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This new report includes an updated discussion of approved and clinical stage agents in immuno-oncology, including recently-approved agents. It also addresses the means by which researchers and companies are attempting to build on prior achievements in immuno-oncology to improve outcomes for more patients. Some researchers and companies refer to this approach as immuno-oncology 2.0. The American Society of Clinical Oncology (ASCO), in its 12th Annual Report on Progress Against Cancer (2017), named Immunotherapy 2.0 as its Advance of the Year. Nevertheless, metastatic melanoma remains incurable. Furthermore, in many studies in advanced melanoma and other cancers, only a minority of patients have benefited from immunotherapy treatments. Researchers and companies are therefore looking for ways to build on the initial successes of the immuno-oncology field to improve outcomes for more patients, hence the need for an immuno-oncology 2.0.  Agents that are intended to improve the results of treatment with agents like checkpoint inhibitors may also be referred to as second-wave immuno-oncology agents. As discussed in this report, researchers have found that checkpoint inhibitors produce tumor responses by reactivating TILs (tumor infiltrating lymphocytes)-especially CD8+ cytotoxic T cells. This key observation is perhaps the most important factor driving development of second-wave immuno-oncology strategies. As a result, researchers have been developing biomarkers that distinguish inflamed (i.e., TIL-containing) tumors-which are susceptible to checkpoint inhibitor therapy-from cold tumors, which are not. They have also been working to develop means to render cold tumors inflamed, via treatment with various conventional therapies and/or development of novel agents. These studies are the major theme of second-wave immuno-oncology, or immuno-oncology 2.0. Highlights of this Report Include: - Approvals of checkpoint inhibitors - Biomarkers for checkpoint inhibitor treatments - Approved and clinical-stage immunotherapy biologics other than checkpoint inhibitors - Immunotherapy with TIL cells - Commercialization of TIL therapy - Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs) - Manufacturing issues with CAR T-cell therapies - General conclusions on the progress of cellular immunotherapy - Outlook for cancer immunotherapy Key Topics Covered: 1: Introduction - The early history of cancer immunotherapy - Coley's toxins - Cytokines as immunomodulatory drugs - Interleukin-2 - Alpha-interferons - Interleukin-12 - Interleukin-12 as a bridge between innate and adaptive immunity - Investigation of interleukin-12 as an anticancer therapeutic - Interleukin-10 - Interleukin-15 - Admune/Novartis' heterodimeric IL-15:IL-15Ra (hetIL-15) - Altor's ALT-803 - Conclusions: Cytokine-based immunotherapies for cancer 2: What are immune checkpoints? - CTLA-4 blocking agents - Ipilimumab - Tremelimumab - PD-1 blocking agents - Nivolumab - Combination therapy of nivolumab plus ipilimumab in melanoma - Pembrolizumab - Pembrolizumab as a first-line treatment for advanced NSCLC - Pembrolizumab in colorectal carcinoma with mismatch-repair deficiency - Studies of pembrolizumab in combination immunotherapies - PDR001 - PD-L1 blocking agents - Atezolizumab - Atezolizumab in treatment of urothelial carcinoma - Atezolizumab for the treatment of NSCLC - Atezolizumab in treatment of other solid tumors - Other anti-PD-L1 mAb agents - Durvalumab - Avelumab - Anti-LAG-3 agents - anti-TIM-3 - NewLink Genetics' small-molecule IDO pathway inhibitors and checkpoint inhibition - Infinity's PI3K? inhibitor IPI-549 for modulation of immune suppression in tumors - Biomarkers for checkpoint inhibitor treatments - Target biomarkers - Genetic biomarkers - Immunological biomarkers - Use of biomarker tests in treatment with checkpoint inhibitors - Checkpoint inhibitors plus radiation therapy - Checkpoint inhibitors plus targeted therapies - Checkpoint inhibitors with cytotoxic chemotherapies - Discussion 3: Immune Agonists - Celldex Therapeutics' Varlilumab (CDX-1127) - OX40 agonists - MedImmune/AZ's OX40 agonist program - Roche/Genentech's OX40 agonist program - Nektar Therapeutics/BMS's NKTR-214, a CD122 agonist - Glucocorticoid-induced TNFR-related (GITR) protein agonist (Leap Therapeutics' TRX518) - Conclusions 4: Bispecific antibodies - Marketed bispecific antibody agents - Catumaxomab - Blinatumomab - Bispecific antibodies as an alternative to CAR-T cells - Xencor's cross-linking monoclonal antibody (XmAb) bispecific platform technology - Regeneron's native human immunoglobulin-format bsAb, REGN1979 - Roche/Genentech's full-length bsAbs: Generated using CrossmAb technology - MacroGenics' MGD007: Generated using dual-affinity re-targeting (DART) technology - Conclusions 5: Therapeutic Anticancer Vaccines and Oncolytic viruses - Introduction - Cancer vaccines-a field rife with clinical failures - Why has the cancer vaccine field been so prone to clinical failure? - Marketed therapeutic cancer vaccines and oncolytic virus therapies - Dendreon/Valeant's sipuleucel-T - Amgen's talimogene laherparepvec (T-Vec)/Imlygic - Therapeutic cancer vaccines and oncolytic virus therapies in clinical development - Celldex's CDX-1401 - Bavarian Nordic's PROSTVAC-VF - Argos Therapeutics' AGS-003 - Sydys Corporation's CVac - Aduro Biotech's CRS-207 - TapImmune's TPIV110 HER2/neu and TPIV200 folate receptor alpha multi-epitope vaccines - Genelux's GL-ONC1 oncolytic virus - Conclusions 6: Adoptive Immunotherapy for Cancer - Introduction - Adoptive immunotherapy with tumor infiltrating lymphocytes - A specific immunodominant mutation in a melanoma patient who had a durable complete remission due to TIL therapy - Adoptive immunotherapy based on mutation-specific CD4+ T cells in an epithelial cancer - Successful targeting of KRAS G12D via adoptive immunotherapy in a case of metastatic colorectal cancer - Dr. Rosenberg's recent studies on neoantigen-reactive TILs for use in adoptive cellular immunotherapy - Commercializing TIL therapy - Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs) - Leading clinical programs in CAR T-cell based immunotherapy - Kite Pharma's KTE-C19 (axicabtagene ciloleucel) - Novartis' CTL019 - Juno's JCAR015 and other Juno anti-CD19 CARs - Other CAR T-cell therapies that target hematologic malignancies - bluebird bio's bb2121 for multiple myeloma - CAR T-cell therapies that target solid tumors - Novartis/University of Pennsylvania's CARTmeso - EGFRvIII CAR T-cell therapies - Companies developing engineered improvements in CAR T-cell therapy - Bellicum Pharmaceuticals' technologies for modulation of CAR T-cell therapies - Cellectis' technologies for design and manufacture of off-the shelf CAR T-cell therapies - Manufacturing issues with CAR T-cell therapies - Can bispecific antibodies be competitive with CAR T-cell therapies? - Adptimmune recombinant TCR clinical candidates - Kite Pharma recombinant TCR program - Juno Therapeutics' recombinant TCR program - Recombinant TCR studies at the NCI - Conclusions - Market size estimates for the T-cell therapy market 7: General Conclusions - Major theme of this report: Immuno-oncology 2.0 or second-wave immuno-oncology - Approvals of checkpoint inhibitors - Biomarkers for checkpoint inhibitor treatments - Approved and clinical-stage immunotherapy biologics other than checkpoint inhibitors - Immunotherapy with TIL cells - Commercialization of TIL therapy - Adoptive immunotherapy with genetically engineered T cells bearing chimeric antigen receptors (CARs) - Manufacturing issues with CAR T-cell therapies - Adoptive immunotherapy via autologous recombinant TCR technology - General conclusions on the progress of cellular immunotherapy - Insight Pharma Reports survey on cancer immunotherapy - Outlook for cancer immunotherapy For more information about this report visit http://www.researchandmarkets.com/research/rkf8pp/cancer Research and Markets Laura Wood, Senior Manager press@researchandmarkets.com For E.S.T Office Hours Call +1-917-300-0470 For U.S./CAN Toll Free Call +1-800-526-8630 For GMT Office Hours Call +353-1-416-8900 U.S. Fax: 646-607-1907 Fax (outside U.S.): +353-1-481-1716 To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/global-cancer-immunotherapy-report-2017-building-on-initial-successes-to-improve-clinical-outcomes---research-and-markets-300441006.html


Donat U.,University of Würzburg | Weibel S.,University of Würzburg | Hess M.,University of Würzburg | Stritzker J.,University of Würzburg | And 12 more authors.
PLoS ONE | Year: 2012

Recently, we showed that the oncolytic vaccinia virus GLV-1h68 has a significant therapeutic potential in treating lymph node metastases of human PC-3 prostate carcinoma in tumor xenografts. In this study, underlying mechanisms of the virus-mediated metastases reduction were analyzed. Immunohistochemistry demonstrated that virus-treatment resulted in a drastically decrease of blood and lymph vessels, representing essential routes for PC-3 cell migration, in both tumors and metastases. Thus, GLV-1h68 drastically reduced essential routes for the metastatic spread of PC-3 cells. Furthermore, analysis of viral distribution in GLV-1h68-injected tumor-bearing mice by plaque assays, revealed significantly higher virus titers in metastases compared to solid tumors. To elucidate conditions potentially mediating the preferential viral colonization and eradication of metastases, microenvironmental components of uninfected tumors and metastases were compared by microscopic studies. These analyses revealed that PC-3 lymph node metastases showed increased vascular permeability, higher proliferation status of tumor cells as determined by BrdU- and Ki-67 assays and lesser necrosis of PC-3 cells than solid tumors. Moreover, an increased number of immune cells (MHCII+/CD68+ macrophages, MHCII+/CD19+ B lymphocytes) combined with an up-regulated expression of pro-inflammatory cytokines was observed in metastases in comparison to primary PC-3 tumors. We propose that these microenvironmental components mediated the metastatic tropism of GLV-1h68. Therefore, vaccinia virus-based oncolytic virotherapy might offer a novel treatment of metastatic prostate carcinomas in humans. © 2012 Donat et al.


Adelfinger M.,University of Würzburg | Gentschev I.,University of Würzburg | Gentschev I.,Genelux Corporation | De Guibert J.G.,University of Würzburg | And 19 more authors.
PLoS ONE | Year: 2014

Virotherapy on the basis of oncolytic vaccinia virus (VACV) infection is a promising approach for cancer therapy. In this study we describe the establishment of a new preclinical model of feline mammary carcinoma (FMC) using a recently established cancer cell line, DT09/06. In addition, we evaluated a recombinant vaccinia virus strain, GLV-5b451, expressing the anti-vascular endothelial growth factor (VEGF) single-chain antibody (scAb) GLAF-2 as an oncolytic agent against FMC. Cell culture data demonstrate that GLV-5b451 virus efficiently infected, replicated in and destroyed DT09/06 cancer cells. In the selected xenografts of FMC, a single systemic administration of GLV-5b451 led to significant inhibition of tumor growth in comparison to untreated tumor-bearing mice. Furthermore, tumor-specific virus infection led to overproduction of functional scAb GLAF-2, which caused drastic reduction of intratumoral VEGF levels and inhibition of angiogenesis. In summary, here we have shown, for the first time, that the vaccinia virus strains and especially GLV-5b451 have great potential for effective treatment of FMC in animal model. © 2014 Adelfinger et al.


Donat U.,University of Würzburg | Rother J.,University of Würzburg | Schafer S.,University of Würzburg | Hess M.,University of Würzburg | And 14 more authors.
PLoS ONE | Year: 2014

More than 90% of cancer mortalities are due to cancer that has metastasized. Therefore, it is crucial to intensify research on metastasis formation and therapy. Here, we describe for the first time the metastasizing ability of the human cervical cancer cell line C33A in athymic nude mice after subcutaneous implantation of tumor cells. In this model, we demonstrated a steady progression of lumbar and renal lymph node metastases during tumor development. Besides predominantly occurring lymphatic metastases, we visualized the formation of hematogenous metastases utilizing red fluorescent protein (RFP) expressing C33A-RFP cells. RFP positive cancer cells were found migrating in blood vessels and forming micrometastases in lungs of tumor-bearing mice. Next, we set out to analyze the influence of oncolytic virotherapy in the C33A-RFP model and demonstrated an efficient virus-mediated reduction of tumor size and metastatic burden. These results suggest the C33A-RFP cervical cancer model as a new platform to analyze cancer metastases as well as to test novel treatment options to combat metastases. © 2014 Donat et al.


Hess M.,University of Würzburg | Stritzker J.,University of Würzburg | Stritzker J.,Genelux GmbH | Stritzker J.,Genelux Corporation | And 8 more authors.
Journal of Translational Medicine | Year: 2011

Background: Oncolytic viral tumor therapy is an emerging field in the fight against cancer with rising numbers of clinical trials and the first clinically approved product (Adenovirus for the treatment of Head and Neck Cancer in China) in this field. Yet, until recently no general (bio)marker or reporter gene was described that could be used to evaluate successful tumor colonization and/or transgene expression in other biological therapies.Methods: Here, a bacterial glucuronidase (GusA) encoded by biological therapeutics (e.g. oncolytic viruses) was used as reporter system.Results: Using fluorogenic probes that were specifically activated by glucuronidase we could show 1) preferential activation in tumors, 2) renal excretion of the activated fluorescent compounds and 3) reproducible detection of GusA in the serum of oncolytic vaccinia virus treated, tumor bearing mice in several tumor models. Time course studies revealed that reliable differentiation between tumor bearing and healthy mice can be done as early as 9 days post injection of the virus. Regarding the sensitivity of the newly developed assay system, we could show that a single infected tumor cell could be reliably detected in this assay.Conclusion: GusA therefore has the potential to be used as a general marker in the preclinical and clinical evaluation of (novel) biological therapies as well as being useful for the detection of rare cells such as circulating tumor cells. © 2011 Hess et al; licensee BioMed Central Ltd.


ROCHESTER, Minn., Feb. 23, 2017 /PRNewswire/ -- Imanis Life Sciences announced today the launch of a new product line of oncolytic vaccinia viruses for virotherapy research. These viruses are licensed from Genelux Corporation as part of Genelux's proprietary, vaccinia virus-based...

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