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Le Touquet – Paris-Plage, France

Georgoulias V.,University of Crete | Douillard J.-Y.,Center uducheau | Khayat D.,Salpetriere Hospital | Manegold C.,University of Heidelberg | And 7 more authors.
Clinical Lung Cancer

We present the treatment rationale and study design of a multicenter, open-label, randomized, 2-arm, phase IIb study. Patients with stage IV or recurrent stage I to III non-small-cell lung cancer (NSCLC) whose disease does not progress after 4 cycles of first-line platinum-based chemotherapy will be randomized in a 1:1 ratio to 1 of 2 study arms. Patients will receive the cancer vaccine Vx-001 + Montanide ISA51 VG (Seppic, Paris, France) adjuvant subcutaneously, at a dose of 2 mg, or placebo + Montanide ISA51 VG adjuvant subcutaneously. The vaccination protocol comprises 2 injections with the TYR-Vx001 or placebo (1 at day 0 and another at week 3) and 4 injections with the ARG-Vx001 or placebo, at weeks 6, 9, 12, and 15. After the treatment assessment at week 18, patients will receive the ARG-Vx001 or placebo every 12 weeks starting from week 27 until disease progression, unacceptable toxicity, withdrawal of informed consent, or death. The primary end point of this study is the survival rate at 12 months. Secondary end points include time-to-event comparison of overall survival and comparison of time to treatment failure. Exploratory objectives include comparison of disease control rate after the end of subsequent second-line treatments, comparisons of vaccine immune responses, comparison of survival rate at 12 months in patients with vaccine-induced immune response detected after the second and sixth injections, identification of biomarkers on lymphocytes and on tumors, and comparison of safety and tolerability. © 2013 Elsevier Inc. Source

Tumors use several strategies to evade the host immune response, including creation of an immune-suppressive and hostile tumor environment. Tissue hypoxia due to inadequate blood supply is reported to develop very early during tumor establishment. Hypoxic stress has a strong impact on tumor cell biology. In particular, tissue hypoxia contributes to therapeutic resistance, heterogeneity and progression. It also interferes with immune plasticity, promotes the differentiation and expansion of immune-suppressive stromal cells, and remodels the metabolic landscape to support immune privilege. Therefore, tissue hypoxia has been regarded as a central factor for tumor aggressiveness and metastasis. In this regard, manipulating host–tumor interactions in the context of the hypoxic tumor microenvironment may be important in preventing or reverting malignant conversion. We will discuss how tumor microenvironment-driven transient compositional tumor heterogeneity involves hypoxic stress. Tumor hypoxia is a therapeutic concern since it can reduce the effectiveness of conventional therapies as well as cancer immunotherapy. Thus, understanding how tumor and stromal cells respond to hypoxia will allow for the design of innovative cancer therapies that can overcome these barriers. A better understanding of hypoxia-dependent mechanisms involved in the regulation of immune tolerance could lead to new strategies to enhance antitumor immunity. Therefore, discovery and validation of therapeutic targets derived from the hypoxic tumor microenvironment is of major importance. In this context, critical hypoxia-associated pathways are attractive targets for immunotherapy of cancer. In this review, we summarize current knowledge regarding the molecular mechanisms induced by tumor cell hypoxia with a special emphasis on therapeutic resistance and immune suppression. We emphasize mechanisms of manipulating hypoxic stress and its associated pathways, which may support the development of more durable and successful cancer immunotherapy approaches in the future.Oncogene advance online publication, 27 June 2016; doi:10.1038/onc.2016.225. © 2016 Macmillan Publishers Limited Source

Kotsakis A.,University of Crete | Vetsika E.-K.,University of Crete | Christou S.,University of Crete | Hatzidaki D.,University of Crete | And 8 more authors.
Annals of Oncology

Background: TERT (telomerase reverse transcriptase) plays a critical role in tumor cell growth and survival. In an expanded phase II study, we evaluated the immunological and clinical responses to the TERT-targeting Vx-001 vaccine in patients with advanced solid tumors. Methods: HLA-A*0201-positive patients received two subcutaneous injections of the optimized TERT. 572Y peptide followed by four injections of the native TERT. 572 peptide, every 3 weeks. Peptide-specific immune responses were evaluated by enzyme-linked immunosorbent spot at baseline, and after the second and the sixth vaccinations. Results: Fifty-five patients were enrolled and 34 (62%) completed the six vaccinations. A TERT-specific T-cell immune response was observed in 55% and 70% of patients after the second and the sixth vaccinations, respectively. The disease control rate (DCR) was 36% [95% confidence interval (CI) 24% to 49%], including one complete and one partial response. Immunologically responding patients had a better clinical outcome than non responders [DCR: 44% versus 14% (P = 0.047); progression-free survival (PFS): 5.2 versus 2.2 months (P = 0.0001) and overall survival: 20 versus 10 months (P = 0.041)]. Multivariate analysis revealed that the immunological response was an independent variable associated with increased PFS (hazard ratio = 3.35; 95% CI 1.7-6.7). Conclusion: Vx-001 vaccine was well tolerated and induced a TERT-specific immunological response, which was significantly correlated with improved clinical outcome. © The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. Source

The present invention pertains to the field of vaccination, and more particularly to the fields of antitumor and antiviral vaccination. The invention relates to the use of a native peptide in a medicinal composition, for selecting and/or boosting part of a CTL immune response which has been initiated by an optimized immunogenic peptide derived from said native peptide. The invention also concerns vaccination kits which comprise several doses of optimized peptides and of their cognate native peptides.

The invention provides methods for identifying a HLA-B*0702-restricted cryptic epitope in an antigen, as well as methods for increasing the immunogenicity of HLA-B*0702-restricted cryptic epitopes. The HLA-B*0702-restricted cryptic epitopes and their cognate immunogenic epitopes are useful for stimulating an immune reaction against the cryptic epitopes in a subject. Accordingly, the invention further provides pharmaceutical compositions comprising a HLA-B*0702-restricted cryptic epitope or a cognate immunogenic epitope thereof, and vaccination kits comprising such epitopes. The novel materials of the invention are particularly useful for efficiently treating patients having an HLA-B*0702 phenotype.

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