IL-12 Augments Antitumor Responses to Cycled Chemotherapy
In this study of mouse tumor models, we demonstrate that loss of antitumor response during multiple cycles of chemotherapy is associated with a lack of immune activation, and not intrinsic tumor cell drug resistance. More importantly, we show that adding interleukin-12 (IL-12) to cycled chemotherapy maintains and even increases antitumor immune response in both immunogenic and nonimmunogenic murine tumors and significantly prolongs survival. In some instances, larger tumor burdens that relapse following an initial cycle of cyclophosphamide and IL-12 are eradicated by subsequent cycles of the same treatment at the same dose...
Source: Journal of Immunotherapy - April 16, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Large-scale Clinical-grade Retroviral Vector Production in a Fixed-Bed Bioreactor
The successful genetic engineering of patient T cells with γ-retroviral vectors expressing chimeric antigen receptors or T-cell receptors for phase II clinical trials and beyond requires the large-scale manufacture of high-titer vector stocks. The production of retroviral vectors from stable packaging cell lines using roller bottles or 10- to 40-layer cell factories is limited by a narrow harvest window, labor intensity, open-system operations, and the requirement for significant incubator space. To circumvent these shortcomings, we optimized the production of vector stocks in a disposable fixed-bed bioreactor using ...
Source: Journal of Immunotherapy - March 19, 2015 Category: Allergy & Immunology Tags: Clinical Study Source Type: research

Proapoptotic and Antiapoptotic Proteins of the Bcl-2 Family Regulate Sensitivity of Pancreatic Cancer Cells Toward Gemcitabine and T-Cell–mediated Cytotoxicity
In conclusion, expression of Bcl-2, Bcl-xL, and Bax in pancreatic tumor cells determines sensitivity towards both Gem-mediated and CTL-mediated toxicity. Bcl-2 silencing could be exploited therapeutically in tumor vaccine approaches. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - March 19, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Enhanced Dendritic Cell–based Immunotherapy Using Low-dose Cyclophosphamide and CD25-targeted Antibody for Transplanted Lewis Lung Carcinoma Cells
Regulatory T cells (Tregs) is one of the main obstacles to the success of cancer immunotherapy. The effect of dendritic cell (DC)-based immunotherapy can be attenuated by immune suppressive functions of Tregs. We used a CD25-targeted antibody and low-dose cyclophosphamide (CTX) as immunomodulators to increase the antitumor effect of intratumoral injection of immature DCs into the irradiated tumor cells (IR/iDC). CTX or CD25-targeted antibody alone showed a significant reduction in the number of Tregs within the tumor microenvironment. When they are combined with IR/iDC, the number of Tregs was further reduced. Although IR/...
Source: Journal of Immunotherapy - March 19, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Enhanced T-Cell Immunity to Osteosarcoma Through Antibody Blockade of PD-1/PD-L1 Interactions
Osteosarcoma is the most common bone cancer in children and adolescents. Although 70% of patients with localized disease are cured with chemotherapy and surgical resection, patients with metastatic osteosarcoma are typically refractory to treatment. Numerous lines of evidence suggest that cytotoxic T lymphocytes (CTLs) limit the development of metastatic osteosarcoma. We have investigated the role of PD-1, an inhibitory TNFR family protein expressed on CTLs, in limiting the efficacy of immune-mediated control of metastatic osteosarcoma. We show that human metastatic, but not primary, osteosarcoma tumors express a ligand fo...
Source: Journal of Immunotherapy - March 19, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Angiogenin Mutants as Novel Effector Molecules For the Generation of Fusion Proteins With Increased Cytotoxic Potential
Human cytolytic fusion proteins (hCFPs) are therapeutically efficacious recombinant polypeptides comprising a target cell-specific binding component and a human effector domain that induces apoptosis. Compared with former generations of immunotoxins, which contain immunogenic cytotoxic domains derived from bacteria or plants, hCFPs contain solely human proteins that do not induce an immune response, thus avoiding the development of neutralizing antibodies. Here, we investigated the suitability of human angiogenin (Ang) mutants as effector domains. We engineered 3 different Ang variants that outperformed the wild-type enzym...
Source: Journal of Immunotherapy - March 19, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Vogt-Koyanagi-Harada-like Syndrome After CTLA-4 Inhibition With Ipilimumab for Metastatic Melanoma
We describe a case of VKH-like syndrome in a 45-year-old HLA-A02-positive patient with metastatic melanoma treated with ipilimumab. Disruption of immune tolerance by ipilimumab led to melanoma remission while also inciting systemic and ophthalmic autoimmunity toward melanocytic antigen. These observations provide insight into the pathophysiology of the VKH syndrome, and the balance between tumor-associated tolerance and autoimmunity. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - February 1, 2015 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Peripheral Neuropathy Associated With Ipilimumab: A Report of 2 Cases
We report 2 cases of ipilimumab-induced polyneuropathy. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - February 1, 2015 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

A Phase I Clinical Trial of CD1c (BDCA-1)+ Dendritic Cells Pulsed With HLA-A*0201 Peptides for Immunotherapy of Metastatic Hormone Refractory Prostate Cancer
Preclinical studies have suggested that purified populations of CD1c (BDCA-1+) blood-derived dendritic cells (BDC) loaded with tumor-specific peptides may be a feasible option for prostate cancer immunotherapy. We performed an open-label dose-finding Phase I study to evaluate the safe use of CD1c+ BDC in patients with advanced metastatic hormone refractory prostate cancer. HLA-A*0201-positive patients with advanced metastatic prostate cancer were recruited and consented. The vaccine was manufactured by pulsing autologous CD1c+ BDC, prepared by magnetic bead immunoselection from apheresed peripheral blood mononuclear cells,...
Source: Journal of Immunotherapy - February 1, 2015 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Simple and Efficient Generation of Virus-specific T Cells for Adoptive Therapy Using Anti-4-1BB Antibody
In conclusion, VSTs can be generated rapidly and efficiently by simply stimulating peripheral blood mononuclear cells with viral peptide and anti-4-1BB antibody without using antigen-presenting cells. We propose using anti-4-1BB antibody as a novel strategy to generate VSTs for adoptive therapy. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - February 1, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

CTLA-4 Blockade Plus Adoptive T-Cell Transfer Promotes Optimal Melanoma Immunity in Mice
Immunotherapeutic approaches to the treatment of advanced melanoma have relied on strategies that augment the responsiveness of endogenous tumor-specific T-cell populations [eg, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade-mediated checkpoint inhibition] or introduce exogenously prepared tumor-specific T-cell populations [eg, adoptive cell transfer (ACT)]. Although both approaches have shown considerable promise, response rates to these therapies remain suboptimal. We hypothesized that a combinatorial approach to immunotherapy using both CTLA-4 blockade and nonlymphodepletional ACT could offer additive the...
Source: Journal of Immunotherapy - February 1, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Virological and Preclinical Characterization of a Dendritic Cell Targeting, Integration-deficient Lentiviral Vector for Cancer Immunotherapy
Dendritic cells (DCs) are essential antigen-presenting cells for the initiation of cytotoxic T-cell responses and therefore attractive targets for cancer immunotherapy. We have developed an integration-deficient lentiviral vector termed ID-VP02 that is designed to deliver antigen-encoding nucleic acids selectively to human DCs in vivo. ID-VP02 utilizes a genetically and glycobiologically engineered Sindbis virus glycoprotein to target human DCs through the C-type lectin DC-SIGN (CD209) and also binds to the homologue murine receptor SIGNR1. Specificity of ID-VP02 for antigen-presenting cells in the mouse was confirmed thro...
Source: Journal of Immunotherapy - February 1, 2015 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Arthritis and Tenosynovitis Associated With the Anti-PD1 Antibody Pembrolizumab in Metastatic Melanoma
We report the acute onset of polyarticular inflammatory arthritis in 2 patients receiving the immune check-point inhibitor, pembrolizumab (MK-3475), anti-PD1 drug for metastatic melanoma after 14 and 11 months therapy, respectively. The first patient had severe tenosynovitis, synovitis, bone marrow edema, and myositis, whereas the second patient had predominantly synovitis and tenosynovitis. Good symptomatic control was obtained with bisphosphonates and salazopyrin, avoiding the use of T-cell immunosuppressants. These cases raise important questions on whether anti-PD1 therapy allows preexisting autoimmune T-cell clones to...
Source: Journal of Immunotherapy - December 11, 2014 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Ex Vivo–expanded Natural Killer Cells Demonstrate Robust Proliferation In Vivo in High-risk Relapsed Multiple Myeloma Patients
In conclusion, infusion of large numbers of expanded NK cells was feasible and safe; infusing fresh cells was critical to their expansion in vivo. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - December 11, 2014 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

BRAF and MEK Inhibition Variably Affect GD2-specific Chimeric Antigen Receptor (CAR) T-Cell Function In Vitro
We report that, although all these drugs lead to inhibition of stimulated T cells at high concentrations in vitro, only Vem inhibited T cells at concentrations equivalent to reported plasma concentrations in treated patients. Although the combination of Dab and Tram also resulted in inhibition of T-cell effector functions at some therapeutic concentrations, Dab itself had little adverse effect on CAR T-cell function. These findings may have implications for novel therapeutic combinations of adoptive CAR T-cell immunotherapy and MAPK pathway inhibitors. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - December 11, 2014 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

PD-1/PD-L1 Blockade Together With Vaccine Therapy Facilitates Effector T-Cell Infiltration Into Pancreatic Tumors
In this study, we evaluated blockade of the PD-1/PD-L1 pathway. We found that PD-L1 is weakly expressed at a low frequency in untreated human and murine PDAs but treatment with a granulocyte macrophage colony-stimulating factor secreting PDA vaccine (GVAX) significantly upregulates PD-L1 membranous expression after treatment of tumor-bearing mice. In addition, combination therapy with vaccine and PD-1 antibody blockade improved murine survival compared with PD-1 antibody monotherapy or GVAX therapy alone. Furthermore, PD-1 blockade increased effector CD8+ T lymphocytes and tumor-specific interferon-γ production of CD...
Source: Journal of Immunotherapy - December 11, 2014 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Retrospective Analysis of the Safety and Efficacy of High-dose Interleukin-2 After Prior Tyrosine Kinase Inhibitor Therapy in Patients with Advanced Renal Cell Carcinoma: Erratum
No abstract available (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - October 15, 2014 Category: Allergy & Immunology Tags: Erratum Source Type: research

Health-related Quality of Life, Fatigue, and Depression Under Low-Dose IFN-α Therapy in Melanoma Patients
Adjuvant melanoma treatment with interferon-α (IFN-α) has proven to be accompanied by several side effects and to decrease patients’ health-related quality of life (HRQOL), fatigue and depression being essential factors at that. Although a large body of evidence exists for HRQOL under IFN-α therapy, we now specifically address this topic combining the HRQOL survey in the first months of IFN-α low-dose treatment with a structured assessment of relevant neuropsychiatric side effects, fatigue and depression, with specific validated assessment tools. The present study is a longitudinal observation...
Source: Journal of Immunotherapy - October 15, 2014 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Activation and Propagation of Tumor-infiltrating Lymphocytes on Clinical-grade Designer Artificial Antigen-presenting Cells for Adoptive Immunotherapy of Melanoma
Conclusions:TIL can be rapidly expanded with aAPC to clinical scale generating T cells with similar phenotypic and effector profiles as with PBMC feeders. These data support the clinical application of aAPC to manufacture TIL for the treatment of melanoma. (Source: Journal of Immunotherapy)
Source: Journal of Immunotherapy - October 15, 2014 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Adjuvant Low-Dose Interleukin-2 (IL-2) Plus Interferon-α (IFN-α) in Operable Renal Cell Carcinoma (RCC): A Phase III, Randomized, Multicentre Trial of the Italian Oncology Group for Clinical Research (GOIRC)
There is currently no standard therapy to reduce the recurrence rate after surgery for renal cell carcinoma (RCC). The aim of this study was to assess efficacy and safety of adjuvant treatment with low doses of interleukin-2 (IL-2)+interferon-α (IFN-α) in operable RCC. The patients were randomized 1:1 to receive a 4-week cycle of low-dose IL-2+IFN-α or observation after primary surgery for RCC. Treatment cycles were repeated every 4 months for the first 2 years and every 6 months for the subsequent 3 years. The primary endpoint was recurrence-free survival (RFS); safety; and overall survival (OS) were sec...
Source: Journal of Immunotherapy - October 15, 2014 Category: Allergy & Immunology Tags: Clinical Studies Source Type: research

Cyclophosphamide and IL-12-transduced DCs Enhance the Antitumor Activity of Tumor Antigen–stimulated DCs and Reduce Tregs and MDSCs Number
A hostile tumor microenvironment, characterized by an abundance of T regulatory cells and myeloid-derived suppressor cells (MDSCs), considerably limits the efficacy of dendritic cell (DC)-based vaccines. The intention of this study was to enhance the antitumor activity of vaccines consisting of bone marrow-derived DCs stimulated with TAg (BMDC/TAg) via single administration of cyclophosphamide and multiple injections of interleukin (IL)-12-transduced DCs (BMDC/IL-12). The combined chemoimmunotherapy was applied in the treatment of mice with subcutaneously (SC) growing, advanced MC38 colon carcinoma. The highest level of tu...
Source: Journal of Immunotherapy - October 15, 2014 Category: Allergy & Immunology Tags: Basic Study Source Type: research

TCR+CD4−CD8− T cells in Antigen-specific MHC Class I–restricted T-cell Responses After Allogeneic Hematopoietic Stem Cell Transplantation
We examined the frequency of DN T cells in 17 patients after allogeneic hematopoietic stem cell transplantation (aHSCT) at 1, 2, 3, 6, and 12 months post-aHSCT and show that these cells increase early after aHSCT and decrease with time after aHSCT. DN T cells reside in the terminally differentiated effector (CD45RA+CCR7−) T-cell population and are polyclonal, determined by T-cell receptor Vβ CDR3 analysis. Gene expression analysis of ex vivo sorted DN T cells showed a distinct set of gene expression, including interleukin-8, as compared with CD4+ or CD8+ T cells. DN T cells contributed to MHC class I-restricted ...
Source: Journal of Immunotherapy - October 1, 2014 Category: Allergy & Immunology Tags: Clinical Study Source Type: research

Toward Immunotherapy With Redirected T Cells in a Large Animal Model: Ex Vivo Activation, Expansion, and Genetic Modification of Canine T Cells
Adoptive transfer of T cells expressing chimeric antigen receptors (CARs) has shown promising antitumor activity in early phase clinical studies, especially for hematological malignancies. However, most preclinical models do not reliably mimic human disease. We reasoned that developing an adoptive T-cell therapy approach for spontaneous osteosarcoma (OS) occurring in dogs would more closely reproduce the condition in human cancer. To generate CAR-expressing canine T cells, we developed expansion and transduction protocols that allow for the generation of sufficient numbers of CAR-expressing canine T cells for future clinic...
Source: Journal of Immunotherapy - October 1, 2014 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

A Monoclonal Antibody Against Neem Leaf Glycoprotein Recognizes Carcinoembryonic Antigen (CEA) and Restricts CEA Expressing Tumor Growth
Carcinoembryonic antigen (CEA) is one of the promising tumor antigens mainly associated with carcinoma of the colon, lung, breast, etc. and received wide attention for cancer immunotherapy. Neem leaf glycoprotein (NLGP), an effective immunomodulator, is able to generate humoral and cellular immune responses in murine tumor models. We have generated a monoclonal antibody (mAb) against NLGP by fusing NLGP-immunized mice splenocytes with nonsecretory myeloma cells. A highly anti-NLGP mAb secreting clone (1C8; IgG2a in nature) has been identified and propagated in culture. 1C8 recognizes human CEA as good as NLGP by enzyme lin...
Source: Journal of Immunotherapy - October 1, 2014 Category: Allergy & Immunology Tags: Basic Studies Source Type: research

Therapeutic Antitumor Efficacy of B Cells Loaded With Tumor-derived Autophagasomes Vaccine (DRibbles)
In this report, we demonstrated that a booster vaccination with naive B cells loaded with DRibbles eradicated E.G7-OVA tumors in mice that were previously treated with adoptive transfer naive OT-I T cells and intranodal immunization with DRibbles derived from E.G7 tumors. The antitumor efficacy was accompanied by a heighten number of tumor-specific interferon-γ-producing T cells and antibodies. However, the same treatment in the absence of adoptive T-cell transfer exhibited a limited efficacy. In contrast, when DRibble-loaded B cells were activated with CpG and anti-CD40 antibody before use as booster vaccines, estab...
Source: Journal of Immunotherapy - October 1, 2014 Category: Allergy & Immunology Tags: Basic Studies Source Type: research