HCT-116 colorectal cancer cells secrete chemokines which induce chemoattraction and intracellular calcium mobilization in NK92 cells
AbstractWe recently reported that pretreatment of IL-2 activated human natural killer (NK) cells with the drugs dimethyl fumarate (DMF) and monomethyl fumarate (MMF) upregulated the expression of surface chemokine receptor CCR10. Ligands for CCR10, namely CCL27 and CCL28, induced the chemotaxis of these cells. Here, we performed a bioinformatics analysis to see which chemokines might be expressed by the human HCT-116 colorectal cancer cells. We observed that, in addition to CCL27 and CCL28, HCT-116 colorectal cancer cells profoundly express CXCL16 which binds CXCR6. Consequently, NK92 cells were treated with DMF and MMF fo...
Source: Cancer Immunology, Immunotherapy - March 7, 2019 Category: Cancer & Oncology Source Type: research

Absolute numbers of regulatory T cells and neutrophils in corticosteroid-free patients are predictive for response to bevacizumab in recurrent glioblastoma patients
AbstractBevacizumab (Bv) remains frequently prescribed in glioblastoma (GBM) patients, especially at recurrence. We conducted a prospective clinical trial with 29 recurrent GBM patients treated with Bv alone with a longitudinal follow-up of different circulating immune cells [complete blood count, myeloid-derived suppressor cells (MDSCs), classical, intermediate, non-classical and Tie2 monocytes, VEGFR1+ and regulatory T cells (Treg)]. We observed a significant increase for leucocytes, neutrophils, eosinophils and classical monocytes and a decrease for the fraction of Treg during the treatment. The best prognostic values f...
Source: Cancer Immunology, Immunotherapy - March 4, 2019 Category: Cancer & Oncology Source Type: research

Expression of a soluble IL-10 receptor enhances the therapeutic effects of a papillomavirus-associated antitumor vaccine in a murine model
In conclusion, the proposed treatment involving the expression of IL-10R enhanced the antitumor protective immunity induced by pgDE7h administration and may contribute to the development of more efficient clinical interventions against HPV-induced tumors. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 26, 2019 Category: Cancer & Oncology Source Type: research

First-line therapy-stratified survival in BRAF-mutant melanoma: a retrospective multicenter analysis
ConclusionFirst-line treatment with a PD-1 blocking antibody might be associated with longer OS than first-line inhibition of the MAPK pathway in patients with advanced melanoma harboring mutant BRAF. These hypothesis-generating data need to be confirmed or rejected in prospective, randomized trials. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 26, 2019 Category: Cancer & Oncology Source Type: research

Melanoma-associated antigen-A and programmed death-ligand 1 expression are associated with advanced urothelial carcinoma
ConclusionMAGE-A and PD-L1 expression is increased in advanced disease and associated with shorter PFS. Furthermore, MAGE-A expression was significantly associated with higher-grade and -stage disease and associated with shorter RFS and PFS. The worse prognosis associated with MAGE-A+/PD-L1+  provides evidence that a combinatorial treatment strategy co-targeting MAGE/PD-L1 might be feasible. Further studies are needed to validate these findings. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 21, 2019 Category: Cancer & Oncology Source Type: research

Natural T cell autoreactivity to melanoma antigens: clonally expanded melanoma-antigen specific CD8  + memory T cells can be detected in healthy humans
AbstractWe used four-color ImmunoSpot ® assays, in conjunction with peptide pools that cover the sequence of tyrosinase (Tyr), melanoma-associated antigen A3 (MAGE-A3), melanocyte antigen/melanoma antigen recognized by T cells 1 (Melan-A/MART-1), glycoprotein 100 (gp100), and New York esophageal squamous cell carcinoma-1 (NY-ESO-1) to characterize the melanoma antigen (MA)-specific CD8 + cell repertoire in PBMC of 40 healthy human donors (HD). Tyr triggered interferon gamma (IFN-γ)-secreting CD8 + T cells in 25% of HD within 24 h of antigen stimulation ex vivo. MAGE-A3, Melan-A/MA...
Source: Cancer Immunology, Immunotherapy - February 19, 2019 Category: Cancer & Oncology Source Type: research

A phase I/IIa study of the mRNA-based cancer immunotherapy CV9201 in patients with stage IIIB/IV non-small cell lung cancer
AbstractCV9201 is an RNActive®-based cancer immunotherapy encoding five non-small cell lung cancer-antigens: New York esophageal squamous cell carcinoma-1, melanoma antigen family C1/C2, survivin, and trophoblast glycoprotein. In a phase I/IIa dose-escalation trial, 46 patients with locally advanced (n = 7) or metastatic (n = 39) NSCLC and at least stable disease after first-line treatment received five intradermal CV9201 injections (400–1600 µg of mRNA). The primary objective of the trial was to assess safety. Secondary objectives included assessment of antibody and ex vivo...
Source: Cancer Immunology, Immunotherapy - February 15, 2019 Category: Cancer & Oncology Source Type: research

Tumor infiltrating mast cells determine oncogenic HIF-2 α-conferred immune evasion in clear cell renal cell carcinoma
AbstractPurposeHypoxia-inducible factor 2 α (HIF-2α) overexpression leads to activation of angiogenic pathways. However, little is known about the association between HIF-2α expression and anti-tumor immunity in clear cell renal cell carcinoma (ccRCC). We aimed to explore how HIF-2α influenced the microenvironment and the underlying mec hanisms.Experimental designWe immunohistochemically evaluated immune cells infiltrations and prognostic value of HIF-2 α expression in a retrospective Zhongshan Hospital cohort of 280 ccRCC patients. Fresh tumor samples, non-tumor tissues and autologous periphe...
Source: Cancer Immunology, Immunotherapy - February 13, 2019 Category: Cancer & Oncology Source Type: research

Phase II clinical trial of adoptive cell therapy for patients with metastatic melanoma with autologous tumor-infiltrating lymphocytes and low-dose interleukin-2
This study shows that this protocol of low-dose IL-2 following adoptive cell transfer of TIL is feasible and clinically active. (ClinicalTrials.gov identifier NCT01883323.) (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 11, 2019 Category: Cancer & Oncology Source Type: research

Metronomic cyclophosphamide attenuates mTOR-mediated expansion of regulatory T cells, but does not impact clinical outcome in patients with metastatic renal cell cancer treated with everolimus
ConclusionAlthough the comprehensive immunomonitoring analysis performed in this study provides relevant information for the design of future immunotherapeutic approaches, the addition of metronomic cyclophosphamide to mRCC patients receiving everolimus cannot be recommended. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 11, 2019 Category: Cancer & Oncology Source Type: research

Imbalances in cellular immunological parameters in blood predetermine tumor onset in a natural mouse model of breast cancer
In this study, we focused on revealing informative CBIPs for mammary cancer (MC) onset prediction in the BLRB/BYRB mouse model with a high incidence of natural MC development. Blood samples were collected from 80 aging females of these original mouse strains, 12 basic CBIPs were estimated by flow cytometry. Then mice were followed up for 28 weeks, and the outcome of females (MC diagnosis, death without MC or MC-free survival) was registered. We estimated the patterns of changes in CBIPs with age and in accordance with the outcome. An increasing imbalance in 11 CBIPs during natural aging of females clearly resembled human i...
Source: Cancer Immunology, Immunotherapy - February 11, 2019 Category: Cancer & Oncology Source Type: research

Immunotherapy with checkpoint inhibitors in non-small cell lung cancer: insights from long-term survivors
AbstractImmune checkpoint inhibitors (ICIs) targeting the programmed cell death-1 (PD-1) –programmed cell death ligand-1 (PD-L1) axis have shown promising results in non-small cell lung cancer (NSCLC) patients, some of them with persistent responses to these agents that form a population of long-term survivors. Despite the variable definition of PD-L1 positivity in tumors, an associat ion between expression and response has been reasonably consistent in advanced NSCLC. In addition, the clinical efficacy of ICIs seems to be related to the genomic landscape of the tumor in terms of mutational burden and clonal neoantig...
Source: Cancer Immunology, Immunotherapy - February 6, 2019 Category: Cancer & Oncology Source Type: research

Mutations resulting in the formation of hyperactive complement convertases support cytocidal effect of anti-CD20 immunotherapeutics
We present a novel approach, which utilizes gain-of-function variants of complement factor B (FB), a component of alternative C3/C5 convertases, which augment mAb-activated reactions through a positive feedback mechanism called an amplification loop. If complement concentration is limited, an addition of quadruple gain-of-function FB mutant p.D279G p.F286L p.K323E p.Y363A (or selected single mutants) results in significantly increased complement-mediated lysis of ofatumumab-resistant tumour cells, as well as the complete lysis of moderately sensitive cells. Importantly, this effect cannot be achieved by further increasing ...
Source: Cancer Immunology, Immunotherapy - February 6, 2019 Category: Cancer & Oncology Source Type: research

A pilot study of interferon-alpha-2b dose reduction in the adjuvant therapy of high-risk melanoma
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 6, 2019 Category: Cancer & Oncology Source Type: research

Early objective response to avelumab treatment is associated with improved overall survival in patients with metastatic Merkel cell carcinoma
ConclusionsPatients with OR by 7 or 13  weeks had significantly longer OS than patients without, confirming that early OR is an endpoint of major importance. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 5, 2019 Category: Cancer & Oncology Source Type: research

Correction to: CD73 expression in normal and pathological human hepatobiliopancreatic tissues
The following information must be added to the published article: (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 5, 2019 Category: Cancer & Oncology Source Type: research

The effect of anti-CTLA4 treatment on peripheral and intra-tumoral T cells in patients with hepatocellular carcinoma
ConclusionIn summary, we observed a clear activation of T cell responses in HCC patients treated with tremelimumab and identified potential biomarkers which will help identify patients responding to immunotherapy with anti-CTLA4. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 28, 2019 Category: Cancer & Oncology Source Type: research

Deciphering myeloid-derived suppressor cells: isolation and markers in humans, mice and non-human primates
AbstractIn cancer, infection and inflammation, the immune system ’s function can be dysregulated. Instead of fighting disease, immune cells may increase pathology and suppress host-protective immune responses. Myeloid cells show high plasticity and adapt to changing conditions and pathological challenges. Despite their relevance in disease pathophysiology, the identity, heterogeneity and biology of myeloid cells is still poorly understood. We will focus on phenotypical and functional markers of one of the key myeloid regulatory subtypes, the myeloid derived suppressor cells (MDSC), in humans, mice and non-human prima...
Source: Cancer Immunology, Immunotherapy - January 25, 2019 Category: Cancer & Oncology Source Type: research

A potential role for peripheral natural killer cell activity induced by preoperative chemotherapy in breast cancer patients
AbstractTumor-infiltrating lymphocytes are an important prognostic factor after neoadjuvant chemotherapy (NAC) in patients with breast cancer. Natural killer (NK) cells play critical roles in antitumor immune surveillance. Here, we assessed the relationship between peripheral natural killer (pNK) cell activity, tumor microenvironmental factors (TMEFs), and the therapeutic efficacy of preoperative chemotherapy in patients with breast cancer. In a cohort of 39 patients diagnosed with stage II –IV breast cancer who received NAC, we measured pNK cell activity by chromium release assay and assessed TMEF levels by next-gen...
Source: Cancer Immunology, Immunotherapy - January 23, 2019 Category: Cancer & Oncology Source Type: research

Prognostic value of tumour-infiltrating CD8+  lymphocytes in rectal cancer after neoadjuvant chemoradiation: is indoleamine-2,3-dioxygenase (IDO1) a friend or foe?
In this study, we examined the prognostic role of indoleamine-2,3-Dioxygenase (IDO1) and infiltrating cytotoxic T lymphocytes (CD8+) in locally advanced rectal carcinomas after neoadjuvant treatment. Expression of IDO1 and CD8 was evaluated by immunohistochemistry in 106 archival tumour tissue samples from patients following neoadjuvant chemoradiation and radical resection. The average infiltration of IDO1+  and CD8+ cells was calculated along the tumour invasive front, in the tumour centre and within the neoplastic cells and expressed as total scores. Of the tumour specimens evaluable for immunohistochemistr...
Source: Cancer Immunology, Immunotherapy - January 22, 2019 Category: Cancer & Oncology Source Type: research

Immune checkpoint inhibitor-induced colitis as a predictor of survival in metastatic melanoma
AbstractBackgroundGastrointestinal (GI) immune-related adverse events (irAEs) commonly limit immune checkpoint inhibitors ’ (ICIs) treatment, which is very effective for metastatic melanoma. The independent impact of GI-irAEs on patients’ survival is not well studied. We aimed to assess the impact of GI-irAEs on survival rates of patients with metastatic melanoma using multivariate model.MethodsThis is a retrospective study of patients with metastatic melanoma who developed GI-irAEs from 1/2010 through 4/2018. A number of randomized patients who did not have GI-irAEs were included as controls. Kaplan –Mei...
Source: Cancer Immunology, Immunotherapy - January 21, 2019 Category: Cancer & Oncology Source Type: research

Adverse events need for hospitalization and systemic immunosuppression in very elderly patients (over 80  years) treated with ipilimumab for metastatic melanoma
ConclusionSerious AEs occurred in 80  + adults at the same rate as observed in our younger patients and as previously reported in younger populations. Ipilimumab can be an option in elderly patients, as patients may benefit from therapy and safety seems to be manageable. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 19, 2019 Category: Cancer & Oncology Source Type: research

Strong antigen-specific T-cell immunity induced by a recombinant human TERT measles virus vaccine and amplified by a DNA/viral vector prime boost in IFNAR/CD46 mice
AbstractCancer immunotherapy is seeing an increasing focus on vaccination with tumor-associated antigens (TAAs). Human telomerase (hTERT) is a TAA expressed by most tumors to overcome telomere shortening. Tolerance to hTERT can be easily broken both naturally and experimentally and hTERT DNA vaccine candidates have been introduced in clinical trials. DNA prime/boost strategies have been widely developed to immunize efficiently against infectious diseases. We explored the use of a recombinant measles virus (MV) hTERT vector to boost DNA priming as recombinant live attenuated measles virus has an impressive safety and effica...
Source: Cancer Immunology, Immunotherapy - January 17, 2019 Category: Cancer & Oncology Source Type: research

The effect of everolimus and low-dose cyclophosphamide on immune cell subsets in patients with metastatic renal cell carcinoma: results from a phase I clinical trial
AbstractFor the treatment of metastatic renal cell cancer several strategies are used among which the mTOR inhibitor everolimus. As mTOR plays an important role in the immune system, e.g., by controlling the expression of the transcription factor FoxP3 thereby regulating regulatory T cells (Tregs), it plays a key role in the balance between tolerance and inflammation. Previous reports showed stimulatory effects of mTOR inhibition on the expansion of Tregs, an effect that can be considered detrimental in terms of cancer control. Since metronomic cyclophosphamide (CTX) was shown to selectively deplete Tregs, a phase 1 clinic...
Source: Cancer Immunology, Immunotherapy - January 17, 2019 Category: Cancer & Oncology Source Type: research

STAT3 inhibition specifically in human monocytes and macrophages by CD163-targeted corosolic acid-containing liposomes
AbstractTumor-associated macrophages (TAMs) are of major importance in cancer-related immune suppression, and tumor infiltration by CD163pos TAMs is associated with poor outcome in most human cancers. Therefore, therapeutic strategies for reprogramming TAMs from a tumor-supporting (M2-like) phenotype towards a tumoricidal (M1-like) phenotype are of great interest. Activation of the transcription factor STAT3 within the tumor microenvironment is associated with worse prognosis, and STAT3 activation promotes the immunosuppressive phenotype of TAMs. Therefore, we aimed to develop a drug for inhibition of STAT3 specifically wi...
Source: Cancer Immunology, Immunotherapy - January 14, 2019 Category: Cancer & Oncology Source Type: research

Chronic retroviral infection of mice promotes tumor development, but CD137 agonist therapy restores effective tumor immune surveillance
AbstractT cell responses are crucial for anti-tumor immunity. In chronic viral infections, anti-tumor T cell responses can be compromised due to various immunological mechanisms, including T cell exhaustion. To study mechanisms of anti-tumor immunity during a chronic viral infection, we made use of the well-established Friend virus (FV) mouse model. Chronically FV-infected mice are impaired in their ability to reject FBL-3 cells —a virus-induced tumor cell line of C57BL/6 origin. Here we aimed to explore therapeutic strategies to overcome the influence of T cell exhaustion during chronic viral infection, and reactiva...
Source: Cancer Immunology, Immunotherapy - January 11, 2019 Category: Cancer & Oncology Source Type: research

CD73 expression in normal and pathological human hepatobiliopancreatic tissues
AbstractBackgroundThe tumor-expressed CD73 ectonucleotidase generates immune tolerance and promotes invasiveness via adenosine production from degradation of AMP. While anti-CD73 blockade treatment is a promising tool in cancer immunotherapy, a characterization of CD73 expression in human hepatobiliopancreatic system is lacking.Patients and methodsCD73 expression was investigated by immunohistochemistry in a variety of non-neoplastic and neoplastic conditions of the liver, pancreas, and biliary tract.ResultsCD73 was expressed in normal hepatobiliopancreatic tissues with subcellular-specific patterns of staining: canalicula...
Source: Cancer Immunology, Immunotherapy - January 4, 2019 Category: Cancer & Oncology Source Type: research

Schwann cells shape the neuro-immune environs and control cancer progression
AbstractAt present, significant experimental and clinical data confirm the active involvement of the peripheral nervous system (PNS) in different phases of cancer development and progression. Most of the research effort focuses on the impact of distinct neuronal types, e.g., adrenergic, cholinergic, dopaminergic, etc. in carcinogenesis, generally ignoring neuroglia. The very fact that these cells far outnumber the other cellular types may also play an important role worthy of study in this context. The most prevalent neuroglia within the PNS consists of Schwann cells (SCs). These cells play a substantial role in maintainin...
Source: Cancer Immunology, Immunotherapy - January 3, 2019 Category: Cancer & Oncology Source Type: research

The route of administration dictates the immunogenicity of peptide-based cancer vaccines in mice
We report here that peptide vaccines and poly-ICLC adjuvant administered via the unconventional intravenous route of immunization generate substantially higher CTL responses as compared to conventional subcutaneous injections, resulting in more successful antitumor effects in mice. Fu rthermore, amphiphilic antigen constructs such as palmitoylated peptides were shown to be better immunogens than long peptide constructs, which now are in vogue in the clinic. The present findings if translated into the clinical setting could help dissipate the wide-spread skepticism of whether pept ide vaccines will ever work to treat cancer...
Source: Cancer Immunology, Immunotherapy - January 2, 2019 Category: Cancer & Oncology Source Type: research

Distinct immunological properties of the two histological subtypes of adenocarcinoma of the ampulla of Vater
AbstractAdenocarcinoma of the ampulla of Vater (AOV) is classified into intestinal type (IT) and pancreatobiliary type (PB); however, the immunological properties of these subtypes remain to be characterized. Here, we evaluated the clinical implications of PD-L1 expression and CD8+ T lymphocyte density in adenocarcinomas of the AOV and their potential association with Yes-associated protein (YAP). We analyzed 123 adenocarcinoma-of-the-AOV patients who underwent surgical resection, and tumors were classified into IT or PB type. Tumor or inflammatory cell PD-L1 expression, CD8+ T lymphocyte density in the cancer cell nest (i...
Source: Cancer Immunology, Immunotherapy - January 2, 2019 Category: Cancer & Oncology Source Type: research

Randomized-controlled phase II trial of salvage chemotherapy after immunization with a TP53 -transfected dendritic cell-based vaccine (Ad.p53-DC) in patients with recurrent small cell lung cancer
AbstractSmall cell lung cancerTP53 mutations lead to expression of tumor antigens that elicits specific cytotoxic T-cell immune responses. In this phase II study, dendritic cells transfected with wild-typeTP53 (vaccine) were administered to patients with extensive-stage small cell lung cancer after chemotherapy. Patients were randomized 1:1:1 to arm A (observation), arm B (vaccine alone), or arm C (vaccine plus all-trans-retinoic acid). Vaccine was administered every 2 weeks (3 times), and all patients were to receive paclitaxel at progression. Our primary endpoint was overall response rate (ORR) to paclitaxel. The study w...
Source: Cancer Immunology, Immunotherapy - December 27, 2018 Category: Cancer & Oncology Source Type: research

MDSCs in infectious diseases: regulation, roles, and readjustment
AbstractMany pathogens, ranging from viruses to multicellular parasites, promote expansion of MDSCs, which are myeloid cells that exhibit immunosuppressive features. The roles of MDSCs in infection depend on the class and virulence mechanisms of the pathogen, the stage of the disease, and the pathology associated with the infection. This work compiles evidence supported by functional assays on the roles of different subsets of MDSCs in acute and chronic infections, including pathogen-associated malignancies, and discusses strategies to modulate MDSC dynamics to benefit the host. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 19, 2018 Category: Cancer & Oncology Source Type: research

Immune cell infiltration as a biomarker for the diagnosis and prognosis of stage I –III colon cancer
AbstractTumour-infiltrating immune cells are a source of important prognostic information for patients with resectable colon cancer. We developed a novel immune model based on systematic assessments of the immune landscape inferred from bulk tumor transcriptomes of stage I –III colon cancer patients. The “Cell type Identification By Estimating Relative Subsets Of RNA Transcripts (CIBERSORT)” algorithm was used to estimate the fraction of 22 immune cell types from six microarray public datasets. The random forest method and least absolute shrinkage and selection operator model were then used to establish i...
Source: Cancer Immunology, Immunotherapy - December 19, 2018 Category: Cancer & Oncology Source Type: research

Identification and characterization of an alternative cancer-derived PD-L1 splice variant
In this study, we extended this observation by performing a computational analysis of 33 other cancer types as well as human cancer cell lines, and identified additionalPD-L1 isoforms with an exon 4 enrichment expressed in 20 cancers and human cancer cell lines. We demonstrate that cancer cell lines with high expression levels of exon 4-enrichedPD-L1 generate a secreted form of PD-L1. Further biochemical studies of exon 4-enriched PD-L1 demonstrated that this form is secreted and maintains the capacity to bind PD-1 as well as to serve as a negative regulator on T cell function, as measured by inhibition of IL-2 and IFNg se...
Source: Cancer Immunology, Immunotherapy - December 18, 2018 Category: Cancer & Oncology Source Type: research

A secreted PD-L1 splice variant that covalently dimerizes and mediates immunosuppression
AbstractTargeting immune checkpoint pathways, such as programmed death ligand-1 (PD-L1, also known as CD274 or B7-H1) or its receptor programmed cell death-1 (PD-1) has shown improved survival for patients with numerous types of cancers, not limited to lung cancer, melanoma, renal cell carcinoma, and Hodgkin lymphoma. PD-L1 is a co-inhibitory molecule whose expression on the surface of tumor cells is associated with worse prognosis in many tumors. Here we describe a splice variant (secPD-L1) that does not splice into the transmembrane domain, but instead produces a secreted form of PD-L1 that has a unique 18 amino acid tai...
Source: Cancer Immunology, Immunotherapy - December 18, 2018 Category: Cancer & Oncology Source Type: research

Addressing current challenges and future directions in immuno-oncology: expert perspectives from the 2017 NIBIT Foundation Think Tank, Siena, Italy
AbstractA collaborative think tank involving panellists from immuno-oncology networks, clinical/translational investigators and the pharmaceutical industry was held in Siena, Italy, in October 2017 to discuss the evolving immune-oncology landscape, identify selected key challenges, and provide a perspective on the next steps required in the translation of current research and knowledge to clinical reality. While there is a trend of combining new agents (e.g., co-stimulator agonists) with a PD-1/PD-L1 treatment backbone, use of alternative combination therapy approaches should also be considered. While the rapid evolution i...
Source: Cancer Immunology, Immunotherapy - December 18, 2018 Category: Cancer & Oncology Source Type: research

The Italian Network for Tumor Bio-Immunotherapy (NIBIT) Foundation: ongoing and prospective activities in immuno-oncology
AbstractThe ongoing revolution in cancer immunotherapy stems from the knowledge that distinct immune-checkpoints regulate the physiological crosstalk between and among immune cells by delivering inhibitory or activating signals. These notions, and the availability of mAb directed to diverse immune-checkpoint molecules, have led to a significant clinical improvement in cancer treatment. In this scenario, further achievements are undoubtedly to be expected from the contribution of novel, proof-of-principle clinical trials designed to explore the therapeutic efficacy of new immunotherapy-based combinations and treatment seque...
Source: Cancer Immunology, Immunotherapy - December 18, 2018 Category: Cancer & Oncology Source Type: research

Ex vivo conditioning with IL-12 protects tumor-infiltrating CD8 + T cells from negative regulation by local IFN- γ
In this report, we further elucidate the mechanism of this potency, showing that IL-12 additionally counteracts the negative regulatory effects of autocrine IFN-γ. IL-12 not only downregulates PD-1 expression by T cells, thus minimizing the effects of IFN-γ-induced PD-L1 upregulation by tumor stromal cells, but also inhibits IFNγR2 expression, thereby protecting T cells from IFN-γ-induced cell death. Thus, the enhanced anti-tumor activity of CD8+ T cells expanded ex vivo in the presence of IL-12 is due not only to the ability of IL-12-stimulated cells to secrete sustained levels of IFN- γ, but...
Source: Cancer Immunology, Immunotherapy - December 14, 2018 Category: Cancer & Oncology Source Type: research

Enhanced anti-tumor efficacy of checkpoint inhibitors in combination with the histone deacetylase inhibitor Belinostat in a murine hepatocellular carcinoma model
AbstractImmune checkpoint inhibitors are currently tested in different combinations in patients with advanced hepatocellular carcinoma (HCC). Nivolumab, an anti-PD-1 agent, has gained approval in the second-line setting in the USA. Epigenetic drugs have immune-mediated antitumor effects that may improve the activity of immunotherapy agents. Our aim was to study the therapeutic efficacy of checkpoint inhibitors (anti-CTLA-4 and anti-PD-1 antibodies) in combination with the histone deacetylase inhibitor (HDACi) Belinostat. In a subcutaneous Hepa129 murine HCC model, we demonstrated that Belinostat improves the antitumor acti...
Source: Cancer Immunology, Immunotherapy - December 13, 2018 Category: Cancer & Oncology Source Type: research

CRISPR/Cas9-mediated PD-1 disruption enhances human mesothelin-targeted CAR T cell effector functions
AbstractThe interaction between programmed cell death protein 1 (PD-1) on activated T cells and its ligands on a target tumour may limit the capacity of chimeric antigen receptor (CAR) T cells to eradicate solid tumours. PD-1 blockade could potentially enhance CAR T cell function. Here, we show that mesothelin is overexpressed in human triple-negative breast cancer cells and can be targeted by CAR T cells. To overcome the suppressive effect of PD-1 on CAR T cells, we utilized CRISPR/Cas9 ribonucleoprotein-mediated editing to disrupt the programmed cell death-1 (PD-1) gene locus in human primary T cells, resulting in a sign...
Source: Cancer Immunology, Immunotherapy - December 6, 2018 Category: Cancer & Oncology Source Type: research

The correlation and prognostic value of serum levels of soluble programmed death protein 1 (sPD-1) and soluble programmed death-ligand 1 (sPD-L1) in patients with hepatocellular carcinoma
ConclusionsOur findings indicate that sPD-1 and sPD-L1 are independent prognostic factors with opposite prognostic roles in predicting both DFS and OS in HCC patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 1, 2018 Category: Cancer & Oncology Source Type: research

Tumor-infiltrating immune cell subpopulations and programmed death ligand 1 (PD-L1) expression associated with clinicopathological and prognostic parameters in ependymoma
This study showed that the analysis of tumor-infiltrating immune cells could aid in predicting the prognosis of ependymoma patients and in determining therapeutic strategies to target the tumor microenvironment. PD-L1 expression in the ST-RELA subgroup suggests that this marker has a potential added value for future immunotherapy treatments. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 27, 2018 Category: Cancer & Oncology Source Type: research

Can benign lymphoid tissue changes in 18 F-FDG PET/CT predict response to immunotherapy in metastatic melanoma?
ConclusionBased on our findings, 10% patients in the interim or late PET/CT showed ‘sarcoid-like lymphadenopathy’ as response to treatment. All these patients showed disease control, implying a relation between the appearance of sarcoid-like lymphadenopathy and the clinical benefit of anti-CTLA-4 therapy. On the other hand, quantitative18F-FDG PET analysis of the spleen showed a poor performance in predicting clinical benefit to ipilimumab. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 26, 2018 Category: Cancer & Oncology Source Type: research

An alphavirus-based therapeutic cancer vaccine: from design to clinical trial
AbstractCancer immunotherapy has greatly advanced in recent years. Most immunotherapeutic strategies are based on the use of immune checkpoint blockade to unleash antitumor immune responses or on the induction or adoptive transfer of immune effector cells. We aim to develop therapeutic vaccines based on recombinant Semliki Forest virus vectors to induce tumor-specific effector immune cells. In this review, we describe our ongoing work on SFV-based vaccines targeted against human papillomavirus- and hepatitis C virus-related infections and malignancies, focusing on design, delivery, combination strategies, preclinical effic...
Source: Cancer Immunology, Immunotherapy - November 21, 2018 Category: Cancer & Oncology Source Type: research

Upregulation of tumor PD-L1 by neoadjuvant chemoradiotherapy (neoCRT) confers improved survival in patients with lymph node metastasis of locally advanced rectal cancers
In this study, we examined the roles of tumor PD-L1 and IFN-γ before and after neoCRT in locally advanced rectal cancer (LARC) patients. Our results demonstrate that patients with high PD-L1 expression in post-neoCRT tissues exhibit improved 5-year disease-free survival (DFS) and overall survival (OS) compared with those with low PD-L1 e xpression (p 
Source: Cancer Immunology, Immunotherapy - November 17, 2018 Category: Cancer & Oncology Source Type: research

A phase I clinical study of a cocktail vaccine of Wilms ’ tumor 1 (WT1) HLA class I and II peptides for recurrent malignant glioma
ConclusionThe safety of a cocktail vaccine of WT1 HLA class I and II peptides for malignant gliomas was verified. This vaccine is, therefore, considered promising for patients with recurrent malignant glioma. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 14, 2018 Category: Cancer & Oncology Source Type: research

Targeting the polarization of tumor-associated macrophages and modulating mir-155 expression might be a new approach to treat diffuse large B-cell lymphoma of the elderly
This study aims to evaluate the relationship between macrophage polarization pattern in the tumor microenvironment and relative expression of miR-155 in EBV + DLBCLe and EBV-negative DLBCL patients. We studied 28 EBV + DLBCLe and 65 EBV-negative DLBCL patient s. Tumor-associated macrophages (TAM) were evaluated by expression of CD68, CD163 and CD163/CD68 ratio (degree of M2 polarization), using tissue microarray. RNA was extracted from paraffin-embedded tumor samples for miR-155 relative expression study. We found a significantly higher CD163/CD68 ratio in EBV + DLBCLe compared to ...
Source: Cancer Immunology, Immunotherapy - November 14, 2018 Category: Cancer & Oncology Source Type: research

Phase 1 study of everolimus and low-dose oral cyclophosphamide in patients with metastatic renal cell carcinoma
In conclusion, the optimal Treg depleting dose and schedule of CTX, when combined with everolimus, is 50 mg once daily. This combination leads to acceptable adverse events in comparison with everolimus alone. Currently, the here selected combin ation is being evaluated in a phase II clinical trial.Trial registrationNCT01462214. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 9, 2018 Category: Cancer & Oncology Source Type: research

Apoptosis of tumor-infiltrating T lymphocytes: a new immune checkpoint mechanism
AbstractImmunotherapy based on checkpoint inhibitors is providing substantial clinical benefit, but only to a minority of cancer patients. The current priority is to understand why the majority of patients fail to respond. Besides T-cell dysfunction, T-cell apoptosis was reported in several recent studies as a relevant mechanism of tumoral immune resistance. Several death receptors (Fas, DR3, DR4, DR5, TNFR1) can trigger apoptosis when activated by their respective ligands. In this review, we discuss the immunomodulatory role of the main death receptors and how these are shaping the tumor microenvironment, with a focus on ...
Source: Cancer Immunology, Immunotherapy - November 7, 2018 Category: Cancer & Oncology Source Type: research

The nature of the human T cell response to the cancer antigen 5T4 is determined by the balance of regulatory and inflammatory T cells of the same antigen-specificity: implications for vaccine design
This study mapped the fine specificity of Th1 and Treg cell responses to the 5T4 protein. Surprisingly, both immunogenic peptides and those recognised by Tregs clustered in the same HLA-DR transcending epitope-rich hotspots within the 5T4 protein. Similarly, regions of low Th1-cell immunogenicity also did not contain peptides capable of stimulating Tregs, further supporting the notion that Treg and Th1 cells recognise the same peptides. Understanding the rules which govern the balance of Th1 and Treg cells responding to a given peptide specificity is, therefore, of fundamental importance to designing strategies for manipul...
Source: Cancer Immunology, Immunotherapy - November 7, 2018 Category: Cancer & Oncology Source Type: research