Liver myeloid-derived suppressor cells expand in response to liver metastases in mice and inhibit the anti-tumor efficacy of anti-CEA CAR-T
Abstract Chimeric antigen receptor-modified T cell (CAR-T) technology, a promising immunotherapeutic tool, has not been applied specifically to treat liver metastases (LM). While CAR-T delivery to LM can be optimized by regional intrahepatic infusion, we propose that liver CD11b+Gr-1+ myeloid-derived suppressor cells (L-MDSC) will inhibit the efficacy of CAR-T in the intrahepatic space. We studied anti-CEA CAR-T in a murine model of CEA+ LM and identified mechanisms through which L-MDSC expand and inhibit CAR-T function. We established CEA+ LM in mice and studied purified L-MDSC and responses to treatment with int...
Source: Cancer Immunology, Immunotherapy - April 8, 2015 Category: Cancer & Oncology Source Type: research

Adoptive T cell therapy combined with intralesional administrations of TG1042 (adenovirus expressing interferon-γ) in metastatic melanoma patients
Abstract Tumor immune escape has recently been shown to be related to the development of an immune tolerance state of the microenvironment. Cytokines activating the immune system such as IFN-γ can be used to reverse the immune escape and thus to potentiate the efficacy of immunotherapy. A clinical study was conducted in 18 stage IIIc/IV melanoma patients treated with tumor-infiltrating lymphocytes (TILs) in combination with intratumoral TG1042 injection (adenovirus expressing IFN-γ). The primary objective was to investigate the safety of treatment. Secondary objectives were to study the clinical re...
Source: Cancer Immunology, Immunotherapy - April 6, 2015 Category: Cancer & Oncology Source Type: research

Two distinct effector memory cell populations of WT1 (Wilms’ tumor gene 1)-specific cytotoxic T lymphocytes in acute myeloid leukemia patients
In this study, we generated single-cell gene-expression profiles of the effector memory (EM) subset of WT1-specific cytotoxic T lymphocytes (CTLs) in peripheral blood of nine acute myeloid leukemia patients treated with WT1 peptide vaccine, in order to discriminate responders (WT1 mRNA levels in peripheral blood decreased to undetectable levels, decreased but stayed at abnormal levels, were stable at undetectable levels, or remained unchanged from the initial abnormal levels more than 6 months after WT1 vaccination) from non-responders (leukemic blast cells and/or WT1 mRNA levels increased relative to the initial stat...
Source: Cancer Immunology, Immunotherapy - April 3, 2015 Category: Cancer & Oncology Source Type: research

Growth arrest and DNA damage-inducible protein (GADD34) enhanced liver inflammation and tumorigenesis in a diethylnitrosamine (DEN)-treated murine model
Abstract Growth arrest and DNA damage-inducible protein (GADD34/Ppp1r15a) is induced by various stimuli including DNA damage and ER stress. DNA damage and oncogene activation, accompanied by tumor-specific DNA repair defects and a failure to stall the cell cycle, are early markers of hepatocellular carcinoma (HCC). However, whether GADD34 accounts for regulating HCC tumorigenesis remains elusive. Here, we demonstrated that GADD34 expression was upregulated in the liver of mice after exposure to a carcinogen, diethylnitrosamine (DEN). In both acute and chronic DEN treatment models, GADD34 deficiency not only decrea...
Source: Cancer Immunology, Immunotherapy - April 2, 2015 Category: Cancer & Oncology Source Type: research

Evaluation of serum osteopontin level and gene polymorphism as biomarkers: analyses from the Nordic Adjuvant Interferon alpha Melanoma trial
In conclusion, serum OPN (its level or the genotype) cannot distinguish melanoma patients with poor prognosis, or patients that might benefit from adjuvant treatment with IFN-α. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - April 2, 2015 Category: Cancer & Oncology Source Type: research

Crosstalk of carcinoembryonic antigen and transforming growth factor-β via their receptors: comparing human and canine cancer
Abstract There is accumulating evidence that the transforming growth factor beta (TGF-β) and nuclear factor kappa-B (NFκB) pathways are tightly connected and play a key role in malignant transformation in cancer. Immune infiltration by regulatory T- and B-lymphocytes (Tregs, Bregs) has recently gained increased attention for being an important source of TGF-β. There is a plethora of studies examining the pro-tumorigenic functions of carcinoembryonic antigen (CEA), but its receptor CEAR is far less studied. So far, there is a single connecting report that TGF-β also may signal through CEAR....
Source: Cancer Immunology, Immunotherapy - April 2, 2015 Category: Cancer & Oncology Source Type: research

Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report
We describe for the first time the case of an adult patient who developed autoimmune diabetes likely as a consequence of PD-1 inhibition with pembrolizumab. The presence of high serum titres of anti-glutamic acid decarboxylase antibodies together with a suggestive clinical presentation, age of the patient and preclinical data strongly support an autoimmune aetiology of the diabetes. Moreover, the patient was found to have a well-known high-risk human leucocyte antigen type for the development of type 1 diabetes in children, so the PD-1 inhibition is very likely to have triggered the autoimmune phenomenon. Our case suggests...
Source: Cancer Immunology, Immunotherapy - April 1, 2015 Category: Cancer & Oncology Source Type: research

A combined approach of human leukocyte antigen ligandomics and immunogenicity analysis to improve peptide-based cancer immunotherapy
Abstract The breakthrough development of immune checkpoint inhibitors as clinically effective novel therapies demonstrates the potential of cancer immunotherapy. The identification of suitable targets for specific immunotherapy, however, remains a challenging task. Most peptides previously used for vaccination in clinical trials were able to elicit strong immunological responses but failed with regard to clinical benefit. This might, at least partly, be caused by an inadequate peptide selection, usually derived from established tumor-associated antigens which are not necessarily presented as human leukocyte antige...
Source: Cancer Immunology, Immunotherapy - March 30, 2015 Category: Cancer & Oncology Source Type: research

Impairment of lymphocyte function following yttrium-90 DOTATOC therapy
Abstract The radiolabeled somatostatin analogue, yttrium-90 DOTA-d-Phe(1)-Tyr(3)-octreotide (DOTATOC), is currently applied to treat advanced somatostatin receptor-positive tumors, e.g., neuroendocrine tumors of the pancreas, lung or gut. However, effects of this treatment on antimicrobial immune responses are not yet defined. In 20 patients treated with DOTATOC, cellular in vitro immune function was determined. Their antimicrobial lymphocyte responses were assessed by lymphocyte transformation test and enzyme-linked immunospot—measuring lymphocyte proliferation and on a single cell level production of pro- ...
Source: Cancer Immunology, Immunotherapy - March 30, 2015 Category: Cancer & Oncology Source Type: research

Gene-mediated cytotoxic immunotherapy as adjuvant to surgery or chemoradiation for pancreatic adenocarcinoma
Conclusions AdV-tk can be safely combined with pancreatic cancer SOC without added toxicity. Response and survival compare favorably to expected outcomes and immune activity increased. These results support further evaluation of GMCI with more modern chemoradiation and surgery as well as PD-1/PD-L1 inhibitors in pancreatic cancer. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 21, 2015 Category: Cancer & Oncology Source Type: research

FoxP3 + and IL-17 + cells are correlated with improved prognosis in cervical adenocarcinoma
Abstract Cervical adenocarcinoma comprises approximately 15 % of cervical cancer cases. This histological subtype has different characteristics than cervical squamous cell carcinoma, which may influence disease progression. To study whether the infiltration of T cell subpopulations was correlated with cervical adenocarcinoma patient survival, similar to squamous cell carcinoma, the tumor-infiltrating T cells, Tregs, Th17 cells and IL-17+ cell frequencies were analyzed in a cohort of cervical adenocarcinoma patients (n = 67). Intraepithelial, stromal and total cell frequencies were scored using tripl...
Source: Cancer Immunology, Immunotherapy - March 21, 2015 Category: Cancer & Oncology Source Type: research

Augmentation of autologous T cell reactivity with acute myeloid leukemia (AML) blasts by Toll-like receptor (TLR) agonists
This study investigated whether TNF-α, Toll-like receptors (TLRs) 7/8 agonist resiquimod (R848), the TLR4 agonist lipopolysaccharide (LPS) and their combinations can enhance autologous AML-reactive T cell generation in an in vitro culture. AML peripheral blood or bone marrow mononuclear cells were cultured in medium supplemented with GM-CSF/IL-4 to induce dendritic cell (DC) differentiation of AML blasts (AML-DC). The impact of TNF-α, LPS, R848 and their combinations on AML-DC cultures was analyzed. Significantly enhanced CD80, CD40, CD83, CD54, HLA-DR and CD86 expression of AML cells was observed by addition o...
Source: Cancer Immunology, Immunotherapy - March 21, 2015 Category: Cancer & Oncology Source Type: research

Overexpression of apolipoprotein A-I fused to an anti-transforming growth factor beta peptide modulates the tumorigenicity and immunogenicity of mouse colon cancer cells
In this study, we analyzed the effect of overexpressing an anti-TGF-β peptide fused to apolipoprotein A-I (ApoA-I) as a scaffold molecule. We generated and characterized stable MC38 colon carcinoma clones expressing ApoA-I fused to the anti-TGF-β peptide P144 and ApoA-I as control cells. We evaluated in vitro the gene expression profile, cell cycle and anchorage-independent growth. The in vivo tumorigenic potential and immunogenicity were analyzed inoculating the MC38 clones into C57BL/6 mice, recombination-activating gene 1 knockout mice or mice deficient in NK cells either subcutaneously or intrasplenically to ...
Source: Cancer Immunology, Immunotherapy - March 21, 2015 Category: Cancer & Oncology Source Type: research

Novel strategies for inhibiting PD-1 pathway-mediated immune suppression while simultaneously delivering activating signals to tumor-reactive T cells
Abstract We previously developed cell-based vaccines as therapeutics for metastatic cancers. The vaccines were aimed at activating type I CD4+T cells and consisted of tumor cells transfected with genes encoding syngeneic MHC class II and CD80 costimulatory molecules, and lacking the MHC II-associated invariant chain. The vaccines showed some efficacy in mice with sarcoma, melanoma, and breast cancer and activated MHC class II syngeneic T cells from breast, lung, and melanoma patients. During the course of the vaccine studies, we observed that CD80 not only costimulated naïve T cells, but also bound to PD-L1 a...
Source: Cancer Immunology, Immunotherapy - March 19, 2015 Category: Cancer & Oncology Source Type: research

Wilms tumor 1 peptide vaccination combined with temozolomide against newly diagnosed glioblastoma: safety and impact on immunological response
Abstract To investigate the safety of combined Wilms tumor 1 peptide vaccination and temozolomide treatment of glioblastoma, a phase I clinical trial was designed. Seven patients with histological diagnosis of glioblastoma underwent concurrent radiotherapy and temozolomide therapy. Patients first received Wilms tumor 1 peptide vaccination 1 week after the end of combined concurrent radio/temozolomide therapy, and administration was continued once per week for 7 weeks. Temozolomide maintenance was started and performed for up to 24 cycles, and the observation period for safety encompassed 6 weeks...
Source: Cancer Immunology, Immunotherapy - March 14, 2015 Category: Cancer & Oncology Source Type: research

The Fourteenth International Conference on Progress in Vaccination Against Cancer (PIVAC-14), September 24–26, 2014, Rome, Italy: rethinking anti-tumor vaccines in a new era of cancer immunotherapy
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 12, 2015 Category: Cancer & Oncology Source Type: research

Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer
This study assessed the ability of an intravesical immunotherapy composed of a coformulation of the biopolymer chitosan with interleukin-12 (CS/IL-12) to induce systemic adaptive tumor-specific immunity. Intravesical CS/IL-12 immunotherapy was used to treat established orthotopic MB49 and MBT-2 bladder tumors. All mice receiving intravesical CS/IL-12 immunotherapy experienced high cure rates of orthotopic disease. To investigate the durability and extent of the resultant adaptive immune response, cured mice were rechallenged both locally (intravesically) and distally. Cured mice rejected 100 % of intravesical tumor re...
Source: Cancer Immunology, Immunotherapy - March 10, 2015 Category: Cancer & Oncology Source Type: research

CCL17 and CCL22/CCR4 signaling is a strong candidate for novel targeted therapy against nasal natural killer/T-cell lymphoma
Abstract Nasal natural killer/T-cell lymphoma (NNKTL) is associated with Epstein–Barr virus and has a poor prognosis because of local invasion and/or multiple dissemination. Various chemokines play a role in tumor proliferation and invasion, and chemokine receptors including the C-C chemokine receptor 4 (CCR4) are recognized as potential targets for treating hematologic malignancies. The aim of the present study was to determine whether specific chemokines are produced by NNKTL. We compared chemokine expression patterns in culture supernatants of NNKTL cell lines with those of other lymphoma or leukemia cell...
Source: Cancer Immunology, Immunotherapy - March 10, 2015 Category: Cancer & Oncology Source Type: research

Acknowledgement
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 7, 2015 Category: Cancer & Oncology Source Type: research

CEA/CD3-bispecific T cell-engaging (BiTE) antibody-mediated T lymphocyte cytotoxicity maximized by inhibition of both PD1 and PD-L1
In conclusion, our findings demonstrate that dual blockade of PD-1 and PD-L1 maximizes T cell killing of tumor directed by CEA BiTE in vitro, is more effective if applied early, and provides a rationale for clinical use. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - March 6, 2015 Category: Cancer & Oncology Source Type: research

Preclinical activity of anti-CCR7 immunotherapy in patients with high-risk chronic lymphocytic leukemia
Abstract Chronic lymphocytic leukemia (CLL) with deletions of the p53 locus on chromosome 17 and/or refractory to fludarabine chemoimmunotherapy remains a major clinical problem with few therapeutic options. Currently, these types of CLL are treated with approaches that do not target the p53 pathway, such as small molecules and monoclonal antibodies (mAb). We have previously postulated anti-CCR7 mAb therapy as a novel CLL treatment. In the present study, we evaluated the in vitro efficacy of anti-CCR7 mAb as a single agent in CLL patients with high-risk cytogenetics and/or refractory to fludarabine, by measuring C...
Source: Cancer Immunology, Immunotherapy - February 28, 2015 Category: Cancer & Oncology Source Type: research

siRNA silencing of PD-1 ligands on dendritic cell vaccines boosts the expansion of minor histocompatibility antigen-specific CD8 + T cells in NOD/SCID/IL2Rg(null) mice
In conclusion, adoptive transfer of ex vivo primed MiHA-specific CD8+ T cells in combination with PD-L silenced DC vaccination, targeting MiHAs restricted to the hematopoietic system, is an interesting approach to boost GVT immunity in allo-SCT patients and thereby prevent relapse. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 28, 2015 Category: Cancer & Oncology Source Type: research

The antibody-mediated targeted delivery of interleukin-13 to syngeneic murine tumors mediates a potent anticancer activity
This study indicates that IL13 can be efficiently delivered to the tumor neo-vasculature and that it mediates a potent anticancer activity in the two models of cancer investigated in this study. The observed mechanism of action for F8-IL13 was surprising, since immunocytokines based on other payloads (e.g., IL2, IL4, IL12 and TNF) eradicate cancer by the combined contribution of natural killer cells and cluster of differentiation 8-positive T cells. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 27, 2015 Category: Cancer & Oncology Source Type: research

Disialoganglioside-specific human natural killer cells are effective against drug-resistant neuroblastoma
Abstract The disialoganglioside GD2 is a well-established target antigen for passive immunotherapy in neuroblastoma (NB). Despite the recent success of passive immunotherapy with the anti-GD2 antibody ch14.18 and cytokines, treatment of high-risk NB remains challenging. We expanded the approach of GD2-specific, antibody-based immunotherapy to an application of a GD2-specific natural killer (NK) cell line, NK-92-scFv(ch14.18)-zeta. NK-92-scFv(ch14.18)-zeta is genetically engineered to express a GD2-specific chimeric antigen receptor generated from ch14.18. Here, we show that chimeric receptor expression enables NK-...
Source: Cancer Immunology, Immunotherapy - February 25, 2015 Category: Cancer & Oncology Source Type: research

Prostate cancer vaccines: the long road to clinical application
Abstract Cancer vaccines as a modality of immune-based cancer treatment offer the promise of a non-toxic and efficacious therapeutic alternative for patients. Emerging data suggest that response to vaccination largely depends on the magnitude of the type I immune response generated, epitope spreading and immunogenic modulation of the tumor. Moreover, accumulating evidence suggests that cancer vaccines will likely induce better results in patients with low tumor burden and less aggressive disease. To induce long-lasting clinical responses, vaccines will need to be combined with immunoregulatory agents to overcome t...
Source: Cancer Immunology, Immunotherapy - February 19, 2015 Category: Cancer & Oncology Source Type: research

Data analysis as a source of variability of the HLA-peptide multimer assay: from manual gating to automated recognition of cell clusters
Abstract Multiparameter flow cytometry is an indispensable method for assessing antigen-specific T cells in basic research and cancer immunotherapy. Proficiency panels have shown that cell sample processing, test protocols and data analysis may all contribute to the variability of the results obtained by laboratories performing ex vivo T cell immune monitoring. In particular, analysis currently relies on a manual, step-by-step strategy employing serial gating decisions based on visual inspection of one- or two-dimensional plots. It is therefore operator dependent and subjective. In the context of continuing effort...
Source: Cancer Immunology, Immunotherapy - February 18, 2015 Category: Cancer & Oncology Source Type: research

Broadening the repertoire of melanoma-associated T-cell epitopes
Abstract Immune therapy has provided a significant breakthrough in the treatment of metastatic melanoma. Despite the remarkable clinical efficacy and established involvement of effector CD8 T cells, the knowledge of the exact peptide-MHC complexes recognized by T cells on the tumor cell surface is limited. Many melanoma-associated T-cell epitopes have been described, but this knowledge remains largely restricted to HLA-A2, and we lack understanding of the T-cell recognition in the context of other HLA molecules. We selected six melanoma-associated antigens (MAGE-A3, NY-ESO-1, gp100, Mart1, tyrosinase and TRP-2) th...
Source: Cancer Immunology, Immunotherapy - February 18, 2015 Category: Cancer & Oncology Source Type: research

Role of NKG2D, DNAM-1 and natural cytotoxicity receptors in cytotoxicity toward rhabdomyosarcoma cell lines mediated by resting and IL-15-activated human natural killer cells
Abstract Children with advanced stages (relapsed/refractory and stage IV) of rhabdomyosarcoma (RMS) have a poor prognosis despite intensive chemotherapy and autologous stem cell rescue, with 5-year survival rates ranging from 5 to 35 %. Development of new, additional treatment modalities is necessary to improve the survival rate. In this preclinical study, we investigated the potential of resting and cytokine-activated natural killer (NK) cells to lyse RMS cell lines, as well as the pathways involved, to explore the eventual clinical application of (activated) NK cell immunotherapy. RMS cell lines (n ...
Source: Cancer Immunology, Immunotherapy - February 18, 2015 Category: Cancer & Oncology Source Type: research

NZ28-induced inhibition of HSF1, SP1 and NF-κB triggers the loss of the natural killer cell-activating ligands MICA/B on human tumor cells
Abstract The activity of natural killer (NK) cells is regulated by activating and inhibiting receptors, whereby the C-type lectin natural killer group 2D (NKG2D) receptor serves as the major activating receptor on NK cells which recognizes major histocompatibility class I chain-related proteins A and B (MICA/B). The MICA/B expression has been described to be regulated by the transcription factor heat shock factor 1 (HSF1). Inhibition of heat shock protein 90 (Hsp90) is known to induce the heat shock response via activation of HSF1 which is associated with tumor development, metastasis and therapy resistance an...
Source: Cancer Immunology, Immunotherapy - February 18, 2015 Category: Cancer & Oncology Source Type: research

Intra-adrenal murine TH-MYCN neuroblastoma tumors grow more aggressive and exhibit a distinct tumor microenvironment relative to their subcutaneous equivalents
In this report, we describe an orthotopic TH-MYCN transplantable model where the tumor cells were injected intra-adrenally (IA) by microsurgery. Strikingly, 9464D cells grew out much faster in IA tumors compared to the subcutis. Tumors were infiltrated by equal numbers of lymphocytes and myeloid cells. Within the myeloid cell population, however, tumor-infiltrating macrophages were more abundant in IA tumors compared to SC tumors and expressed lower levels of MHC class II, indicative of a more immunosuppressive phenotype. Using 9464D cells stably expressing firefly luciferase, enhanced IA tumor growth could be confirmed us...
Source: Cancer Immunology, Immunotherapy - February 17, 2015 Category: Cancer & Oncology Source Type: research

“Tumor immunology meets oncology” (TIMO) X, May 23–24, 2014, Halle/Saale, Germany
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 13, 2015 Category: Cancer & Oncology Source Type: research

The safety of allogeneic innate lymphocyte therapy for glioma patients with prior cranial irradiation
Abstract The standard treatment of high-grade glioma presents a combination of radiotherapy, chemotherapy and surgery. Immunotherapy is proposed as a potential adjunct to standard cytotoxic regimens to target remaining microscopic disease following resection. We have shown ex vivo expanded/activated γδ T cells to be a promising innate lymphocyte therapy based on their recognition of stress antigens expressed on gliomas. However, successful integration of γδ T cell therapy protocols requires understanding the efficacy and safety of adoptively transferred immune cells in the post-treatment en...
Source: Cancer Immunology, Immunotherapy - February 13, 2015 Category: Cancer & Oncology Source Type: research

Interleukin-12 enhances the function and anti-tumor activity in murine and human CD8 + T cells
Abstract Mouse CD8+ T cells conditioned with interleukin (IL)-12 ex vivo mediate the potent regression of established melanoma when transferred into lymphodepleted mice. However, the quantitative and qualitative changes induced by IL-12 in the responding mouse CD8+ T cells have not been well defined. Moreover, the mechanisms by which IL-12-conditioning impacts human CD8+ T cells, and how such cells might be expanded prior to infusion into patients is not known. We found that ex vivo IL-12-conditioning of mouse CD8+ T cells led to a tenfold–100-fold increase in persistence and anti-tumor efficacy upon ado...
Source: Cancer Immunology, Immunotherapy - February 13, 2015 Category: Cancer & Oncology Source Type: research

Low-dose cyclophosphamide enhances antigen-specific CD4 + T cell responses to NY-ESO-1/ISCOMATRIX™ vaccine in patients with advanced melanoma
Abstract Clinical outcomes from cancer vaccine trials in patients with advanced melanoma have so far been disappointing. This appears at least partially due to a state of immunosuppression in these patients induced by an expansion of regulatory cell populations including regulatory T cells (Tregs). We have previously demonstrated potent immunogenicity of the NY-ESO-1/ISCOMATRIX™ vaccine in patients with resected melanoma (study LUD99-08); however, the same vaccine induced only a few vaccine antigen-specific immune responses in patients with advanced disease (study LUD2002-013). Pre-clinical models suggest th...
Source: Cancer Immunology, Immunotherapy - February 7, 2015 Category: Cancer & Oncology Source Type: research

Phase I trial of a cancer vaccine consisting of 20 mixed peptides in patients with castration-resistant prostate cancer: dose-related immune boosting and suppression
Abstract The heterogeneity expression of tumor-associated antigens (TAA) and variability of human T cell repertoire suggest that effective cancer vaccine requires induction of a wide breadth of cytotoxic T lymphocyte (CTL) specificities. This can be achieved with vaccines targeting multiple TAA. We evaluated the safety and immune dynamics of a cancer vaccine consisting of 20 mixed peptides (KRM-20) designed to induce CTLs against 12 different TAA in patients with castration-resistant prostate cancer (CRPC). Patients received each of three different randomly assigned doses of KRM-20 (6, 20, or 60 mg) once ...
Source: Cancer Immunology, Immunotherapy - February 7, 2015 Category: Cancer & Oncology Source Type: research

Strengthened tumor antigen immune recognition by inclusion of a recombinant Eimeria antigen in therapeutic cancer vaccination
In this report, we investigated whether rAd5-rEA could promote and/or alter cytotoxic memory responses toward carcinoembryonic antigen (CEA), a colorectal cancer-related TAA. We found that the addition of rAd5-rEA to an Ad-based CEA vaccine induced a dose-dependent increase in several anti-CEA T and B cell responses. Moreover, inclusion of rAd5-rEA increased the number of CEA-derived antigenic epitopes that elicited significant cell-mediated and IgG-mediated recognition. These enhanced anti-CEA immune responses also translated into superior CEA-targeted cell killing, as evaluated by an in vivo cytotoxic T lymphocyte assay....
Source: Cancer Immunology, Immunotherapy - February 5, 2015 Category: Cancer & Oncology Source Type: research

Local expression of complement factor I in breast cancer cells correlates with poor survival and recurrence
Abstract Tumor cells often evade killing by the complement system by overexpressing membrane-bound complement inhibitors. However, production of soluble complement inhibitors in cells other than hepatocytes was rarely reported. We screened several breast cancer cell lines for expression of soluble complement inhibitor, complement factor I (FI). We also analyzed local production of FI in tissue microarrays with tumors from 130 breast cancer patients by in situ hybridization and immunohistochemistry. We found expression of FI in breast adenocarcinoma cell line MDA-MB-468 and confirmed its functional activity. Expres...
Source: Cancer Immunology, Immunotherapy - January 24, 2015 Category: Cancer & Oncology Source Type: research

The prognostic significance of stable disease following high-dose interleukin-2 (IL-2) treatment in patients with metastatic melanoma and renal cell carcinoma
Abstract High-dose interleukin-2 (HD IL-2) is an approved immunotherapy agent for metastatic melanoma and renal cell carcinoma resulting in objective responses in 15–20 % of patients. An additional subset of patients achieves stable disease, and the natural history of these patients has not been well documented. We hypothesized that stable disease following HD IL-2 is associated with a survival advantage. To explore this hypothesis, a retrospective chart review of 305 patients diagnosed with metastatic melanoma or renal cell carcinoma treated with HD IL-2 was conducted. Patient characteristics, response...
Source: Cancer Immunology, Immunotherapy - January 22, 2015 Category: Cancer & Oncology Source Type: research

Enhancement of glioma-specific immunity in mice by “NOBEL”, an insulin-like growth factor 1 receptor antisense oligodeoxynucleotide
Abstract Autologous glioblastoma multiforme tumor cells treated with an antisense oligodeoxynucleotide (AS-ODN) targeting insulin-like growth factor receptor-1 (IGF-1R) are the basis of a vaccine with therapeutic effects on tumor recurrence in a pilot clinical trial. As a preface to continued clinical investigation of this vaccination strategy, we have studied the contribution of an optimized IGF-1R AS-ODN, designated “NOBEL”, to the induction of immunity to mouse GL261 glioma cells. The impact of NOBEL on mechanisms contributing to the development of GL261 immunity was first examined in the perip...
Source: Cancer Immunology, Immunotherapy - January 12, 2015 Category: Cancer & Oncology Source Type: research

Cutaneous keratoacanthomas/squamous cell carcinomas associated with neutralization of transforming growth factor β by the monoclonal antibody fresolimumab (GC1008)
Abstract Fresolimumab is an antibody capable of neutralizing all human isoforms of transforming growth factor beta (TGFβ) and has demonstrated anticancer activity in investigational studies. Inhibition of TGFβ by fresolimumab can potentially result in the development of cutaneous lesions. The aim of this study was to investigate the clinical, histological, and immunohistochemical characteristics of cutaneous neoplasms associated with fresolimumab. Skin biopsies (n = 24) were collected and analyzed from patients (n = 5) with treatment-emergent, cutaneous lesions arising during a ph...
Source: Cancer Immunology, Immunotherapy - January 12, 2015 Category: Cancer & Oncology Source Type: research

Inhibition of induced nitric oxide synthase enhances the anti-tumor effects on cancer immunotherapy using TLR7 agonist in mice
Abstract Toll-like receptor (TLR) agonists have been shown to have anti-tumor activity in basic research and clinical studies. However, TLR agonist monotherapy in cancer treatment dose not sufficiently eliminate tumors. Activation of the innate immune response by TLR agonists and other pathogen-associated molecular patterns is effective for driving adaptive immunity via interleukin (IL)-12 or IL-1, but is counteracted by the simultaneous induction of immunosuppressive cytokines and other molecules, including IL-10, tumor growth factor-β, and induced nitric oxide synthase (iNOS). In the present study, we e...
Source: Cancer Immunology, Immunotherapy - January 8, 2015 Category: Cancer & Oncology Source Type: research

Increased proportion of FoxP3+ regulatory T cells in tumor infiltrating lymphocytes is associated with tumor recurrence and reduced survival in patients with glioblastoma
Abstract Glioblastoma multiforme (GBM) is an aggressive malignancy associated with profound host immunosuppression mediated in part by FoxP3 expressing regulatory CD4+ T lymphocytes (Tregs) that down-regulate anti-tumor immunity. In order to assess whether FoxP3 was an independent driver differentially expressed in primary versus recurrent GBMs, we stained resected primary and recurrent GBM tumors for CD3, CD4, CD8 and FoxP3 expression using standard immunohistochemistry. Slides were scanned with a high-resolution scanner (ScanScope CS; Aperio), and image analysis software (Aperio ScanScope) was used to enumerate ...
Source: Cancer Immunology, Immunotherapy - January 3, 2015 Category: Cancer & Oncology Source Type: research

Immune checkpoint combinations from mouse to man
Abstract The discovery that antibody blockade of the T cell co-inhibitory receptor cytotoxic T lymphocyte-associated protein 4 (CTLA-4) can restore tumor immunity against many murine transplantable tumors leading to complete rejection of established cancer forever changed the field of immunotherapy. In more robust murine models as well as human cancer, however, CTLA-4 blockade alone can slow tumor growth and extend patient survival, but is rarely curative. Subsequent studies have revealed a large family of T cell immune checkpoint receptors which tumors engage to shield themselves from host immunity. As with CTLA-...
Source: Cancer Immunology, Immunotherapy - January 3, 2015 Category: Cancer & Oncology Source Type: research

Novel N -amidinopiperidine-based proteasome inhibitor preserves dendritic cell functionality and rescues their Th1-polarizing capacity in Ramos-conditioned tumor environment
Abstract The tumor microenvironment represents a burden that hampers the proper activation of immune cells, including the dendritic cells (DCs). It is, therefore, desired that the important characteristics of a given anticancer drug candidate be seen as consisting not solely of its antitumor properties, but that it also lacks potential side effects that could additionally constrain the development and function of immune cells associated with tumor immunity. We have previously identified compounds with a N-amidinopiperidine scaffold that selectively induce apoptosis in Burkitt’s lymphoma cells through pr...
Source: Cancer Immunology, Immunotherapy - January 1, 2015 Category: Cancer & Oncology Source Type: research

Modulation of the myeloid compartment of the immune system by angiogenic- and kinase inhibitor-targeted anti-cancer therapies
Abstract Targeted therapies were rationally designed to inhibit molecular pathways in tumor cells critically involved in growth and survival; however, many drugs used in targeted therapies may affect the immune system. In addition, selected conventional chemotherapeutic agents have also been reported to be endowed with direct or indirect effects on immunity, for instance via immunogenic death of tumors. Thus, cancer therapies may have off-target effects, some of which are directed to the immune system. Here, we will review some of these effects in specific therapeutic approaches. We will examine the modulatio...
Source: Cancer Immunology, Immunotherapy - January 1, 2015 Category: Cancer & Oncology Source Type: research

Cancer stem cells: perspectives for therapeutic targeting
Abstract Cells with “stemness” and tumor-initiating properties have been isolated from both hematological and solid tumors. These cells denominated as cancer stem cells (CSCs), representing rare populations within tumors, have the ability to metastasize and are resistant to standard therapies and immunotherapy. Heterogeneity and plasticity in the phenotype of CSCs have been described in relation to their tissue origin. Few definitive markers have been isolated for CSCs from human solid tumors, limiting their usage for in vivo identification of these cells. Nevertheless, progress in the emerging CSCs c...
Source: Cancer Immunology, Immunotherapy - January 1, 2015 Category: Cancer & Oncology Source Type: research

“ Cancer Bio-Immunotherapy in Siena ”: Eleventh Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT), Siena, Italy, October 17–19, 2013
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 1, 2015 Category: Cancer & Oncology Source Type: research

Somatically mutated tumor antigens in the quest for a more efficacious patient-oriented immunotherapy of cancer
Abstract Although cancer immunotherapy shows efficacy with adoptive T cell therapy (ACT) and antibody-based immune checkpoint blockade, efficacious therapeutic vaccination of cancer patients with tumor-associated antigens (TAAs) remains largely unmet. Current cancer vaccines utilize nonmutated shared TAAs that may have suboptimal immunogenicity. Experimental evidence underscores the strong immunogenicity of unique TAAs derived from somatically mutated cancer proteins, whose massive characterization has been precluded until recently by technical limitations. The development of cost-effective, high-throughput DNA s...
Source: Cancer Immunology, Immunotherapy - January 1, 2015 Category: Cancer & Oncology Source Type: research

Immunotherapies and novel combinations: the focus of advances in the treatment of melanoma
Abstract Since 2011, the approval of four different classes of novel drugs (the anti-CTLA-4 agent, ipilimumab; BRAF inhibitors [BRAFi]; MEK inhibitors [MEKi]; and the anti-PD-1 drug, pembrolizumab) has revolutionized the care of advanced melanoma, with the disease becoming a model for the development of new treatments for other types of cancer. Further advances in the treatment of melanoma represented some of the key highlights of the European Society of Medical Oncology (ESMO) 2014 congress. The first phase III trial of an anti-PD-1 agent to report the CA209-037 study included 405 patients with metastatic melanom...
Source: Cancer Immunology, Immunotherapy - December 30, 2014 Category: Cancer & Oncology Source Type: research

DNAM-1-based chimeric antigen receptors enhance T cell effector function and exhibit in vivo efficacy against melanoma
In conclusion, DNAM-1-based CARs may have the potential to treat PVR and nectin-2 expressing hematological and solid tumors. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 30, 2014 Category: Cancer & Oncology Source Type: research