scholarly journals Orf Virus-Based Therapeutic Vaccine for Treatment of Papillomavirus-Induced Tumors

2020 ◽  
Vol 94 (15) ◽  
Author(s):  
M. Schneider ◽  
M. Müller ◽  
A. Yigitliler ◽  
J. Xi ◽  
C. Simon ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Therapeutic Efficacy ◽  
Tumor Regression ◽  
Therapeutic Vaccine ◽  
Tumor Burden ◽  
Orf Virus ◽  
Cottontail Rabbit ◽  
Induced Tumors ◽  
First Time ◽  
Complete Tumor

ABSTRACT Orf virus (ORFV) represents a suitable vector for the generation of efficient, prophylactic antiviral vaccines against different pathogens. The present study investigated for the first time the therapeutic application of ORFV vector-based vaccines against tumors induced by cottontail rabbit papillomavirus (CRPV). ORFV-CRPV recombinants were constructed expressing the early CRPV gene E1, E2, E7, or LE6. In two independent experiments we used in total 23 rabbits which were immunized with a mixture of the four ORFV-CRPV recombinants or empty ORFV vector as a control 5 weeks after the appearance of skin tumors. For the determination of the therapeutic efficacy, the subsequent growth of the tumors was recorded. In the first experiment, we could demonstrate that three immunizations of rabbits with high tumor burden with the combined four ORFV-CRPV recombinants resulted in significant growth retardation of the tumors compared to the control. A second experiment was performed to test the therapeutic effect of 5 doses of the combined vaccine in rabbits with a lower tumor burden than in nonimmunized rabbits. Tumor growth was significantly reduced after immunization, and one vaccinated rabbit even displayed complete tumor regression until the end of the observation period at 26 weeks. Results of delayed-type hypersensitivity (DTH) skin tests suggest the induction of a cellular immune response mediated by the ORFV-CRPV vaccine. The data presented show for the first time a therapeutic potential of the ORFV vector platform and encourage further studies for the development of a therapeutic vaccine against virus-induced tumors. IMPORTANCE Viral vectors are widely used for the development of therapeutic vaccines for the treatment of tumors. In our study we have used Orf virus (ORFV) strain D1701-V for the generation of recombinant vaccines expressing cottontail rabbit papillomavirus (CRPV) early proteins E1, E2, LE6, and E7. The therapeutic efficacy of the ORFV-CRPV vaccines was evaluated in two independent experiments using the outbred CRPV rabbit model. In both experiments the immunization achieved significant suppression of tumor growth. In total, 84.6% of all outbred animals benefited from the ORFV-CRPV vaccination, showing reduction in tumor size and significant tumor growth inhibition, including one animal with complete tumor regression without recurrence.

scholarly journals Tumor growth characteristics of the Walker 256 AR tumor, a regressive variant of the rat Walker 256 A tumor

2010 ◽  
Vol 53 (5) ◽  
pp. 1101-1108 ◽  
Author(s):  
Fernando Guimarães ◽  
Alessandra Soares Schanoski ◽  
Tereza Cristina Samico Cavalcanti ◽  
Priscila Bianchi Juliano ◽  
Ana Neuza Viera-Matos ◽  
...  
Keyword(s):  
Growth Rate ◽  
Tumor Growth ◽  
Wistar Rats ◽  
Tumor Regression ◽  
Growth Characteristics ◽  
Tumor Growth Rate ◽  
Continuous Growth ◽  
Tumor Bearing ◽  
Walker 256 ◽  
Complete Tumor

The present study aimed at characterizing the subcutaneous development of the Walker 256 (W256) AR tumor, a regressive variant of the rat W256 A tumor. Wistar rats were injected subcutaneously with 4x10(6) W256 A or W256 AR tumor cells. The development of tumors was evaluated daily by percutaneous measurements. None of the W256 A tumors (n=20) regressed, but 62% of the W256 AR tumor-bearing rats (n=21) underwent complete tumor regression within 35 days. Continuous growth of AR tumors was characterized by an increase of the tumor growth rate from day 12, which reached values above 1.0 g/day, and were significantly higher (p<0.05) than those of the regressive AR tumors. Immunosuppression by irradiation before subcutaneous injection of AR cells completely abrogated tumor regression and was associated with severe metastatic dissemination. Daily evaluation of the tumor growth rate enabled the discrimination, in advance, between continuously growing tumors and those that regressed later on.

Protein corona in drug delivery for multimodal cancer therapy in vivo

Nanoscale ◽  
2018 ◽  
Vol 10 (5) ◽  
pp. 2461-2472 ◽  
Author(s):  
Eugenia Li Ling Yeo ◽  
Patricia Soo Ping Thong ◽  
Khee Chee Soo ◽  
James Chen Yong Kah
Keyword(s):  
Drug Delivery ◽  
Cancer Therapy ◽  
Therapeutic Efficacy ◽  
Tumor Regression ◽  
Protein Corona ◽  
Mouse Serum ◽  
Complete Tumor Regression ◽  
Tumor Accumulation ◽  
Complete Tumor

Intravenous delivery of NR-MS-Ce6, wherein Ce6 was loaded on NRs using a protein corona formed from mouse serum, resulted in tumor accumulation and synergy between PTT and PDT, leading to enhanced therapeutic efficacy and complete tumor regression in 19 days.

scholarly journals Case Report: Exceptional Response to Avelumab After Failure of Electrochemotherapy in a Patient With Rapidly Progressive, PD-L1-Negative Merkel Cell Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Martina Torchio ◽  
Laura Cattaneo ◽  
Massimo Milione ◽  
Natalie Prinzi ◽  
Francesca Corti ◽  
...  
Keyword(s):  
Cell Death ◽  
Case Report ◽  
Disease Progression ◽  
Mhc Class I ◽  
Tumor Regression ◽  
Complete Response ◽  
Merkel Cell ◽  
Extensive Disease ◽  
First Time ◽  
Complete Tumor

This case report shows, for the first time, a patient experiencing a complete response after one dose of avelumab following extensive disease progression with prior electrochemotherapy (ECT) treatment. We suggest that ECT may help to establish a tumor microenvironment favorable to immunotherapy. Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with seldom durable chemotherapy responses. ECT has recently emerged as a potential treatment option for several malignancies, including MCC. Avelumab, an anti-programmed cell death-ligand 1 (PD-L1) monoclonal antibody, became the first approved treatment for patients with metastatic MCC. ECT has been shown to activate the immune response, but it is still unknown how ECT may affect patient’s response to subsequent immunotherapy. We report a case of a patient with MCC who presented with a rapidly growing skin nodule of the right cheek and experienced extensive disease progression following surgical debulking and ECT treatment. The patient received a flat dose of 800 mg avelumab intravenously every 2 weeks showing complete tumor regression after only one dose. Immunohistochemical analysis of surgical and post-ECT biopsies collected from the primary lesion revealed tumor expression of programmed cell death protein-1 (PD-1), but not PD-L1. Analysis of the tumor samples also revealed no expression of Merkel cell polyomavirus (MCPyV). Comparison of the biopsies showed a decrease in myeloid and T-cell markers after ECT but an increase in major histocompatibility complex (MHC) class I expression on tumor cells. Additionally, the patient experienced an increase in neutrophil-to-lymphocyte ratio and lactate dehydrogenase values post-ECT, which subsequently decreased with avelumab treatment. As of 30 October 2019, the patient was still receiving avelumab treatment and had an ongoing complete response. In this case report, a patient with PD-L1-negative and MCPyV-negative MCC who had disease progression following ECT experienced complete tumor regression with avelumab treatment, suggesting, for the first time to our knowledge, that ECT may help to establish a tumor microenvironment favorable to immunotherapy via a potential abscopal effect. Tumor-intrinsic PD-1 expression and modulation of MHC class I antigens after ECT may contribute to the clinical efficacy of avelumab in this context.

scholarly journals In VivoImaging-Based Mathematical Modeling Techniques That Enhance the Understanding of Oncogene Addiction in relation to Tumor Growth

2013 ◽  
Vol 2013 ◽  
pp. 1-8
Author(s):  
Chinyere Nwabugwu ◽  
Kavya Rakhra ◽  
Dean Felsher ◽  
David Paik
Keyword(s):  
Mathematical Model ◽  
Tumor Growth ◽  
Cellular Response ◽  
Time Course ◽  
Tumor Regression ◽  
Tumor Burden ◽  
Oncogene Addiction ◽  
Complex Interactions ◽  
Immune Mediated ◽  
Delay Differential

The dependence on the overexpression of a single oncogene constitutes an exploitable weakness for molecular targeted therapy. These drugs can produce dramatic tumor regression by targeting the driving oncogene, but relapse often follows. Understanding the complex interactions of the tumor’s multifaceted response to oncogene inactivation is key to tumor regression. It has become clear that a collection of cellular responses lead to regression and that immune-mediated steps are vital to preventing relapse. Our integrative mathematical model includes a variety of cellular response mechanisms of tumors to oncogene inactivation. It allows for correct predictions of the time course of events following oncogene inactivation and their impact on tumor burden. A number of aspects of our mathematical model have proven to be necessary for recapitulating our experimental results. These include a number of heterogeneous tumor cell states since cells following different cellular programs have vastly different fates. Stochastic transitions between these states are necessary to capture the effect of escape from oncogene addiction (i.e., resistance). Finally, delay differential equations were used to accurately model the tumor growth kinetics that we have observed. We use this to model oncogene addiction in MYC-induced lymphoma, osteosarcoma, and hepatocellular carcinoma.

Radioimmunotherapy Utilizing the Humanized Anti-CD25 Mab Daclizumab Is Highly Effective in Mice Bearing Human Hodgkin’s Lymphoma Xenografts.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4632-4632
Author(s):  
Jan O. Staak ◽  
David Colcher ◽  
Jianyi Wang ◽  
Andreas Engert ◽  
Andrew A. Raubitschek
Keyword(s):  
Cell Surface ◽  
Tumor Progression ◽  
Nude Mice ◽  
Therapeutic Efficacy ◽  
Tumor Regression ◽  
Hodgkin's Lymphoma ◽  
Imaging Studies ◽  
Complete Tumor Regression ◽  
Tumor Bearing ◽  
Complete Tumor

Abstract Objectives: CD25 is overexpressed on the cell surface by a variety of malignant diseases including Hodgkin’s lymphoma (HL). It is cleaved from the cell surface releasing a soluble ectodomain (sCD25) which may interfere with a radiolabeled MAb’s ability to reach the target cell. Daclizumab (Zenapax®), a humanized IgG1 that binds to the alpha subunit of the human interleukin-2 (IL-2) receptor (CD25, Tac), is FDA-approved for the prophylaxis of renal transplant rejection, as part of an immunosuppressive regimen. We performed biodistribution and γ-imaging studies of 111In-labeled Zenapax and investigated the therapeutic efficacy of the 90Y-labeled version in a human CD25+ human HL xenograft mouse model. Materials & Methods: Zenapax was conjugated to the macrocyclic bifunctional chelate DOTA-NHS active ester. For biodistribution studies athymic nude mice bearing s.c. L540 (human HL line) tumors were injected i.v. with 111In-DOTA-Zenapax or 111In-DOTA-M5A (humanized anti-CEA; 3-5μCi, 2-3μCi/μg) as a control. At various timepoints tumors, blood and major organs were collected, weighed and analyzed for radioactivity. The percent injected dose per gram (%ID/g) was determined. Serum samples were analyzed by HPLC size exclusion chromatography (SEC). For γ-imaging studies L540-tumor-bearing mice received 111In-Zenapax (10.5μCi, 1.8μCi/μg) and serial images were acquired at various timepoints. For the evaluation of therapeutic efficacy, groups of 8 L540 tumor bearing nude mice were injected i.v. with a single dose of 90Y-labeled-Zenapax (0, 40, 60, 80, 100, or 120μCi). Tumor progression was monitored by physical measurements. Results: Maximum tumor accretion for Zenapax was 35 %ID/g at 72h vs. 9 %ID/g for the control MAb. There were no significant differences in normal organ distribution or clearance from the blood between both MAbs. HPLC analysis of serum from Zenapax treated mice showed complexes formation (6–16%; ~210kD), consisting of the MAb and sCD25. γ-imaging studies demonstrated significant tumor retention of 111In-Zenapax. Therapeutic efficacy was dose-dependent with complete tumor regression in all mice receiving 100–120 μCi, as well as 5/8 after 80μCi, and 4/8 after 40–60μCi. No severe toxicities were observed. In animals with regrowth of tumors the average delay was 18, 37, and 41 days for mice treated with 40, 60, and 80μCi, respectively. Untreated mice were sacrificed after 21 days due to excessive tumor progression or tumor ulceration. Conclusions: Radiolabeled Zenapax demonstrated favorable biodistribution properties and excellent tumor localization. It was highly efficacious in the treatment of mice bearing human HL xenografts with complete tumor regression in the two higher dose groups and high response rates at lower doses. In mice with incomplete regression significant delay of tumor progression was observed. 90Y-Zenapax was well tolerated without evidence of toxicity. A clinical therapy trial with 90Y-Zenapax in patients with HL is planned.

scholarly journals Photodynamic therapy of the experimental tumors of different morphological types with liposomal boronated chlorin е6

2021 ◽  
Vol 10 (3) ◽  
pp. 12-22
Author(s):  
O. B. Abramova ◽  
V. V. Drozhzhina ◽  
T. P. Churikova ◽  
E. A. Kozlovtceva ◽  
L. M. Arkhipova ◽  
...  
Keyword(s):  
Photodynamic Therapy ◽  
Tumor Growth ◽  
Antitumor Effect ◽  
Tumor Regression ◽  
Radiation Energy ◽  
Chlorin E6 ◽  
Radiation Energy Density ◽  
Complete Tumor Regression ◽  
Complete Tumor

The article summarizes the results of studies of the effectiveness of photodynamic therapy using a new domestic photosensitizer liposomal borated chlorin e6 (LBC) after its parenteral administration (intraperitoneal and intravenous). Antitumor efficacy was evaluated in rats with M-1 sarcoma and PC-1 alveolar liver cancer and mice with B16 melanoma and Ehrlich’s carcinoma, which were transplanted subcutaneously into the thigh area of the animals. The aim of the study was to determine the optimal regimes of photodynamic therapy that would allow achieving the maximum antitumor effect up to 21 days after the photodynamic therapy. The therapy was carried out under the control of the accumulation of the photosensitizer in the tumor and surrounding tissues of the thigh by selecting the doses of the drug and the parameters of laser radiation (energy density and power density). The effectiveness of therapy was assessed by the inhibition of tumor growth, by the percentage of animals with complete tumor regression, by the absolute growth rate in animals with continued tumor growth compared to controls. The results of our studies have shown that the domestic photosensitizer liposomal borated chlorin e6 has high antitumor activity in vivo. In an experimental study of the photosensitizer under certain PDT modes, the maximum antitumor effect (complete tumor regression in 100% of animals) was obtained up to 21 days after PDT in all tumor models used.

Porphyrin-lipid nanovesicles (Porphysomes) are effective photosensitizers for photodynamic therapy

Nanophotonics ◽  
2021 ◽  
Vol 0 (0) ◽  
Author(s):  
Keegan Guidolin ◽  
Lili Ding ◽  
Juan Chen ◽  
Brian C. Wilson ◽  
Gang Zheng
Keyword(s):  
Photodynamic Therapy ◽  
Tumor Growth ◽  
Intrinsic Structure ◽  
Therapeutic Applications ◽  
Positron Emission ◽  
Theranostic Agents ◽  
Negative Controls ◽  
And Control ◽  
Complete Tumor

Abstract Porphysomes (PS) are liposome-like nanoparticles comprising pyropheophorbide-conjugated phospholipids that have demonstrated potential as multimodal theranostic agents for applications that include phototherapies, targeted drug delivery and in vivo fluorescence, photoacoustic, magnetic resonance or positron emission imaging. Previous therapeutic applications focused primarily on photothermal therapy (PTT) and suggested that PSs require target-triggered activation for use as photodynamic therapy (PDT) sensitizers. Here, athymic nude mice bearing subcutaneous A549 human lung tumors were randomized into treatment and control groups: PS-PDT at various doses, PS-only and no treatment negative controls, as well as positive controls using the clinical photosensitizer Photofrin. Animals were followed for 30 days post-treatment. PS-PDT at all doses demonstrated a significant tumor ablative effect, with the greatest effect seen with 10 mg/kg PS at a drug-light interval of 24 h. By comparison, negative controls (PS-only, Photofrin-only, and no treatment) showed uncontrolled tumor growth. PDT with Photofrin at 5 mg/kg and PS at 10 mg/kg demonstrated similar tumor growth suppression and complete tumor response rates (15 vs. 25%, p = 0.52). Hence, porphysome nanoparticles are an effective PDT agent and have the additional advantages of multimodal diagnostic and therapeutic applications arising from their intrinsic structure. Porphysomes may also be the first single all-organic agent capable of concurrent PDT and PTT.

scholarly journals 601 Development of improved small molecule STING agonists suitable for systemic administration

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A636-A636
Author(s):  
Maciej Rogacki ◽  
Stefan Chmielewski ◽  
Magdalena Zawadzka ◽  
Jolanta Mazurek ◽  
Katarzyna Wnuk-Lipińska ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Small Molecule ◽  
Immune Cells ◽  
Systemic Administration ◽  
Cytokine Release ◽  
Major Player ◽  
Human Immune ◽  
New Generation ◽  
Dose Dependent ◽  
Complete Tumor

BackgroundStimulator of Interferon Genes (STING) is a major player in the activation of robust innate immune response leading to initiation and enhancement of tumor-specific adaptive immunity. Several clinical and pre-clinical programs have shown that activation of the STING pathway triggers immune-mediated antitumor response. Although vast majority of programs focus on development of analogues of the endogenous STING ligands, their chemical nature and stability often limit their use to local administration. Herein, we present recent results from the development of our selective non-nucleotide, non-macrocyclic, small molecule direct STING agonists, suitable for systemic administration, characterized by improved activity in human immune cells.MethodsBinding to recombinant STING protein was examined using FTS, MST, FP and crystallography studies. Phenotypic screen was performed in THP-1 Dual reporter cells. Mouse bone marrow-derived dendritic cells (BMDC) were obtained from C57BL/6 mice and differentiated with mIL-4 and mGM-CSF. STING agonists were administered into BALB/c mice and cytokine release was measured in plasma. Additionally, mice were inoculated with CT26 murine colon carcinoma or EMT6 murine breast carcinoma cells and the compound was administered, followed by the regular tumor growth and body weight monitoring.ResultsRyvu’s small-molecule agonists demonstrate strong binding affinity to recombinant STING proteins across all tested species. The compounds bind to all human STING protein variants and trigger pro-inflammatory cytokine release from human immune cells regardless of the STING haplotype. Moreover, new generation of developed agonists show significantly improved binding to human protein as well as in vitro activity on human cells. Systemic, intravenous in vivo administration leads to a dose-dependent upregulation of STING-dependent pro-inflammatory cytokines, which results in a dose-dependent antitumor efficacy observed in CT26 and EMT6 mouse cancer models, leading to complete tumor remissions in all treated animals. Furthermore, observed efficacy is accompanied by development of a lasting immunological response demonstrated by lack of tumor engraftment or a delayed tumor growth in cured animals challenged with repeated inoculation of cancer cells.ConclusionsNew generation Ryvu’s STING agonists are strong and selective activators of STING-dependent signaling in both mouse and human immune cells promoting anti-tumor immunity. Treatment with Ryvu’s small-molecule STING agonists leads to engagement of the immune system which results in a complete tumor remission and development of immunological memory of the cancer antigens. The compounds show good selectivity and ADME properties enabling development for systemic administration. In addition developed compounds maintain small functional handles amenable to linker attachment making the series suitable for versatile development as single agents, for combinations with immunotherapies or as targeted agents.

245 Human TLR8 knock-in mice potentiate immunotherapy responses of MC38 syngeneic tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A264-A264
Author(s):  
Shanshan Qi ◽  
Hongjuan Zhang ◽  
Ruilin Sun ◽  
Annie An ◽  
Henry Li ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Growth ◽  
Cancer Immunotherapy ◽  
Tumor Regression ◽  
Tumor Growth Rate ◽  
Tumor Growth Inhibition ◽  
List Type ◽  
Rna Recognition ◽  
Ethical Guidelines ◽  
Ifn Γ

BackgroundToll-like receptors (TLRs) serve critical roles in mediating innate immune responses against many pathogens. However, they may also bind to endogenous ligands and lead to the pathogenesis of autoimmunity. Although TLR8 belongs to the same TLR family as TLR7, its role in inflammation and tumor progression is not yet fully understood due to the lack of suitable animal models. In humans, both TLR7 and TLR8 recognize single-stranded self-RNA, viral RNA, and synthetic small molecule agonists.1, 2 However, mouse Tlr8 is non-functional due to the absence of 5 amino acids necessary for RNA recognition. In order to create a mouse model with functional TLR8, we replaced exon 3 of mouse Tlr8 with human TLR8, therefore developing a hTLR8 knock-in (KI) model. Both heterozygous and homozygous hTLR8 KI mice are viable with inflammatory phenotypes, i.e. enlarged spleens and livers, and significantly higher IL-12 p40 levels under TLR8 agonist treatment. In this study, we evaluated the potential use of hTLR8 mice for cancer immunotherapy studies.MethodshTLR8 mice, together with naïve C57BL/6 mice, were inoculated with MC38 syngeneic tumor cells. Tumor bearing mice were grouped at a mean tumor volume of approximately 100 mm3 for treatment with PBS or 10 mg/kg anti-PD-1 (RMP1-14) antibody. At the efficacy endpoint, spleens and tumors were collected for flow cytometry profiling.ResultsAnti-PD-1 treatment of MC38 tumors in naïve C57BL/6 led to moderate tumor growth inhibition (TGI = 54%). Interestingly, anti-PD-1 treatment showed improved efficacy in hTLR8 mice (TGI = 79%), including 2/10 tumors with complete tumor regression. In comparison, non-treated MC38 tumor growth rate was slower in hTLR8 mice than in naïve mice. Anti-PD-1 treated hTLR8 mice also had significantly increased IFN-γ and TNF-a positive CD4+ T cells in the spleen, along with higher numbers of differentiated effector T cells. In addition, hTLR8 mice have activated dendritic cells and macrophages, acting as critical steps in initiation of the inflammatory process, with higher levels of pro-inflammatory cytokines, such as IL-6, IFN-γ, TNF-a, and IL-1β, which may promote Th1 priming and differentiation of T cells into IFN-γ or TNF-a producing cells.ConclusionshTLR8 mice offer a great tool to model cancer immunotherapy in an inflammatory/autoimmunity prone background. Moreover, hTLR8 mice can be effectively used to shift a ‘cold’ tumor phenotype to ‘hot’ tumors in a syngeneic setting.Ethics ApprovalAnimal experiments were conducted in accordance with animal welfare law, approved by local authorities, and in accordance with the ethical guidelines of CrownBio (Taicang).ReferencesKugelberg E. Making mice more human the TLR8 way. Nat Rev Immunol 2014;14:6.Guiducci C, Gong M, Cepika A-M, et al. RNA recognition by human TLR8 can lead to autoimmune inflammation. J Exp Med 2013;210:2903–2919.

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