivo. A TLR4 polymorphism that affects the binding of HMGB1 to TLR4 predicts early relapse after anthracycline-based chemotherapy in breast cancer patients. This knowledge may be clinically exploited to predict the immunogenicity and hence the efficacy of chemotherapeutic regimens. [ABSTRACT FROM AUTHOR]