Understanding TCR affinity, antigen specificity, and cross-reactivity to improve TCR gene-modified T cells for cancer immunotherapy
AbstractAdoptive cell transfer (ACT) using T cell receptor (TCR) gene-modified T cells is an exciting and rapidly evolving field. Numerous preclinical and clinical studies have demonstrated various levels of feasibility, safety, and efficacy using TCR-engineered T cells to treat cancer and viral infections. Although evidence suggests their use can be effective, to what extent and how to improve these therapeutics are still matters of investigation. As TCR affinity has been generally accepted as the central role in defining T cell specificity and sensitivity, selection for and generation of high affinity TCRs has remained a...
Source: Cancer Immunology, Immunotherapy - October 7, 2019 Category: Cancer & Oncology Source Type: research

PTPN3 expressed in activated T lymphocytes is a candidate for a non-antibody-type immune checkpoint inhibitor
AbstractIt has been shown that protein tyrosine phosphatase non-receptor type (PTPN) 3 inhibits T-cell activation. However, there is no definitive conclusion about how the inhibition of PTPN3 in lymphocytes affects immune functions in human lymphocytes. In the present study, we showed that PTPN3 inhibition significantly contributes to the enhanced activation of activated human lymphocytes. The PTPN3 expression of lymphocytes was significantly increased through the activation process using IL-2 and anti-CD3 mAb. Interestingly, inhibiting thePTPN3 expression in activated lymphocytes significantly augmented the proliferation,...
Source: Cancer Immunology, Immunotherapy - September 26, 2019 Category: Cancer & Oncology Source Type: research

Activation of dendritic cells by targeted DNA: a potential addition to the armamentarium for anti-cancer immunotherapy
AbstractIn the past decade, remarkable progress has been made in immunotherapy against cancer. Specifically, the introduction of immune checkpoint inhibitors has revolutionized the field. However, many patients are unable to benefit significantly from this treatment option. One of the major reasons for this is most likely the absence of an adequate tumor-specific T cell response in these patients. A way to circumvent this problem might be to combine immune checkpoint inhibitor treatment with new strategies to activate tumor-specific T cells. One such  strategy could be to activate and mature dendritic cells in situ. D...
Source: Cancer Immunology, Immunotherapy - September 25, 2019 Category: Cancer & Oncology Source Type: research

Gastrin vaccine improves response to immune checkpoint antibody in murine pancreatic cancer by altering the tumor microenvironment
AbstractPancreatic cancer has been termed a ‘recalcitrant cancer’ due to its relative resistance to chemotherapy and immunotherapy. This resistance is thought to be due in part to the dense fibrotic tumor microenvironment and lack of tumor infiltrating CD8 + T cells. The gastrointestinal peptide, gastrin, has been shown to stimulate g rowth of pancreatic cancer by both a paracrine and autocrine mechanism. Interruption of gastrin at the CCK receptor may reduce tumor-associated fibrosis and alter tumor immune cells. Polyclonal Ab Stimulator (PAS) is a vaccine that targets gastrin and has been shown ...
Source: Cancer Immunology, Immunotherapy - September 23, 2019 Category: Cancer & Oncology Source Type: research

The BRCA2 mutation status shapes the immune phenotype of prostate cancer
AbstractDefects in DNA damage repair caused by mutations inBRCA1/2, ATM or other genes have been shown to play an important role in the development and progression of prostate cancer. The influence of such mutations on anti-tumor immunity in prostate cancer, however, is largely unknown. To better understand the correlation betweenBRCA1/2 mutations and the immune phenotype in prostate cancer, we characterized the immune infiltrate of eightBRCA2-mutated tumors in comparison with eightBRCA1/2 wild-type patients by T-cell receptor sequencing and immunohistochemistry for CD45, CD4, CD8, FOXP3, and CD163. In addition, we analyze...
Source: Cancer Immunology, Immunotherapy - September 22, 2019 Category: Cancer & Oncology Source Type: research

Conventional CARs versus modular CARs
AbstractThe clinical application of immune effector cells genetically modified to express chimeric antigen receptors (CARs) has shown impressive results including complete remissions of certain malignant hematological diseases. However, their application can also cause severe side effects such as cytokine release syndrome (CRS) or tumor lysis syndrome (TLS). One limitation of currently applied CAR T cells is their lack of regulation. Especially, an emergency shutdown of CAR T cells in case of life-threatening side effects is missing. Moreover, targeting of tumor-associated antigens (TAAs) that are not only expressed on tum...
Source: Cancer Immunology, Immunotherapy - September 20, 2019 Category: Cancer & Oncology Source Type: research

T cell engineering for adoptive T cell therapy: safety and receptor avidity
AbstractSince the first bone marrow transplantation, adoptive T cell therapy (ACT) has developed over the last 80  years to a highly efficient and specific therapy for infections and cancer. Genetic engineering of T cells with antigen-specific receptors now provides the possibility of generating highly defined and efficacious T cell products. The high sensitivity of engineered T cells towards their targets, ho wever, also bears the risk of severe off-target toxicities. Therefore, different safety strategies for engineered T cells have been developed that enable removal of the transferred cells in case of adverse event...
Source: Cancer Immunology, Immunotherapy - September 20, 2019 Category: Cancer & Oncology Source Type: research

Anti-PD-1 therapy combined with chemotherapy in patients with advanced biliary tract cancer
ConclusionsAnti-PD-1 therapy plus chemotherapy is an effective and tolerable approach for advanced BTC. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 17, 2019 Category: Cancer & Oncology Source Type: research

Induction of tumor-specific CD8 + cytotoxic T lymphocytes from na ïve human T cells by using Mycobacterium -derived mycolic acid and lipoarabinomannan-stimulated dendritic cells
AbstractThe main effectors in tumor control are the class I MHC molecule-restricted CD8+ cytotoxic T lymphocytes (CTLs). Tumor-specific CTL induction can be regulated by dendritic cells (DCs) expressing both tumor-derived epitopes and co-stimulatory molecules. Immunosuppressive tolerogenic DCs, having down-regulated co-stimulatory molecules, are seen within the tumor mass and can suppress tumor-specific CTL induction. The tolerogenic DCs expressing down-regulated XCR1+CD141+ appear to be induced by tumor-derived soluble factors or dexamethasone, while the immunogenic DCs usually express XCR1+CD141+ molecules with a cross-p...
Source: Cancer Immunology, Immunotherapy - September 16, 2019 Category: Cancer & Oncology Source Type: research

ANTXR1 (TEM8) overexpression in gastric adenocarcinoma makes the protein a potential target of immunotherapy
ConclusionsOur findings suggest that ANTXR1 is a promising candidate for preclinical and clinical evaluation for gastric adenocarcinoma immunotherapy. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 13, 2019 Category: Cancer & Oncology Source Type: research

Lymphocyte-specific kinase expression is a prognostic indicator in ovarian cancer and correlates with a prominent B cell transcriptional signature
ConclusionsLCK is a better prognostic factor than CYT in ovarian cancer. In HGSOC, LCK high samples were characterized by higher expression of immunoglobulin and B-cell related genes suggesting that a cooperative interaction between tumor infiltrating T and B cells may correlate with better survival in this disease. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 11, 2019 Category: Cancer & Oncology Source Type: research

Peripheral changes in immune cell populations and soluble mediators after anti-PD-1 therapy in non-small cell lung cancer and renal cell carcinoma patients
AbstractPatients with non-small cell lung cancer (NSCLC) and renal cell carcinoma (RCC) have shown benefit from anti-PD-1 therapies. However, not all patients experience tumor shrinkage, durable responses or prolonged survival, demonstrating the need to find response markers. In blood samples from NSCLC and RCC patients obtained before and after anti-PD-1 treatment, we studied leukocytes by complete blood cell count, lymphocyte subsets using flow cytometry and plasma concentration of nine soluble mediators, in order to find predictive biomarkers of response and to study changes produced after anti-PD-1 therapy. In baseline...
Source: Cancer Immunology, Immunotherapy - September 11, 2019 Category: Cancer & Oncology Source Type: research

Desmoid tumors display a strong immune infiltration at the tumor margins and no PD-L1-driven immune suppression
AbstractDesmoid tumors (DTs) are local aggressive neoplasms, whose therapeutic approach has remained so far unsolved and in many instances controversial. Nowadays, immunotherapy appears to play a leading role in the treatment of various tumor types. Characterization of the tumor immune microenvironment (TME) and immune checkpoints can possibly help identify new immunotherapeutic targets for DTs. We performed immunohistochemistry (IHC) on 33 formalin-fixed paraffin-embedded (FFPE) tissue sections from DT samples to characterize the TME and the immune checkpoint expression profile. We stained for CD3, CD4, CD8, CD20, FoxP3, ...
Source: Cancer Immunology, Immunotherapy - September 10, 2019 Category: Cancer & Oncology Source Type: research

TNFSF4 (OX40L) expression and survival in locally advanced and metastatic melanoma
AbstractImmunotherapy with checkpoint inhibitors revolutionized melanoma treatment in both the adjuvant and metastatic setting, yet not all metastatic patients respond, and metastatic disease still often recurs among immunotherapy-treated patients with locally advanced disease. TNFSF4 is a co-stimulatory checkpoint protein expressed by several types of immune and non-immune cells, and was shown in the past to enhance the anti-neoplastic activity of T cells. Here, we assessed its expression in melanoma and its association with outcome in locally advanced and metastatic disease. We used publicly available data from The Cance...
Source: Cancer Immunology, Immunotherapy - September 8, 2019 Category: Cancer & Oncology Source Type: research

Survival of the fittest: how myeloid-derived suppressor cells survive in the inhospitable tumor microenvironment
AbstractMyeloid-derived suppressor cells (MDSC) are present in most cancer patients where they are significant contributors to the immune suppressive tumor microenvironment (TME). The TME is a hostile locale due to deficiencies in oxygen (hypoxia) and nutrients, and the presence of reactive oxygen species (ROS). The survival of tumor cells within the TME is partially governed by two mechanisms: (1) Activation of the transcription factor Nuclear Factor Erythroid-derived 2-like 2 (Nrf2) which turns on genes that attenuate oxidative stress; and (2) The presence of High Mobility Group Box Protein-1 (HMGB1), a damage-associated...
Source: Cancer Immunology, Immunotherapy - September 8, 2019 Category: Cancer & Oncology Source Type: research

Presence of T cells directed against CD20-derived peptides in healthy individuals and lymphoma patients
In this study, we have characterized human CD20-derived epitopes restricted by HLA-DR1, HLA-DR3, HLA-DR4, and HLA-DR7, and investigated whether T cell responses directed against CD20-derived peptides can be elicited in human HLA-DR-transgenic mice and human samples. Based on in vitro binding assays to recombinant human MHC II molecules and on in vivo immunization assays in H-2 KO/HLA-A2+-DR1+ transgenic mice, we have identified 21 MHC II-restricted long peptides derived from intracellular, membrane, or extracellular domains of the human non-mutated CD20 protein that trigger in vitro IFN- γ production by PBMCs and spl...
Source: Cancer Immunology, Immunotherapy - September 6, 2019 Category: Cancer & Oncology Source Type: research

Tumor-induced peripheral immunosuppression promotes brain metastasis in patients with non-small cell lung cancer
ConclusionsThe frequency of PD-L1+ myeloid cells correlated with the presence of brain metastases.  Tumor-derived IL-6 was capable of inducing PD-L1+ myeloid cells  in vitro, suggesting that monitoring of immunosuppressive factors in peripheral blood may identify new targets for therapeutic intervention in selected patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 4, 2019 Category: Cancer & Oncology Source Type: research

Independent expression of circulating and tissue levels of PD-L1: correlation of clusters with tumor metabolism and outcome in patients with non-small cell lung cancer
ConclusionPlasma levels of PD-L1 are independent of the expression of PD-1/PD-L1 in NSCLC tumor tissue and, when combined with other clinical –pathological parameters, allow for the identification of clusters with different outcomes. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - September 2, 2019 Category: Cancer & Oncology Source Type: research

A phase II study of the L19IL2 immunocytokine in combination with dacarbazine in advanced metastatic melanoma patients
AbstractEngineered cytokine products represent promising agents for the treatment of immunogenic tumors, such as malignant melanoma, in addition to immune checkpoint inhibitors. Here we describe the results of a controlled, randomized phase II clinical trial, aimed at assessing the therapeutic potential of L19IL2, a fully human fusion protein consisting of the L19 antibody specific to the alternatively spliced extra-domain B of fibronectin, fused to human interleukin-2 in advanced metastatic melanoma. In one arm, patients received dacarbazine (DTIC; 1000  mg/m2 of body surface on day 1 of 21-day cycles) as single agen...
Source: Cancer Immunology, Immunotherapy - September 2, 2019 Category: Cancer & Oncology Source Type: research

An optimized retinoic acid-inducible gene I agonist M8 induces immunogenic cell death markers in human cancer cells and dendritic cell activation
AbstractRIG-I is a cytosolic RNA sensor that recognizes short 5 ′ triphosphate RNA, commonly generated during virus infection. Upon activation, RIG-I initiates antiviral immunity, and in some circumstances, induces cell death. Because of this dual capacity, RIG-I has emerged as a promising target for cancer immunotherapy. Previously, a sequence-optimized RIG-I agonist (termed M8) was generated and shown to stimulate a robust immune response capable of blocking viral infection and to function as an adjuvant in vaccination strategies. Here, we investigated the potential of M8 as an anti-cancer agent by analyzing its ab...
Source: Cancer Immunology, Immunotherapy - August 27, 2019 Category: Cancer & Oncology Source Type: research

Safety and efficacy of PD-1 blockade-activated multiple antigen-specific cellular therapy alone or in combination with apatinib in patients with advanced solid tumors: a pooled analysis of two prospective trials
ConclusionsTreatment with aMASCT plus apatinib was safe and effective for the management of advanced solid tumors. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - August 26, 2019 Category: Cancer & Oncology Source Type: research

CD4 + T cells indirectly kill tumor cells via induction of cytotoxic macrophages in mouse models
AbstractIt is well recognized that CD4+ T cells may play an important role in immunosurveillance and immunotherapy against cancer. However, the details of how these cells recognize and eliminate the tumor cells remain incompletely understood. For the past 25  years, we have focused on how CD4+ T cells reject multiple myeloma cells in a murine model (MOPC315). In our experimental system, the secreted tumor-specific antigen is taken up by tumor-infiltrating macrophages that process it and present a neoepitope [a V region-derived idiotypic (Id) peptide] on MHC class II molecules to Th1 cells. Stimulated Th1 cells produce...
Source: Cancer Immunology, Immunotherapy - August 25, 2019 Category: Cancer & Oncology Source Type: research

Morphomolecular analysis of the immune tumor microenvironment in human head and neck cancer
In conclusion, ieTILs and strTILs were non-redundant biomarkers in HNSCC and should be evaluated separately. The identified prognostic markers should be evaluated for predictivity in ICB-treated patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - August 22, 2019 Category: Cancer & Oncology Source Type: research

Melanoma-conditioned medium promotes cytotoxic immune responses by murine bone marrow-derived monocytes despite their expression of ‘M2’ markers
AbstractMacrophages have been shown to infiltrate a wide range of malignancies and are often considered to promote tumour survival, growth and spread. However, the source and behaviour of discrete tumour-associated macrophage populations are still poorly understood. Here we show a novel method for the rational development of bone marrow-derived monocytes appropriate for the study of processes which involve the contribution of circulating inflammatory monocytes. We have shown that in response to tumour-conditioned medium, these cells upregulate CD206 and CD115, markers traditionally associated with M2-type macrophages. Trea...
Source: Cancer Immunology, Immunotherapy - August 22, 2019 Category: Cancer & Oncology Source Type: research

A VEGFR2 –MICA bispecific antibody activates tumor-infiltrating lymphocytes and exhibits potent anti-tumor efficacy in mice
AbstractMHC class I-related chain A (MICA) is one of the major ligands for natural killer group 2 member D (NKG2D), which is an activating NK receptor. MICA is expressed on the surface of human epithelial tumor cells, and its shedding from tumor cells leads to immunosuppression. To activate immune response in the tumor microenvironment, we designed an anti-VEGFR2 –MICA bispecific antibody (JZC01), consisting of MICA and an anti-VEGFR2 single chain antibody fragment (JZC00) and explored its potential anti-tumor activity. JZC01 targeted vascular endothelial growth factor receptor 2 (VEGFR2) and inhibited tumorigenesis ...
Source: Cancer Immunology, Immunotherapy - August 18, 2019 Category: Cancer & Oncology Source Type: research

Successful combination therapy of systemic checkpoint inhibitors and intralesional interleukin-2 in patients with metastatic melanoma with primary therapeutic resistance to checkpoint inhibitors alone
We describe a case series of nine patients with metastatic melanoma and injectable lesions who developed progressive disease under a PD-1 inhibitor monotherapy. At the time of progressive disease, patients received intratumoral IL-2 treatment in addition to PD-1 inhibitor therapy. Three patients showed complete, three patients partial response and three patients progressive disease upon this combination therapy. IHC stainings were performed from metastases available at baseline (start of PD-1 inhibitor) and under combination therapy with IL-2. IHC results revealed a significant increase of CD4+ and CD8+ T cells and a highe...
Source: Cancer Immunology, Immunotherapy - August 16, 2019 Category: Cancer & Oncology Source Type: research

Anti-CAR-engineered T cells for epitope-based elimination of autologous CAR T cells
AbstractAlthough CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients ’ immune system and on-target/off-side effects of propose...
Source: Cancer Immunology, Immunotherapy - August 13, 2019 Category: Cancer & Oncology Source Type: research

Tumor-induced escape mechanisms and their association with resistance to checkpoint inhibitor therapy
AbstractImmunotherapy aims to activate the immune system to fight cancer in a very specific and targeted manner. Despite the success of different immunotherapeutic strategies, in particular antibodies directed against checkpoints as well as adoptive T-cell therapy, the response of patients is limited in different types of cancers. This attributes to escape of the tumor from immune surveillance and development of acquired resistances during therapy. In this review, the different evasion and resistance mechanisms that limit the efficacy of immunotherapies targeting tumor-associated antigens presented by major histocompatibil...
Source: Cancer Immunology, Immunotherapy - August 2, 2019 Category: Cancer & Oncology Source Type: research

An IL-15-based superagonist ALT-803 enhances the NK cell response to cetuximab-treated squamous cell carcinoma of the head and neck
AbstractSquamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer worldwide and epidermal growth factor receptor (EGFR) is overexpressed in greater than 90% of patient tumors. Cetuximab is a monoclonal antibody that binds to EGFR and can activate immune cells, such as natural killer (NK) cells, that express receptors for the Fc (constant region) of immunoglobulin G. IL-15 (interleukin-15) is a critical factor for the development, proliferation and activation of effector NK cells. A novel IL-15 compound known as ALT-803 that consists of genetically modified IL-15 plus the IL-15 receptor alpha prot...
Source: Cancer Immunology, Immunotherapy - July 22, 2019 Category: Cancer & Oncology Source Type: research

Histopathology-based immunoscore predicts recurrence for intrahepatic cholangiocarcinoma after hepatectomy
AbstractIntrahepatic cholangiocarcinoma (ICC) is a rare malignancy with poor prognosis. The evaluation of recurrence risk after liver resection is of great importance for ICCs. We aimed to assess the prognostic value of intra- and peritumoral immune infiltrations and to establish a novel histopathology-related immunoscore (HRI) associated with ICC recurrence. A total of 280 ICC patients who received curative resection between February 2005 and July 2011 were enrolled in our study. Patients were randomly assigned to the derivation cohort (n = 176) or the validation cohort (n = 104). Sixteen immun...
Source: Cancer Immunology, Immunotherapy - July 22, 2019 Category: Cancer & Oncology Source Type: research

CTLA-4 antibody ipilimumab negatively affects CD4 + T-cell responses in vitro
AbstractImmune checkpoint inhibitors targeting coinhibitory pathways in T cells possess efficacy in combating cancer. In addition to PD-1/PD-L1 and CTLA-4 antibodies which are already established in tumor immunotherapy, immune checkpoints such as LAG-3 or BTLA are emerging, which may have the potential to enhance T-cell responses alone or in combination with PD-1 blockers. CD4+ T cells play a central role in the immune system and contribute to productive immune responses in multiple ways. The effects of immune checkpoint inhibitors on this cell subset may thus critically influence therapeutic outcomes. Here, we have used i...
Source: Cancer Immunology, Immunotherapy - July 21, 2019 Category: Cancer & Oncology Source Type: research

Serum PCSK9 levels at the second nivolumab cycle predict overall survival in elderly patients with NSCLC: a pilot study
AbstractMonoclonal antibodies targeting PD-1 are used for treating NSCLC. To date, proprotein convertase subtilisin/kexin type 9 (PCSK9) has been poorly investigated in the oncologic field. Here, we aimed at evaluating whether serum PCSK9 might represent a predictive factor for OS in older patients with advanced NSCLC under nivolumab treatment. Among 78 patients with advanced, pre-treated NSCLC previously enrolled in a prospective study at Ospedale Policlinico San Martino in Genoa (Italy), 44 patients have been included in this sub-analysis due to the availability of serum samples for the measurement of PCSK9. Before each ...
Source: Cancer Immunology, Immunotherapy - July 19, 2019 Category: Cancer & Oncology Source Type: research

Peri-operative monocyte count is a marker of poor prognosis in gastric cancer: increased monocytes are a characteristic of myeloid-derived suppressor cells
AbstractGastric cancer (GC) is the most common malignant tumor in digestive organs, and the prognosis of GC patients who have undergone surgery remains poor because of frequent recurrence. Therefore, the identification of new markers to predict the outcome of these patients is needed. Monocyte count is a negative prognostic factor associated with inflammation. We investigated the relationship between peripheral monocytes in the peri-operative period and prognosis in GC patients. A high pre-operative monocyte count was identified as a prognostic factor in a retrospective analysis of 278 stage II and III GC patients who unde...
Source: Cancer Immunology, Immunotherapy - July 18, 2019 Category: Cancer & Oncology Source Type: research

Immunity to X-linked inhibitor of apoptosis protein (XIAP) in malignant melanoma and check-point blockade
AbstractExpression of inhibitors of apoptosis protein (IAP) family members is associated with poor prognosis in cancer patients. Immunity to ML-IAP (livin) and survivin has been well studied in patients with a variety of tumors. XIAP, the most potent inhibitor of apoptosis, is widely expressed in melanoma. To better define its potential role as an immunogenic target, cellular and humoral responses to XIAP were investigated in patients with advanced melanoma. An overlapping peptide library covering the full length of the XIAP protein was used to screen T cell responses of peripheral blood mononuclear cells (PBMC) from stage...
Source: Cancer Immunology, Immunotherapy - July 17, 2019 Category: Cancer & Oncology Source Type: research

Interferon beta increases NK cell cytotoxicity against tumor cells in patients with nasopharyngeal carcinoma via tumor necrosis factor apoptosis-inducing ligand
ConclusionIncreased cytotoxicity of NK cells against NPC cells and increased serum levels of biologically active TRAIL in patients treated with IFN β could be a means to eliminate micrometastatic disease and explain the low systemic relapse rate in this patient group. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - July 15, 2019 Category: Cancer & Oncology Source Type: research

4th Symposium on Advances in Cancer Immunology and Immunotherapy, November 29 –December 1, 2018, Athens, Greece
(Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - July 14, 2019 Category: Cancer & Oncology Source Type: research

Adhering to adhesion: assessing integrin conformation to monitor T cells
AbstractMonitoring T cells is of major importance for the development of immunotherapies. Recent sophisticated assays can address particular aspects of the anti-tumor T-cell repertoire or support very large-scale immune screening for biomarker discovery. Robust methods for the routine assessment of the quantity and quality of antigen-specific T cells remain, however, essential. This review discusses selected methods that are commonly used for T-cell monitoring and summarizes the advantages and limitations of these assays. We also present a new functional assay, which specifically detects activated β2 integrins within ...
Source: Cancer Immunology, Immunotherapy - July 14, 2019 Category: Cancer & Oncology Source Type: research

Mouse CD8 + NKT-like cells exert dual cytotoxicity against mouse tumor cells and myeloid-derived suppressor cells
AbstractOur previous work has demonstrated the high efficiency of CD8+ natural killer T (NKT)-like cells in killing antigen-bearing dendritic cells. To evaluate their role in the tumor microenvironment, we performed in vitro and in vivo antitumor experiments to investigate whether CD8+NKT-like cells could kill Yac-1 and B16 cells like NK cells and kill EL4-OVA8 cells in an antigen-specific manner like cytotoxic T lymphocytes (CTLs). Unlike NK1.1−CTLs, CD8+NKT-like cells also exhibit the capability to kill myeloid-derived suppressor cells (MDSCs) in an antigen-specific manner, indicative of their potential role in cle...
Source: Cancer Immunology, Immunotherapy - July 4, 2019 Category: Cancer & Oncology Source Type: research

Reduced CTL motility and activity in avascular tumor areas
AbstractPatchy infiltration of tumors by cytotoxic T cells (CTLs) predicts poorer prognosis for cancer patients. The factors limiting intratumoral CTL dissemination, though, are poorly understood. To study CTL dissemination in tumors, we histologically examined human melanoma samples and used mice to image B16-OVA tumors infiltrated by OT-I CTLs using intravital two-photon microscopy. In patients, most CTLs concentrated around peripheral blood vessels, especially in poorly infiltrated tumors. In mice, OT-I CTLs had to cluster around tumor cells to efficiently kill them in a contact-and perforin-dependent manner and cytotox...
Source: Cancer Immunology, Immunotherapy - June 27, 2019 Category: Cancer & Oncology Source Type: research

Intratumoral delivery of an HPV vaccine elicits a broad anti-tumor immune response that translates into a potent anti-tumor effect in a preclinical murine HPV model
In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic–polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequenc...
Source: Cancer Immunology, Immunotherapy - June 25, 2019 Category: Cancer & Oncology Source Type: research

High levels of tissue inhibitor of metalloproteinase-1 (TIMP-1) in the serum are associated with poor prognosis in HPV-negative squamous cell oropharyngeal cancer
ConclusionOur results indicate that serum TIMP-1 levels may serve as an independent prognostic marker for HPV-negative OPSCC patients. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - June 24, 2019 Category: Cancer & Oncology Source Type: research

The challenges of adoptive cell transfer in the treatment of human renal cell carcinoma
AbstractRenal cell carcinoma (RCC) is one of the most lethal urologic malignancies. Its incidence continues to rise worldwide with a rate of 2% per year. Approximately, one-third of the RCC patients are diagnosed at advanced stages due to the asymptomatic nature of its early stages. This represents a great hurdle, since RCC is largely chemoresistant/radioresistant, and targeted therapy of mRCC still has limited efficacy. The 5-year survival rate of metastatic RCC (mRCC) is only around 10%. Adoptive cell transfer (ACT), a particular form of cell-based anticancer immunotherapy, is a promising approach in the treatment of mRC...
Source: Cancer Immunology, Immunotherapy - June 19, 2019 Category: Cancer & Oncology Source Type: research

Naturally occurring cancers in pet dogs as pre-clinical models for cancer immunotherapy
AbstractDespite the significant progress in tumor prevention, early detection, diagnosis and treatment made over recent decades, cancer is still an enormous public health challenge all around the world, with the number of people affected increasing every year. A great deal of effort is therefore being devoted to the search for novel safe, effective and economically sustainable treatments for the growing population of neoplastic patients. One main obstacle to this process is the extremely low percentage of therapeutic approaches that, after successfully passing pre-clinical testing, actually demonstrate activity when finall...
Source: Cancer Immunology, Immunotherapy - June 19, 2019 Category: Cancer & Oncology Source Type: research

Editing the immunopeptidome of melanoma cells using a potent inhibitor of endoplasmic reticulum aminopeptidase 1 (ERAP1)
AbstractThe efficacy of cancer immunotherapy, including treatment with immune-checkpoint inhibitors, often is limited by ineffective presentation of antigenic peptides that elicit T-cell-mediated anti-tumor cytotoxic responses. Manipulation of antigen presentation pathways is an emerging approach for enhancing the immunogenicity of tumors in immunotherapy settings. ER aminopeptidase 1 (ERAP1) is an intracellular enzyme that trims peptides as part of the system that generates peptides for binding to MHC class I molecules (MHC-I). We hypothesized that pharmacological inhibition of ERAP1 in cells could regulate the cellular i...
Source: Cancer Immunology, Immunotherapy - June 19, 2019 Category: Cancer & Oncology Source Type: research

Preclinical assessment of transiently TCR redirected T cells for solid tumour immunotherapy
AbstractOff-target toxicity due to the expression of target antigens in normal tissue or TCR cross-reactivity represents a major risk when using T cell receptor (TCR)-engineered T cells for treatment of solid tumours. Due to the inherent cross-reactivity of TCRs it is difficult to accurately predict their target recognition pre-clinically. It has become evident that direct testing in a human being represents the best evaluation of the risks. There is, therefore, a clear unmet need for assessing the safety of a therapeutic TCR in a more controllable manner than by the injection of permanently modified cellular products. Usi...
Source: Cancer Immunology, Immunotherapy - June 17, 2019 Category: Cancer & Oncology Source Type: research

Intratumoral plasmacytoid dendritic cells as a poor prognostic factor for hepatocellular carcinoma following curative resection
In conclusion, our study demonstrated that intratumoral infiltration by pDCs is a novel indicator for poor prognosis in patients with HCC, possibly through the induction of an immune tolerogenic and inflammatory tumor microenvironment comprising regulatory T and IL-17-producing cells. An assessment of the combination of these cells represents a superior predictor of patient outcome. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - June 13, 2019 Category: Cancer & Oncology Source Type: research

Clinicopathological implications of TIM3 + tumor-infiltrating lymphocytes and the miR-455-5p/Galectin-9 axis in skull base chordoma patients
AbstractChordoma is difficult to eradicate due to high local recurrence rates. The immune microenvironment is closely associated with tumor prognosis; however, its role in skull base chordoma is unknown. The expression of Galectin-9 (Gal9) and tumor-infiltrating lymphocyte (TIL) markers was assessed by immunohistochemistry. Kaplan –Meier and multivariate Cox analyses were used to assessing local recurrence-free survival (LRFS) and overall survival (OS) of patients. MiR-455-5p was identified as a regulator of Gal9 expression. Immunopositivity for Gal9 was associated with tumor invasion (p = 0.019), Karno...
Source: Cancer Immunology, Immunotherapy - June 12, 2019 Category: Cancer & Oncology Source Type: research

Combination of denosumab and immune checkpoint inhibition: experience in 29 patients with metastatic melanoma and bone metastases
ConclusionsThe combination therapy of metastatic melanoma with PD-1i and denosumab was feasible without unexpected safety issues and showed a promising efficacy signal. Further investigation in prospective studies is needed. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - June 10, 2019 Category: Cancer & Oncology Source Type: research

Comparison of IL-2 vs IL-7/IL-15 for the generation of NY-ESO-1-specific T cells
In conclusion, IL-7/IL-15 does not seem to be superior to IL-2 for the generation of NY-ESO-1-specific T cells. This is in sharp contrast to the observations in CD19-specific CART cells. Changes of cytokine cocktails should be carefully evaluated for individual vector systems. (Source: Cancer Immunology, Immunotherapy)
Source: Cancer Immunology, Immunotherapy - June 7, 2019 Category: Cancer & Oncology Source Type: research

An HER2 DNA vaccine with evolution-selected amino acid substitutions reveals a fundamental principle for cancer vaccine formulation in HER2 transgenic mice
AbstractEnhancement of endogenous immunity to tumor-associated self-antigens and neoantigens is the goal of preventive vaccination. Toward this goal, we compared the efficacy of the following HER2 DNA vaccine constructs: vaccines encoding wild-type HER2, hybrid HER2 vaccines consisting of human HER2 and rat Neu, HER2 vaccines with single residue substitutions and a novel human HER2 DNA vaccine, ph(es)E2TM. ph(es)E2TM was designed to contain fiveevolution-selected substitutions: M198V, Q398R, F425L, H473R and A622T that occur frequently in 12 primate HER2 sequences. These ph(es)E2TM substitutions score 0 to 1 in blocks subs...
Source: Cancer Immunology, Immunotherapy - June 7, 2019 Category: Cancer & Oncology Source Type: research