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Adkins I.,Sotio | Fucikova J.,Sotio | Garg A.D.,Cell Death Research and Therapy CDRT Unit | Agostinis P.,Cell Death Research and Therapy CDRT Unit | Spisek R.,Sotio
OncoImmunology | Year: 2014

The concept of immunogenic cancer cell death (ICD), as originally observed during the treatment with several chemotherapeutics or ionizing irradiation, has revolutionized the view on the development of new anticancer therapies. ICD is defined by endoplasmic reticulum (ER) stress response, reactive oxygen species (ROS) generation, emission of danger-associated molecular patterns and induction of antitumor immunity. Here we describe known and emerging cancer cell death-inducing physical modalities, such as ionizing irradiation, ultraviolet C light, Photodynamic Therapy (PDT) with Hypericin, high hydrostatic pressure (HHP) and hyperthermia (HT), which have been shown to elicit effective antitumor immunity. We discuss the evidence of ICD induced by these modalities in cancer patients together with their applicability in immunotherapeutic protocols and anticancer vaccine development. © 2014 The Author(s). Published with license by Taylor & Francis Group, LLC.


PubMed | Gustave Roussy Cancer Campus, Institute of Hematology and Blood Transfusion, Sotio, Metabolomics and Cell Biology Platforms and 4 more.
Type: | Journal: Blood | Year: 2016

Cancer cell death can be perceived as immunogenic by the host only when malignant cells emit immunostimulatory signals (so-called damage-associated molecular patterns, DAMPs), as they die in the context of failing adaptive responses to stress. Accumulating preclinical and clinical evidence indicates that the capacity of immunogenic cell death (ICD) to (re-)activate an anticancer immune response is key to the success of various chemo- and radiotherapeutic regimens. Malignant blasts from acute myeloid leukemia (AML) patients exposed multiple DAMPs including calreticulin (CRT), heat-shock protein 70 (HSP70) and HSP90 on their plasma membrane irrespective of treatment. In these patients, high levels of surface-exposed (ecto-)CRT correlated with an increased proportion of natural killer (NK) cells and effector memory CD4


Truxova I.,Charles University | Pokorna K.,Sotio | Kloudova K.,Sotio | Partlova S.,Charles University | And 2 more authors.
Immunology Letters | Year: 2014

Background: Dendritic cells (DCs) are professional antigen-presenting cells that are capable of inducing immune responses. DC-based vaccines are normally generated using a standard 5- to 7-day protocol. To shorten the DC-based vaccine production for use in cancer immunotherapy, we have developed a fast DC protocol by comparing standard DCs (Day 5 DCs) and fast DCs (Day 3 DCs). Methods: We tested the generation of Day 5 versus Day 3 DCs using CellGro media and subsequent activation by two activation stimuli: Poly (I:C) and LPS. We evaluated DC morphology, viability, phagocyte activity, cytokine production and ability to stimulate antigen-specific T cells. Results: Day 5 and Day 3 DCs exhibited similar phagocytic capacity. Poly (I:C)-activated Day 5 DCs expressed higher levels of the costimulatory and surface molecules CD80, CD86 and HLA-DR compared to Poly (I:C)-activated Day 3 DCs. Nevertheless, LPS-activated Day 5 and Day 3 DCs were phenotypically similar. Cytokine production was generally stronger when LPS was used as the maturation stimulus, and there were no significant differences between Day 5 and Day 3 DCs. Importantly, Day 5 and Day 3 DCs were able to generate comparable numbers of antigen-specific CD8+ T cells. The number of Tregs induced by Day 5 and Day 3 DCs was also comparable. Conclusion: We identified monocyte-derived DCs generated in CellGro for 3 days and activated using Poly (I:C) similarly potent in most functional aspects as DCs produced by the standard 5 day protocol. These results provide the rationale for the evaluation of faster protocols for DC generation in clinical trials. © 2014 Elsevier B.V.


Fucikova J.,University Hospital Motol | Moserova I.,Sotio | Truxova I.,Sotio | Hermanova I.,University Hospital Motol | And 9 more authors.
International Journal of Cancer | Year: 2014

Recent studies have identified molecular events characteristic of immunogenic cell death (ICD), including surface exposure of calreticulin (CRT), the heat shock proteins HSP70 and HSP90, the release of high-mobility group box protein 1 (HMGB1) and the release of ATP from dying cells. We investigated the potential of high hydrostatic pressure (HHP) to induce ICD in human tumor cells. HHP induced the rapid expression of HSP70, HSP90 and CRT on the cell surface. HHP also induced the release of HMGB1 and ATP. The interaction of dendritic cells (DCs) with HHP-treated tumor cells led to a more rapid rate of DC phagocytosis, upregulation of CD83, CD86 and HLA-DR and the release of interleukin IL-6, IL-12p70 and TNF-α. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific T cells. DCs pulsed with HHP-treated tumor cells also induced the lowest number of regulatory T cells. In addition, we found that the key features of the endoplasmic reticulum stress-mediated apoptotic pathway, such as reactive oxygen species production, phosphorylation of the translation initiation factor eIF2α and activation of caspase-8, were activated by HHP treatment. Therefore, HHP acts as a reliable and potent inducer of ICD in human tumor cells. What's new? Some cytotoxic agents used in cancer treatment activate an immunogenic form of apoptosis, which causes the dying tumor cells to induce an effective antitumor immune response. Here, the authors find that exposure to high hydrostatic pressure (HHP) induces bona fide immunogenic cell death in a wide range of human tumor cell lines and primary tumor cells. As HHP treatment is relatively easily standardized under good manufacturing practices conditions, the authors initiated multiple clinical trials evaluating the potential of dendritic cells loaded with HHP-treated cancer cells to induce tumor cell-specific immune responses in patients with prostate cancer. © 2014 UICC.


Podrazil M.,Charles University | Horvath R.,Charles University | Horvath R.,University Hospital Motol | Becht E.,French Institute of Health and Medical Research | And 17 more authors.
Oncotarget | Year: 2015

Purpose: We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. Experimental design: Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. Results: No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. Conclusions: In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.


PubMed | Sotio and Charles University
Type: Journal Article | Journal: Oncotarget | Year: 2016

In order to select a suitable combination of cancer cell lines as an appropriate source of antigens for dendritic cell-based immunotherapy of ovarian cancer, we analyzed the expression level of 21 tumor associated antigens (BIRC5, CA125, CEA, DDX43, EPCAM, FOLR1, Her-2/neu, MAGE-A1, MAGE-A2, MAGE-A3, MAGE-A4, MAGE-A6, MAGE-A10, MAGE-A12, MUC-1, NY-ESO-1, PRAME, p53, TPBG, TRT, WT1) in 4 established ovarian cancer cell lines and in primary tumor cells isolated from the high-grade serous epithelial ovarian cancer tissue. More than 90% of tumor samples expressed very high levels of CA125, FOLR1, EPCAM and MUC-1 and elevated levels of Her-2/neu, similarly to OVCAR-3 cell line. The combination of OV-90 and OVCAR-3 cell lines showed the highest overlap with patients samples in the TAA expression profile.


PubMed | Eli Lilly and Company, Massachusetts General Hospital, Dana-Farber Cancer Institute, Sloan Kettering Cancer Center and 4 more.
Type: Journal Article | Journal: Clinical cancer research : an official journal of the American Association for Cancer Research | Year: 2016

Tyrosinase-related protein-1 (TYRP1) is a transmembrane glycoprotein that is specifically expressed in melanocytes and melanoma cells. Preclinical data suggest that mAbs targeting TYRP1 confer antimelanoma activity. IMC-20D7S is a recombinant human IgG1 mAb targeting TYRP1. Here, we report the first-in-human phase I/Ib trial of IMC-20D7S.The primary objective of this study was to establish the safety profile and the MTD of IMC-20D7S. Patients with advanced melanoma who progressed after or during at least one line of treatment or for whom standard therapy was not indicated enrolled in this standard 3 + 3 dose-escalation, open-label study. IMC-20D7S was administered intravenously every 2 or 3 weeks.Twenty-seven patients were enrolled. The most common adverse events were fatigue and constipation experienced by nine (33%) and eight (30%) patients, respectively. There were no serious adverse events related to treatment, no discontinuations of treatment due to adverse events, and no treatment-related deaths. Given the absence of dose-limiting toxicities, an MTD was not defined, but a provisional MTD was established at the 20 mg/kg every 2-week dose based on serum concentration and safety data. One patient experienced a complete response. A disease control rate, defined as stable disease or better, of 41% was observed.IMC-20D7S is well tolerated among patients with advanced melanoma with evidence of antitumor activity. Further investigation of this agent as monotherapy in selected patients or as part of combination regimens is warranted. Clin Cancer Res; 22(21); 5204-10. 2016 AACR.


PubMed | Sotio, French Institute of Health and Medical Research, Academy of Sciences of the Czech Republic and Charles University
Type: Journal Article | Journal: Oncoimmunology | Year: 2016

Circulating tumor cells (CTCs) are cancer cells that are released from a tumor into the bloodstream. The presence of CTCs in peripheral blood has been associated with metastasis formation in patients with breast cancer. Therefore, the molecular characterization of CTCs may improve diagnostics and support treatment decisions. We performed gene expression profiling to evaluate the enriched CTCs and peripheral blood mononuclear cells (PBMCs) of breast cancer patients using an expression panel of 55 breast cancer-associated genes. The study revealed several significantly differentially expressed genes in the CTC-positive samples, including a few that were exclusively expressed in these cells. However, the expression of these genes was barely detectable in the PBMC samples. Some genes were differentially expressed in PBMCs, and the expression of these genes was correlated with tumor grade and the formation of metastasis. In this study, we have shown that the enriched CTCs of breast cancer patients overexpress genes involved in proteolytic degradation of the extracellular matrix (ECM) as well as genes that play important roles in the epithelial-mesenchymal transition (EMT) process that may occur in these cells.


PubMed | Sotio, French Institute of Health and Medical Research, Institute of Hematology and Blood Transfusion and Charles University
Type: Clinical Trial, Phase I | Journal: Oncotarget | Year: 2015

We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms.Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis.No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS.In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.


WiseGuyReports.Com Publish a New Market Research Report On – “Immunotherapy Drugs Market Global Potential Growth,Share,Demand and Analysis Of Key Players Research Report Forecasts to 2020”. This market research report presents a comprehensive segmentation of the global immunotherapy drugs market by type of immunotherapy (mAbs, vaccines, immune checkpoint inhibitors, non-specific immunotherapies, and others), by therapy area (oncology, infectious disease, autoimmune and inflammatory disorders, respiratory diseases, and others), and by geography (the Americas, APAC, and EMEA). Key vendors are AbbVie, Amgen, Bristol-Myers Squibb, F.Hoffmann-La Roche, Johnson & Johnson, and Merck. Overview of the global immunotherapy drugs market  The market research analyst predicts that the global immunotherapy drugs market will grow at a steady CAGR of close to 12% by 2020. During a rise in cancer and a number of autoimmune diseases, the need for immunotherapy drugs is on the rise. Furthermore, with the increasing demand for mAbs, the market for immunotherapy drugs will have a positive outlook until the end of the forecast period. mAbs have a high affinity for specific disease cells and areas that need treatment. Consequently, they can be used for therapies like radioimmunotherapy and antibody-directed enzyme prodrug therapy. The augmented usage of these antibodies in drug development will help to bolster the market’s revenue generating capacity over the course of the next four years. For more information or any query mail at [email protected] An important factor impelling the prospects for growth in this market is the emergence of biosimilars. Unlike generic drugs, which have active pharmaceutical ingredients similar to original drugs, biosimilars are almost identical to their originator biologic compounds. Since biosimilars help to make treatments more accessible to patients and are less expensive than biologics, their sale among the end users is anticipated to increase significantly over the next few years. Segmentation by type of immunotherapy and analysis of the immunotherapy drugs market  - mAbs  - Vaccines  - Immune checkpoint inhibitors  - Non-specific immunotherapies During 2015, the mAbs segment dominated this market and accounted for an impressive market share of nearly 61%. The development of new drugs and the entry of new molecules like zanolimumab, elotuzumab, obinutuzumab, and onartuzumab into the market will aid in the growth of this market segment during the forecast period. Geographical segmentation and analysis of the immunotherapy drugs market  - Americas  - APAC  - EMEA The Americas dominated the global market with over 50% market share in 2015. The market is flourishing in this region due to the higher incidences of cancer, infectious diseases, and autoimmune diseases in the US. Additionally, factors such as the high affordability of therapies due to the presence of well-structured reimbursement plans will also spur the prospects for market growth until 2020. Competitive landscape and key vendors  The global market for immunotherapy drugs is highly competitive due to the presence of a number of large and small vendors. Many of these vendors have a huge global presence and enter into strategic alliances to aid in the manufacture and marketing of essential drugs. Safety and effectiveness of drugs are key factors, which will give vendors an edge in the marketplace. Key vendors in this market are - AbbVie  Amgen  Bristol-Myers Squibb  F.Hoffmann-La Roche  Johnson & Johnson  Merck  Other prominent vendors are AB Science. Ablynx, Acorda Therapeutics, ADC Therapeutics, Aduro Biotech, Advantagene, Advaxis, Agensys, Agenus, Alder Biopharmaceuticals, AlphaVax, Altor BioScience, Antares Pharma, Antigen Express, Argos Therapeutics, Astellas Pharma, AstraZeneca, AVAX Technologies, Bavarian Nordic, Baxter, Bayer, Biogen, Biotech Pharmaceutical, Biothera, Boehringer Ingelheim, Can-Fite BioPharma, Celgene, Celldex Therapeutics, Celltrion, Cel-Sci, ChemoCentryx, Chugai Pharmaceutical, Coherus BioSciences, CTI BioPharma, CureVac, Daiichi Sankyo, Eisai, Eli Lilly, Fortress Biotech, Galena Biopharma, Genexine, Genmab, Gilead Sciences, GSK, GlobeImmune, Gradalis, Heat Biologics, Hospira, Idera, Inmatics, ImmunoCellular Therapeutics, Immunomedics, ImmuPharma, Immutep, Incyte, Inovio Pharmaceuticals, Intas Pharmaceuticals, Invion, ISA Pharmaceuticals, Janssen Biotech, Juvaris Biotherapeutics, KaloBios Pharmaceuticals, Kyowa Hakko Kirin, Lexicon Pharmaceuticals, MedImmune, Morphotek, Neovii Biotech, Northwest Biotherapeutics, Novartis, NovaRx, Novo Nordisk, OncoMed Pharmaceuticals, Oncothyreon, Oncovir, Opexa Therapeutics, Oxford BioMedica, Pfizer, Prima BioMed, Principia, Progenics, Provectus Biopharmaceuticals, Regeneron, Sandoz, Sanofi, Santarus, Seattle Genetics, Sotio, Spectrum Pharmaceuticals, Takeda, TG Therapeutics, Transgene, UbiVac, UCB, Vaccinex, Vaccinogen, Vaxon Biotech, Vertex Pharmaceuticals, Vical, Vitae Pharmaceuticals, and XBiotech. Key questions answered in the report include  - What will the market size and the growth rate be in 2020?  - What are the key factors driving the global immunotherapy drugs market?  - What are the key market trends impacting the growth of the global immunotherapy drugs market?  - What are the challenges to market growth for immunotherapy drugs?  - Who are the key vendors in the global immunotherapy drugs market?  - What are the market opportunities and threats faced by the vendors in the immunotherapy drugs market?  - Trending factors influencing the market shares of the Americas, APAC, and EMEA.  - What are the key outcomes of the five forces analysis of the global immunotherapy drugs market? For more information or any query mail at [email protected] Wise Guy Reports is part of the Wise Guy Consultants Pvt. Ltd. and offers premium progressive statistical surveying, market research reports, analysis & forecast data for industries and governments around the globe. Wise Guy Reports features an exhaustive list of market research reports from hundreds of publishers worldwide. We boast a database spanning virtually every market category and an even more comprehensive collection of market research reports under these categories and sub-categories.

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