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Construction of Oncolytic Herpes Simplex Virus with Therapeutic Genes of Interest. Kahramanian Andranik,Kuroda Toshihiko,Wakimoto Hiroaki Methods in molecular biology (Clifton, N.J.) Herpes simplex virus (HSV) is one of the most extensively studied oncolytic virus platforms. The recent FDA approval of talimogene laherparepvec (T-VEC) has been accelerating translational research of oncolytic HSV (oHSV) as a promising therapeutic for refractory cancers such as glioblastoma, the deadliest primary malignancy in the brain. The large genome size of HSV readily allows arming of oHSV by incorporating therapeutic transgenes within the virus, as exemplified by T-VEC carrying GM-CSF, thereby enhancing the anticancer activity of oHSV. Here we describe a bacterial artificial chromosome-based method for construction of an oHSV expressing a transgene, which we routinely use in the laboratory to create a number of different recombinant oHSV bearing either therapeutic or reporter genes. 10.1007/978-1-4939-9065-8_10
Oncolytic virus immunotherapy: future prospects for oncology. Raja Junaid,Ludwig Johannes M,Gettinger Scott N,Schalper Kurt A,Kim Hyun S Journal for immunotherapy of cancer BACKGROUND:Immunotherapy is at the forefront of modern oncologic care. Various novel therapies have targeted all three layers of tumor biology: tumor, niche, and immune system with a range of promising results. One emerging class in both primary and salvage therapy is oncolytic viruses. This therapy offers a multimodal approach to specifically and effectively target and destroy malignant cells, though a barrier oncoviral therapies have faced is a limited therapeutic response to currently delivery techniques. MAIN BODY:The ability to deliver therapy tailored to specific cellular targets at the precise locus in which it would have its greatest impact is a profound development in anti-cancer treatment. Although immune checkpoint inhibitors have an improved tolerability profile relative to cytotoxic chemotherapy and whole beam radiation, severe immune-related adverse events have emerged as a potential limitation. These include pneumonitis, pancreatitis, and colitis, which are relatively infrequent but can limit therapeutic options for some patients. Intratumor injection of oncolytic viruses, in contrast, has a markedly lower rate of serious adverse effects and perhaps greater specificity to target tumor cells. Early stage clinical trials using oncolytic viruses show induction of effector anti-tumor immune responses and suggest that such therapies could also morph and redefine both the local target cells' niche as well as impart distant effects on remote cells with a similar molecular profile. CONCLUSION:It is imperative for the modern immuno-oncologist to understand the biological processes underlying the immune dysregulation in cancer as well as the effects, uses, and limitations of oncolytic viruses. It will be with this foundational understanding that the future of oncolytic viral therapies and their delivery can be refined to forge future horizons in the direct modulation of the tumor bed. 10.1186/s40425-018-0458-z
Combination immunotherapy with interleukin-2 surface-modified tumor cell vaccine and programmed death receptor-1 blockade against renal cell carcinoma. Zhang Xinji,Shi Xiaojun,Li Jinlong,Hu Zhiming,Gao Jimin,Wu Shihao,Long Zhaolin Cancer science Immunotherapy may be an effective way to prevent postoperative recurrence of renal cell carcinoma. Streptavidin-interleukin-2 (SA-IL-2) surface-modified tumor cell vaccine developed through our protein-anchor technology could induce specific antitumor T-cell responses, but this immunotherapy cannot completely eradicate the tumor. These effector T cells highly expressed programmed death receptor-1 (PD-1), and the expression of programmed death ligand-1 (PD-L1) in the tumor environment also was upregulated after SA-IL-2-modified vaccine therapy. PD-1/PD-L1 interaction promotes tumor immune evasion. Adding PD-1 blockade to SA-IL-2-modified vaccine therapy increased the number of CD4 , CD8 and CD8 interferon-γ but not CD4 Foxp3 T cells. PD-1 blockade could rescue the activity of tumor-specific T lymphocytes induced by the SA-IL-2-modified vaccine. Combination therapy delayed tumor growth and protected mice against a second Renca cells but not melanoma cells challenge. Taken together, PD-1 blockade could reverse immune evasion in the treatment with SA-IL-2-modified vaccine, and eventually induce a stronger specific antitumor immune response against renal cell carcinoma. 10.1111/cas.13842
Renal Cell Carcinoma: the Oncologist Asks, Can PSMA PET/CT Answer? Pozzessere Chiara,Bassanelli Maria,Ceribelli Anna,Rasul Sazan,Li Shuren,Prior John O,Cicone Francesco Current urology reports PURPOSE OF REVIEW:To critically review the potential clinical applications of prostate-specific membrane antigen (PSMA) radioactive ligands in renal cell carcinoma (RCC). RECENT FINDINGS:Radioactive probes targeting PSMA hold promise in several malignancies in addition to prostate cancer, owing to the expression of PSMA by tumor neovasculature. The majority of clear cell RCCs (ccRCC), the most malignant RCC subtype, express PSMA on tumor-associated neovasculature. The endothelium of less aggressive RCC subtypes is PSMA positive in a lower, but still significant percentage of cases. PSMA might therefore represent an interesting theragnostic target in RCC. The preliminary data available suggest a potential role for PSMA-targeting radiopharmaceuticals in complementing conventional imaging for staging ccRCC patients at risk of nodal involvement and oligometastatic disease. Additional applications of PSMA imaging may be the selection and the response assessment of patients receiving anti-angiogenic treatments. The effectiveness of PSMA-targeting radionuclide therapy should also be investigated. 10.1007/s11934-019-0938-9
Preclinical development of T-cell receptor-engineered T-cell therapy targeting the 5T4 tumor antigen on renal cell carcinoma. Xu Yuexin,Morales Alicia J,Cargill Michael J,Towlerton Andrea M H,Coffey David G,Warren Edus H,Tykodi Scott S Cancer immunology, immunotherapy : CII 5T4 (trophoblast glycoprotein, TPBG) is a transmembrane tumor antigen expressed on more than 90% of primary renal cell carcinomas (RCC) and a wide range of human carcinomas but not on most somatic adult tissues. The favorable expression pattern has encouraged the development and clinical testing of 5T4-targeted antibody and vaccine therapies. 5T4 also represents a compelling and unexplored target for T-cell receptor (TCR)-engineered T-cell therapy. Our group has previously isolated high-avidity CD8 T-cell clones specific for an HLA-A2-restricted 5T4 epitope (residues 17-25; 5T4). In this report, targeted single-cell RNA sequencing was performed on 5T4-specific T-cell clones to sequence the highly variable complementarity-determining region 3 (CDR3) of T-cell receptor α chain (TRA) and β chain (TRB) genes. Full-length TRA and TRB sequences were cloned into lentiviral vectors and transduced into CD8 T-cells from healthy donors. Redirected effector T-cell function against 5T4 was measured by cytotoxicity and cytokine release assays. Seven unique TRA-TRB pairs were identified. All seven TCRs exhibited high expression on CD8 T-cells with transduction efficiencies from 59 to 89%. TCR-transduced CD8 T-cells demonstrated redirected cytotoxicity and cytokine release in response to 5T4 on target-cells and killed 5T4/HLA-A2 kidney-, breast-, and colorectal-tumor cell lines as well as primary RCC tumor cells in vitro. TCR-transduced CD8 T-cells also detected presentation of 5T4 in TAP1/2-deficient T2 target-cells. TCR-transduced T-cells redirected to recognize the 5T4 epitope from a broadly shared tumor antigen are of interest for future testing as a cellular immunotherapy strategy for HLA-A2 subjects with 5T4 tumors. 10.1007/s00262-019-02419-4
A Review of Prostate-Specific Membrane Antigen (PSMA) Positron Emission Tomography (PET) in Renal Cell Carcinoma (RCC). Ahn Thomas,Roberts Matthew J,Abduljabar Aous,Joshi Andre,Perera Marlon,Rhee Handoo,Wood Simon,Vela Ian Molecular imaging and biology Metastatic renal cell carcinoma (mRCC) is a disease that portends poor prognosis despite an increasing number of novel systemic treatment options including new targeted therapies and immunotherapy. Ablative intervention directed at oligometastatic RCC has demonstrated survival benefit. Consequently, developing techniques for improved staging of mRCC on contemporary imaging modalities including X-ray computed tomography (CT), magnetic resonance imaging (MRI) and/or bone scan (BS) is a clinical priority. This is relevant for metastatic deposits too small to characterize or lymph nodes within physiological normality. Prostate-specific membrane antigen (PSMA) is a type II transmembrane glycoprotein highly expressed on prostate cancer epithelial cells. Recently, small molecules targeting the PSMA receptor, linked to radioactive isotopes have been developed for use with positron emission tomography (PET). Despite its nomenclature, PSMA has also been found to be expressed in the neovasculature of non-prostate cancers such as renal cell carcinoma (RCC) and hence PSMA PET/CT imaging has been proposed as an alternative staging modality. Preliminary small studies involving the use of PSMA PET/CT imaging in mRCC have been encouraging with evidence of improved staging sensitivity which has directly led to change in management in some cases. Given these early encouraging reports, we performed a comprehensive narrative review on the available evidence, including the scientific basis for PSMA expression in RCC, the role of PSMA PET/CT imaging with potential clinical implications in mRCC, its limitations and future opportunities. 10.1007/s11307-018-01307-0