Chimeric antigen receptors with human scFvs preferentially induce T cell anti-tumor activity against tumors with high B7H6 expression
In this study, we validate the functionality of these human scFvs when formatted into chimeric antigen receptors. The data indicate that T cells expressing these B7H6-specific human scFvs as CARs induced potent anti-tumor activity in vitro and in vivo against tumors expressing high amounts of B7H6. Importantly, these human scFv-based CARs are sensitive to changes in B7H6 expression which may potentially spare non-tumor cells that express B7H6 and provides the foundation for future clinical development. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 16, 2018 Category: Cancer & Oncology Source Type: research

Chronic lymphocytic leukemia cells acquire regulatory B-cell properties in response to TLR9 and CD40 activation
In conclusion, CLL cells demonstrate a unique clonal quality of adopting Breg properties which promote modulation of T-cell characteristics. TLR9 appears to be a potent activator of regulatory abilities in CLL cells, possibly contributing to preferential immune escape of TLR9-responsive cells. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 15, 2018 Category: Cancer & Oncology Source Type: research

Identification of tumor-reactive B cells and systemic IgG in breast cancer based on clonal frequency in the sentinel lymph node
AbstractA better understanding of antitumor immune responses is the key to advancing the field of cancer immunotherapy. Endogenous immunity in cancer patients, such as circulating anticancer antibodies or tumor-reactive B cells, has been historically yet incompletely described. Here, we demonstrate that tumor-draining (sentinel) lymph node (SN) is a rich source for tumor-reactive B cells that give rise to systemic IgG anticancer antibodies circulating in the bloodstream of breast cancer patients. Using a synergistic combination of high-throughput B-cell sequencing and quantitative immunoproteomics, we describe the prospect...
Source: Cancer Immunology, Immunotherapy - February 9, 2018 Category: Cancer & Oncology Source Type: research

Pretreatment neutrophil-to-lymphocyte ratio is associated with outcome of advanced-stage cancer patients treated with immunotherapy: a meta-analysis
AbstractBackgroundTo investigate the association between pretreatment blood neutrophil-to-lymphocyte ratio (NLR) and clinical outcomes for advanced-stage cancer patients treated with immunotherapy.MethodsWe conducted a comprehensive literature search to assess the relationship between pretreatment blood NLR and overall survival (OS) or progression-free survival (PFS) in advanced-stage cancer patients treated with immunotherapy. Published data including hazard ratios (HRs) and related 95% confidence interval (CI) were extracted. Pooled estimates of treatment outcomes were calculated using RevMan 5.3.5.ResultsTwenty-seven st...
Source: Cancer Immunology, Immunotherapy - February 8, 2018 Category: Cancer & Oncology Source Type: research

Acknowledgements
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - February 7, 2018 Category: Cancer & Oncology Source Type: research

N- acetyl cysteine protects anti-melanoma cytotoxic T cells from exhaustion induced by rapid expansion via the downmodulation of Foxo1 in an Akt-dependent manner
AbstractTherapeutic outcomes for adoptive cell transfer (ACT) therapy are constrained by the quality of the infused T cells. The rapid expansion necessary to obtain large numbers of cells results in a more terminally differentiated phenotype with decreased durability and functionality. N-acetyl cysteine (NAC) protects against activation-induced cell death (AICD) and improves anti-tumor efficacy of Pmel-1 T cells in vivo. Here, we show that these benefits of NAC can be extended to engineered T cells and significantly increases T-cell survival within the tumor microenvironment. The addition of NAC to the expansion protocol o...
Source: Cancer Immunology, Immunotherapy - February 2, 2018 Category: Cancer & Oncology Source Type: research

An IL-15 superagonist/IL-15R α fusion complex protects and rescues NK cell-cytotoxic function from TGF-β1-mediated immunosuppression
AbstractNatural killer (NK) cells are innate cytotoxic lymphocytes that play a fundamental role in the immunosurveillance of cancers. NK cells of cancer patients exhibit impaired function mediated by immunosuppressive factors released from the tumor microenvironment (TME), such as transforming growth factor (TGF)- β1. An interleukin (IL)-15 superagonist/IL-15 receptor α fusion complex (IL-15SA/IL-15RA; ALT-803) activates the IL-15 receptor on CD8 T cells and NK cells, and has shown significant anti-tumor activity in several in vivo studies. This in vitro study investigated the efficacy of IL-15SA/IL-15RA on TGF-...
Source: Cancer Immunology, Immunotherapy - February 1, 2018 Category: Cancer & Oncology Source Type: research

Clinical translation and regulatory aspects of CAR/TCR-based adoptive cell therapies —the German Cancer Consortium approach
AbstractAdoptive transfer of T cells genetically modified by TCRs or CARs represents a highly attractive novel therapeutic strategy to treat malignant diseases. Various approaches for the development of such gene therapy medicinal products (GTMPs) have been initiated by scientists in recent years. To date, however, the number of clinical trials commenced in Germany and Europe is still low. Several hurdles may contribute to the delay in clinical translation of these therapeutic innovations including the significant complexity of manufacture and non-clinical testing of these novel medicinal products, the limited knowledge ab...
Source: Cancer Immunology, Immunotherapy - January 29, 2018 Category: Cancer & Oncology Source Type: research

Epstein –Barr virus strain heterogeneity impairs human T-cell immunity
AbstractThe Epstein –Barr virus (EBV) establishes lifelong infections in>  90% of the human population. Although contained as asymptomatic infection by the immune system in most individuals, EBV is associated with the pathogenesis of approximately 1.5% of all cancers in humans. Some of these EBV-associated tumors have been successfully treated by the infusion of virus-s pecific T-cell lines. Recent sequence analyses of a large number of viral isolates suggested that distinct EBV strains have evolved in different parts of the world. Here, we assessed the impact of such sequence variations on EBV-specific T-c...
Source: Cancer Immunology, Immunotherapy - January 27, 2018 Category: Cancer & Oncology Source Type: research

Abscopal effects of radiotherapy and combined mRNA-based immunotherapy in a syngeneic, OVA-expressing thymoma mouse model
ConclusionCombined irradiation and immunotherapy is able to induce abscopal responses, even with low, normofractionated radiation doses. Thus, the combination of mRNA-based vaccination with irradiation might be an effective regimen to induce systemic anti-tumor immunity. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 16, 2018 Category: Cancer & Oncology Source Type: research

T cell responses to tumor: how dominant assumptions on immune activity led to a neglect of pathological functions, and how evolutionary considerations can help identify testable hypotheses for improving immunotherapy
We describe how attempting to answer some of these questions experimentally, such as identifying the contributors of tumor-associated fibrosis, has led to potentially useful insights on how to improve immunotherapy. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 15, 2018 Category: Cancer & Oncology Source Type: research

Combined sublethal irradiation and agonist anti-CD40 enhance donor T cell accumulation and control of autochthonous murine pancreatic tumors
AbstractTumor-reactive T lymphocytes can promote the regression of established tumors. However, their efficacy is often limited by immunosuppressive mechanisms that block T cell accumulation or function. ACT provides the opportunity to ameliorate immune suppression prior to transfer of tumor-reactive T cells to improve the therapeutic benefit. We evaluated the combination of lymphodepleting whole body irradiation (WBI) and agonist anti-CD40 ( αCD40) antibody on control of established autochthonous murine neuroendocrine pancreatic tumors following the transfer of naïve tumor-specific CD8 T cells. Sublethal WBI ha...
Source: Cancer Immunology, Immunotherapy - January 13, 2018 Category: Cancer & Oncology Source Type: research

Linear doggybone DNA vaccine induces similar immunological responses to conventional plasmid DNA independently of immune recognition by TLR9 in a pre-clinical model
AbstractVaccination with DNA that encodes cancer antigens is a simple and convenient way to raise immunity against cancer and has already shown promise in the clinical setting. Conventional plasmid DNA is commonly used which together with the encoded antigen also includes bacterial immunostimulatory CpG motifs to target the DNA sensor Toll-like receptor 9. Recently DNA vaccines using doggybone DNA (dbDNA ™), have been developed without the use of bacteria. The cell-free process relies on the use of Phi29 DNA polymerase to amplify the template followed by protelomerase TelN to complete individual closed linear DNA. Th...
Source: Cancer Immunology, Immunotherapy - January 12, 2018 Category: Cancer & Oncology Source Type: research

The role of interleukin-2, all- trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma
AbstractAlthough anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induc...
Source: Cancer Immunology, Immunotherapy - January 11, 2018 Category: Cancer & Oncology Source Type: research

A novel biologic platform elicits profound T cell costimulatory activity and antitumor immunity in mice
AbstractCombination immunotherapies utilizing complementary modalities that target distinct tumor attributes or immunosuppressive mechanisms, or engage different arms of the antitumor immune response, can elicit greater therapeutic efficacy than the component monotherapies. Increasing the number of agents included in a therapeutic cocktail can further increase efficacy, however, this approach poses numerous challenges for clinical translation. Here, a novel platform to simplify combination immunotherapy by covalently linking immunotherapeutic agonists to the costimulatory receptors CD134 and CD137 into a single heterodimer...
Source: Cancer Immunology, Immunotherapy - January 11, 2018 Category: Cancer & Oncology Source Type: research

Correction to: Characterization of the first fully human anti-TEM1 scFv in models of solid tumor imaging and immunotoxin-based therapy
AbstractTumor endothelial marker 1 (TEM1) has been identified as a novel surface marker upregulated on the blood vessels and stroma in many solid tumors. We previously isolated a novel single-chain variable fragment (scFv) 78 against TEM1 from a yeast display scFv library. Here we evaluated the potential applications of scFv78 as a tool for tumor molecular imaging, immunotoxin-based therapy and nanotherapy. Epitope mapping, three-dimensional (3D) structure docking and affinity measurements indicated that scFv78 could bind to both human and murine TEM1, with equivalent affinity, at a well-conserved conformational epitope. T...
Source: Cancer Immunology, Immunotherapy - January 8, 2018 Category: Cancer & Oncology Source Type: research

Reduction of myeloid-derived suppressor cells reinforces the anti-solid tumor effect of recipient leukocyte infusion in murine neuroblastoma-bearing allogeneic bone marrow chimeras
In conclusion, the RLI-induced alloreactivity gives rise to a host-derived cytotoxic T-cell anti-neuroblas toma response, but also drives an expansion of host-type MDSC that counteracts the anti-tumor effect. This finding identifies MDSC as a novel target to increase the effectiveness of RLI, and possibly other cancer immunotherapies. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - January 3, 2018 Category: Cancer & Oncology Source Type: research

Ex vivo-expanded NK cells from blood and ascites of ovarian cancer patients are cytotoxic against autologous primary ovarian cancer cells
AbstractOvarian cancer (OC) is the leading cause of gynecological cancer-related death in North America. Most ovarian cancer patients (OCPs) experience disease recurrence after first-line surgery and chemotherapy; thus, there is a need for novel second-line treatments to improve the prognosis of OC. Although peripheral blood-derived NK cells are known for their ability to spontaneously lyse tumour cells without prior sensitization, ascites-derived NK cells (ascites-NK cells) isolated from OCPs exhibit inhibitory phenotypes, impaired cytotoxicity and may play a pro-tumourigenic role in cancer progression. Therefore, it is o...
Source: Cancer Immunology, Immunotherapy - January 3, 2018 Category: Cancer & Oncology Source Type: research

Anti-PD-1-induced high-grade hepatitis associated with corticosteroid-resistant T cells: a case report
We present an unusually severe case arising in a melanoma patient after more than 6  months uncomplicated treatment with anti-PD-1 in an adjuvant setting. The hepatitis rapidly developed resistance to high-dose steroids, requiring anti-thymocyte globulin (ATG) to achieve control. Mass cytometry allowed comprehensive phenotyping of circulating lymphocytes and revealed that CD4+ T cells were profoundly depleted by ATG, while CD8+ T cells, B cells, NK cells and monocytes were relatively spared. Multiple abnormalities in CD4+ T cell phenotype were stably present in the patient before disease onset. These included a popula...
Source: Cancer Immunology, Immunotherapy - December 30, 2017 Category: Cancer & Oncology Source Type: research

Cytosolic high-mobility group box protein 1 (HMGB1) and/or PD-1+  TILs in the tumor microenvironment may be contributing prognostic biomarkers for patients with locally advanced rectal cancer who have undergone neoadjuvant chemoradiotherapy
In conclusion, our results provide evidence that cyto-HMGB1 and/or PD-1+TIL are not only predictive biomarkers before treatment, but they can also potentially designate patients for personalized oncological management including immunotherap y. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 21, 2017 Category: Cancer & Oncology Source Type: research

Splice variants of human natural cytotoxicity receptors: novel innate immune checkpoints
AbstractThe natural cytotoxicity receptors (NCRs; NKp30, NKp44, and NKp46) were first defined as activating receptors on human NK cells that are important in recognition of and response to tumors. A flurry of recent research, however, has revealed that differential splicing can occur during transcription of each of the NCR genes, resulting in some transcripts that encode receptor isoforms with inhibitory functions. These alternative transcripts can arise in certain tissue microenvironments and appear to be induced by cytokines. Evidence indicates that some of the inhibitory NCRs are triggered by specific ligands, such as t...
Source: Cancer Immunology, Immunotherapy - December 20, 2017 Category: Cancer & Oncology Source Type: research

Correction to: Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells
AbstractThe authors would like to make the following corrections to the published article. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 20, 2017 Category: Cancer & Oncology Source Type: research

IL-6 and IL-10 are associated with good prognosis in early stage invasive breast cancer patients
In this study the roles of IL-6/IL-10 in regulating vascular invasion and their prognostic significance in BC are investigated. MDA-MB-231 and MCF-7 migration ( ± IL-6 or IL-10) was assessed by scratch wound assay. Cancer cell adhesion to IL-6/IL-10 stimulated blood and lymphatic endothelial cells (EC) was investigated. Expression of IL-6 /IL-10 was assessed using immunohistochemistry in an annotated cohort of early stage BC (n = 1380) and associations with clinicopathological variables and clinical outcome evaluated. IL-6 did not alter BC cell migration however a dose-dependent inhibition in MDA-MB-23...
Source: Cancer Immunology, Immunotherapy - December 18, 2017 Category: Cancer & Oncology Source Type: research

Human c-SRC kinase (CSK) overexpression makes T cells dummy
AbstractAdoptive cell therapy with T-cell receptor (TCR)-engineered T cells represents a powerful method to redirect the immune system against tumours. However, although TCR recognition is restricted to a specific peptide –MHC (pMHC) complex, increasing numbers of reports have shown cross-reactivity and off-target effects with severe consequences for the patients. This demands further development of strategies to validate TCR safety prior to clinical use. We reasoned that the desired TCR signalling depends on corre ct pMHC recognition on the outside and a restricted clustering on the inside of the cell. Since the maj...
Source: Cancer Immunology, Immunotherapy - December 16, 2017 Category: Cancer & Oncology Source Type: research

High PD-L1 expression indicates poor prognosis of HIV-infected patients with non-small cell lung cancer
ConclusionHigh PD-L1 expression in tumor tissue was associated with poor prognosis in HIV-infected NSCLC patients but not in non-HIV-infected NSCLC patients. These results suggest that antitumor immunity by PD-1/PD-L1 axis might be suppressed more in HIV-infected NSCLC patients as compared to their non-HIV-infected counterparts. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 14, 2017 Category: Cancer & Oncology Source Type: research

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells
We report a novel phase 2 clinical trial in patients with poor prognosis refractory non-Hodgkin lymphoma (NHL) testing the efficacy of haploidentical donor natural killer (NK) cell therapy (NK dose 0.5 –3.27 × 107 NK cells/kg) with rituximab and IL-2 (clinicaltrials.gov NCT01181258). Therapy was tolerated without graft-versus-host disease, cytokine release syndrome, or neurotoxicity. Of 14 evaluable patients, 4 had objective responses (29%; 95% CI 12 –55%) at 2 months: 2 had complete response lasting 3 and 9 months. Circulating donor NK cells persisted for at least 7 days after infusion at t...
Source: Cancer Immunology, Immunotherapy - December 7, 2017 Category: Cancer & Oncology Source Type: research

Characterization of PD-L1 expression in Chinese non-small cell lung cancer patients with PTEN expression as a means for tissue quality screening
AbstractThe goal of this study is to evaluate PD-L1 prevalence and its association with major clinical characteristics in Chinese non-small cell lung cancer (NSCLC) patients to inform the clinical development of anti-PD1/PD-L1 agents in this population. We used phosphatase and tensin homolog (PTEN) expression through IHC as a surrogate tissue quality marker to screen surgical NSCLC samples in tissue microarray (TMA; 172 cases) or whole-section (268 cases) format. The samples were then analyzed with a clinically validated PD-L1 IHC assay. The results were correlated with baseline characteristics and clinical outcomes. PTEN ...
Source: Cancer Immunology, Immunotherapy - December 6, 2017 Category: Cancer & Oncology Source Type: research

Combination of mAb-AR20.5, anti-PD-L1 and PolyICLC inhibits tumor progression and prolongs survival of MUC1.Tg mice challenged with pancreatic tumors
AbstractA substantial body of evidence suggests the existence of MUC1-specific antibodies and cytotoxic T cell activities in pancreatic cancer patients. However, tumor-induced immunosuppression renders these responses ineffective. The current study explores a novel therapeutic combination wherein tumor-bearing hosts can be immunologically primed with their own antigen, through opsonization with a tumor antigen-targeted antibody, mAb-AR20.5. We evaluated the efficacy of immunization with this antibody in combination with PolyICLC and anti-PD-L1. The therapeutic combination of mAb-AR20.5  + anti-PD-L1 +&...
Source: Cancer Immunology, Immunotherapy - December 4, 2017 Category: Cancer & Oncology Source Type: research

Post-treatment neutrophil-to-lymphocyte ratio at week 6 is prognostic in patients with advanced non-small cell lung cancers treated with anti-PD-1 antibody
Abstract We investigated inflammatory markers such as the neutrophil-to-lymphocyte ratio (NLR) that may predict the response to anti-PD-1 (programmed cell death protein 1) antibody therapy. Data from 54 patients with non-small cell lung cancer (NSCLC) treated with anti-PD-1 antibodies were retrospectively analyzed. The NLR was assessed at baseline and 6  weeks after the start of treatment (post-treatment). Eighteen of 54 patients (33.3%) had objective responses to treatment. Older age, absence of brain metastasis, low post-treatment NLR (
Source: Cancer Immunology, Immunotherapy - December 4, 2017 Category: Cancer & Oncology Source Type: research

The Immunoscore system predicts prognosis after liver metastasectomy in colorectal cancer liver metastases
AbstractBackgroundThe Immunoscore was initially established to evaluate the prognosis of stage I/II/III colorectal cancer patients. However, the feasibility of the Immunoscore for the prognosis of colorectal cancer liver metastases (CRCLM) has not been reported.MethodsLiver metastases in 249 CRCLM patients were retrospectively analyzed. The Immunoscore was assessed according to the counts and densities of CD3+ and CD8+ T cells in the central- and peritumoral areas by immunohistochemistry. The prognostic role of the Immunoscore for relapse –free survival (RFS) and overall survival (OS) was analyzed with Kaplan–M...
Source: Cancer Immunology, Immunotherapy - December 4, 2017 Category: Cancer & Oncology Source Type: research

Therapeutic reduction of cell-mediated immunosuppression in mycosis fungoides and S ézary syndrome
AbstractTumor progression is associated with progressive immunosuppression mediated in part by T regulatory cell(s) (Treg) and/or myeloid-derived suppressor cell(s) (MDSC). Development of strategies to reduce populations of immune cells with suppressive function in cancer patients may enable the induction or recovery of immunity against tumor cells, which may limit or reverse disease progression. With a goal of developing Treg and MDSC neutralizing strategies to treat mycosis fungoides (MF) and S ézary syndrome (SzS), we determined the association between disease stage and suppressor cell populations in patients wit...
Source: Cancer Immunology, Immunotherapy - December 4, 2017 Category: Cancer & Oncology Source Type: research

2nd Symposium on Advances in Cancer Immunology and Immunotherapy, December 15 –17, 2016, Athens, Greece
AbstractThis is the 2nd Symposium of a series organized annually. It aims to integrate tumor immunology basic research with results from most recent clinical trials based on the use of anti-cancer agents targeting immune system components. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - December 1, 2017 Category: Cancer & Oncology Source Type: research

Epidemiology, biology and therapy of Merkel cell carcinoma: conclusions from the EU project IMMOMEC
AbstractMerkel cell carcinoma (MCC) is a highly aggressive, often lethal neuroendocrine cancer. Its carcinogenesis may be either caused by the clonal integration of the Merkel cell polyomavirus into the host genome or by UV-induced mutations. Notably, virally-encoded oncoproteins and UV-induced mutations affect comparable signaling pathways such as RB restriction of cell cycle progression or p53 inactivation. Despite its low incidence, MCC recently received much attention based on its exquisite immunogenicity and the resulting major success of immune modulating therapies. Here, we summarize current knowledge on epidemiolog...
Source: Cancer Immunology, Immunotherapy - November 30, 2017 Category: Cancer & Oncology Source Type: research

Synergistic cytotoxicity of a prostate cancer-specific immunotoxin in combination with the BH3 mimetic ABT-737
AbstractIn many tumors, including prostate cancer, anti-apoptotic members of the Bcl-2 family are overexpressed and cause cell death resistance, which is a typical hallmark of cancer. Different therapeutic approaches, therefore, aim to restore the death mechanisms for enhanced apoptosis. Our recombinant immunotoxin D7(VL-VH)-PE40 is composed of the scFv D7(VL-VH) against the prostate-specific membrane antigen (PSMA) on the surface of prostate cancer cells and of the cytotoxic domain of the bacterial toxinPseudomonas Exotoxin A (PE40). SincePseudomonas Exotoxin A-based immunotoxins are known to preferentially inhibit the ex...
Source: Cancer Immunology, Immunotherapy - November 29, 2017 Category: Cancer & Oncology Source Type: research

High PDL1 mRNA expression predicts better survival of stage pT1 non-muscle-invasive bladder cancer (NMIBC) patients
The objective of the present study was to evaluate the prognostic role of PD1 and PDL1 expression in non-muscle-invasive bladder cancer (NMIBC) and establish an objective measuring method using RNA quantification.Materials and methodsWe retrospectively analyzed clinical data and formalin-fixed paraffin-embedded tissues (FFPE) of patients with stage pT1 NMIBC who underwent transurethral resection of the bladder. mRNA expression of PD1, PDL1 and CD3 was measured by single step RT-qPCR and correlated to clinicopathological parameters, recurrence-free survival (RFS), progression-free survival (PFS) and carcinoma-specific survi...
Source: Cancer Immunology, Immunotherapy - November 17, 2017 Category: Cancer & Oncology Source Type: research

Cancer vaccine strategies: translation from mice to human clinical trials
AbstractWe translated two cancer vaccine strategies from mice into human clinical trials. (1) In preclinical studies on TARP, an antigen expressed in most prostate cancers, we mapped epitopes presented by HLA-A*0201, modified them to increase affinity and immunogenicity in HLA transgenic mice, and induced human T cells that killed human cancer cells ( “epitope enhancement”). In a clinical trial, HLA-A2+ prostate cancer patients with PSA biochemical recurrence (Stage D0) were vaccinated with two peptides either in Montanide-ISA51 or on autologous dendritic cells (DCs). In stage D0, the Prostate-Specific Antigen ...
Source: Cancer Immunology, Immunotherapy - November 15, 2017 Category: Cancer & Oncology Source Type: research

Targeting and suppression of HER3-positive breast cancer by T lymphocytes expressing a heregulin chimeric antigen receptor
In this study, we engineered T cells with a CAR consisting of the extracellular domain of heregulin-1 β (HRG1β) that is a natural ligand for HER3/HER4, and evaluated the specific cytotoxicity of these CAR-T cells in cultured HER3 positive breast cancer cells and xenograft tumors. Our results showed that HRG1β-CAR was successfully constructed, and T cells were transduced at a rate of 50%. The CAR- T cells specifically recognized and killed HER3-overexpressing breast cancer cells SK-BR-3 and BT-474 in vitro, and displayed potent tumoricidal effect on SK-BR-3 xenograft tumor models. Our results suggest that HRG...
Source: Cancer Immunology, Immunotherapy - November 10, 2017 Category: Cancer & Oncology Source Type: research

Prophylactic DNA vaccine targeting Foxp3 + regulatory T cells depletes myeloid-derived suppressor cells and improves anti-melanoma immune responses in a murine model
In conclusion, our results revealed that Foxp3 vaccine promotes an immune response against tumor by targeting both Treg and MDSC, which could b e exploited as a potential immunotherapy approach. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - November 9, 2017 Category: Cancer & Oncology Source Type: research

The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy
AbstractCheckpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment. Mocetinostat is a spectrum-selective inhibitor of class I/IV histone deacetylases (HDACs), a family of proteins implicated in epigenetic silencing of immune regulatory genes in tumor and immu...
Source: Cancer Immunology, Immunotherapy - November 9, 2017 Category: Cancer & Oncology Source Type: research

Tumor-derived high-mobility group box 1 and thymic stromal lymphopoietin are involved in modulating dendritic cells to activate T regulatory cells in a mouse model
AbstractHigh-mobility group box 1 (HMGB1) is involved in the tumor-associated activation of regulatory T cells (Treg), but the mechanisms remain unknown. In a mouse tumor model, silencing HMGB1 in tumor cells or inhibiting tumor-derived HMGB1 not only dampened the capacity of tumor cells to produce thymic stromal lymphopoietin (TSLP), but also aborted the tumor-associated modulation of Treg-activating DC. Tumor-derived HMGB1 triggered the production of TSLP by tumor cells. Importantly, both tumor-derived HMGB1 and TSLP were necessary for modulating DC to activate Treg in a TSLP receptor (TSLPR)-dependent manner. In the the...
Source: Cancer Immunology, Immunotherapy - November 7, 2017 Category: Cancer & Oncology Source Type: research

BRAF peptide vaccine facilitates therapy of murine BRAF-mutant melanoma
AbstractApproximately, 50% of human melanomas are driven by BRAF mutations, which produce tumors that are highly immunosuppressive and often resistant to vaccine therapy. We introduced lipid-coated calcium phosphate nanoparticles (LCP NPs) as a carrier to efficiently deliver a tumor-specific antigen, the BRAFV600E peptide, to drive dendritic cell (DC) maturation and antigen presentation in C57BL6 mice. The BRAF peptide vaccine elicited a robust, antigen-specific cytotoxic T cell response and potent tumor growth inhibition in a murine BRAF-mutant melanoma model. Advanced BRAF-specific immune response was illustrated by IFN-...
Source: Cancer Immunology, Immunotherapy - November 1, 2017 Category: Cancer & Oncology Source Type: research

A phase I vaccination study with dendritic cells loaded with NY-ESO-1 and α-galactosylceramide: induction of polyfunctional T cells in high-risk melanoma patients
AbstractVaccines that elicit targeted tumor antigen-specific T-cell responses have the potential to be used as adjuvant therapy in patients with high risk of relapse. However, the responses induced by vaccines in cancer patients have generally been disappointing. To improve vaccine function, we investigated the possibility of exploiting the immunostimulatory capacity of type 1 Natural killer T (NKT) cells, a cell type enriched in lymphoid tissues that can trigger improved antigen-presenting function in dendritic cells (DCs). In this phase I dose escalation study, we treated eight patients with high-risk surgically resected...
Source: Cancer Immunology, Immunotherapy - November 1, 2017 Category: Cancer & Oncology Source Type: research

Cross-talk between TNF- α and IFN-γ signaling in induction of B7-H1 expression in hepatocellular carcinoma cells
AbstractClinical benefit from immunotherapy of B7-H1/PD-1 checkpoint blockade indicates that it is important to understand the regulatory mechanism of B7-H1 expression in cancer cells. As an adaptive response to the endogenous antitumor immunity, B7-H1 expression is up-regulated in HCC cells. B7-H1 expression is induced mainly by IFN- γ released from tumor-infiltrating T cells in HCC. In addition, HCC is a prototype of inflammation-related cancer and TNF-α is a critical component of inflammatory microenvironment of HCC. In the present study, we asked whether TNF-α can promote the expression of B7-H1 induc...
Source: Cancer Immunology, Immunotherapy - October 31, 2017 Category: Cancer & Oncology Source Type: research

CXCL13 expression is prognostic and predictive for postoperative adjuvant chemotherapy benefit in patients with gastric cancer
ConclusionsIntratumoral CXCL13 expression appears as an independent prognostic marker for patients after gastric cancer resection. In addition, CXCL13 expression may serve as a predictive biomarker of response to postoperative adjuvant chemotherapy in these patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 31, 2017 Category: Cancer & Oncology Source Type: research

A CD3-bispecific molecule targeting P-cadherin demonstrates T cell-mediated regression of established solid tumors in mice
AbstractStrong evidence exists supporting the important role T cells play in the immune response against tumors. Still, the ability to initiate tumor-specific immune responses remains a challenge. Recent clinical trials suggest that bispecific antibody-mediated retargeted T cells are a promising therapeutic approach to eliminate hematopoietic tumors. However, this approach has not been validated in solid tumors. PF-06671008 is a dual-affinity retargeting (DART®)-bispecific protein engineered with enhanced pharmacokinetic properties to extend in vivo half-life, and designed to engage and activate endogenous polyclonal T...
Source: Cancer Immunology, Immunotherapy - October 24, 2017 Category: Cancer & Oncology Source Type: research

Clinical and immunologic evaluation of three metastatic melanoma patients treated with autologous melanoma-reactive TCR-transduced T cells
We describe preliminary results from a Phase I clinical trial (NCT01586403) of adoptive cell therapy in which three patients received autologous CD4+ and CD8+ T cells transduced with a lentivirus carrying a tyrosinase-specific TCR and a marker protein, truncated CD34 (CD34t). This unusual MHC Class I-restricted TCR produces functional responses in both CD4+ and CD8+ T cells. Parameters monitored on transduced T cells included activation (CD25, CD69), inhibitory (PD-1, TIM-3, CTLA-4), costimulatory (OX40), and memory (CCR7) markers. For the clinical trial, T cells were activated, transduced, selected for CD34t+ cells, then ...
Source: Cancer Immunology, Immunotherapy - October 20, 2017 Category: Cancer & Oncology Source Type: research

Fourteenth Meeting of the Network Italiano per la Bioterapia dei Tumori (NIBIT) on Cancer Bio-Immunotherapy, Siena, Italy, October 13 –15, 2016
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - October 20, 2017 Category: Cancer & Oncology Source Type: research

NY-ESO-1- and survivin-specific T-cell responses in the peripheral blood from patients with glioma
AbstractThe prognosis for patients with glioblastoma is grim. Ex vivo expanded tumor-associated antigen (TAA)-reactive T-cells from patients with glioma may represent a viable source for anticancer-directed cellular therapies. Immunohistochemistry was used to test the survivin (n = 40 samples) and NY-ESO-1 (n = 38 samples) protein expression in tumor specimens. T-cells from peripheral blood were stimulated with TAAs (synthetic peptides) in IL-2 and IL-7, or using a combination of IL-2, IL-15 and IL-21. CD4+ and CD8+ T-cells were tested for antigen-specific proliferation by flow cytometry, and IFN- &gamm...
Source: Cancer Immunology, Immunotherapy - October 20, 2017 Category: Cancer & Oncology Source Type: research

Immunotherapy for hepatocellular carcinoma patients: is it ready for prime time?
AbstractHepatocellular carcinoma (HCC) is the most common primary liver malignancy and the second most common cause of cancer death worldwide. Current treatment options for patients with intermediate and advanced HCC are limited, and there is an unmet need for novel therapeutic approaches. HCC is an attractive target for immunomodulation therapy, since it arises in an inflammatory milieu due to hepatitis B and C infections and cirrhosis. However, a major barrier to the development and success of immunotherapy in patients with HCC is the liver ’s inherent immunosuppressive function. Recent advances in the field of can...
Source: Cancer Immunology, Immunotherapy - October 20, 2017 Category: Cancer & Oncology Source Type: research

Absolute lymphocyte counts at end of induction correlate with distinct immune cell compartments in pediatric B cell precursor acute lymphoblastic leukemia
AbstractSeveral retrospective studies in children with B cell precursor (BCP) acute lymphoblastic leukemia (ALL) provided clinical evidence that higher absolute lymphocyte counts (ALC) early into treatment significantly correlated with improved relapse-free and overall survival. It still remains unknown, however, whether the predictive role of higher ALCs reflects general bone marrow recovery or a more specific attribute of immune function. To investigate this question, we implemented a prospective observational cohort study in 20 children with BCP ALL on day 29 (D29) of induction chemotherapy and immunophenotyped their ly...
Source: Cancer Immunology, Immunotherapy - October 20, 2017 Category: Cancer & Oncology Source Type: research