Immunotherapy
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Glioblastoma multiforme (GBM) is the most common and aggressive glial cell-derived primary tumor. Current standard of care for patients with GBM includes maximal tumor resection plus adjuvant radiotherapy and temozolomide chemotherapy, increasing median overall survival to a mere 15 months from diagnosis. Because these therapies are inherently nonspecific, there is an increased likelihood of off-target and incomplete effects; therefore, targeted modalities are required for enhanced safety and efficacy. ⋯ Vaccination with rindopepimut has been shown to specifically eliminate cells expressing EGF receptor variant III. Phase II clinical trials have suggested that vaccination of newly diagnosed GBM patients with rindopepimut plus adjuvant granulocyte-macrophage colony-stimulating factor results in prolonged progression-free and overall survival with minimal toxicity. This review will outline the development of rindopepimut, as well as the current status of this vaccine.
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Peptides and peptidomimetics can function as immunomodulating agents by either blocking the immune response or stimulating the immune response to generate tolerance. Knowledge of B- or T-cell epitopes along with conformational constraints is important in the design of peptide-based immunomodulating agents. ⋯ The design of peptides/peptidomimetics for immunomodulation in autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, systemic lupus and HIV infection is reviewed. In cancer therapy, peptide epitopes are used in such a way that the body is trained to recognize and fight the cancer cells locally as well as systemically.
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Recent research has provided strong support for the utility of broadly neutralizing antibodies generated against viruses, which inherently possess a high degree of antigenic variability (such as influenza virus or HIV) as a feasible means to prevent infection. Many of these antibodies share the ability to bind to highly conserved regions within the stem of the virus 'spike' or surface glycoprotein, in such a way that they interfere with virus entry, including membrane fusion. As a result, broadly neutralizing antibodies could be supplied to patients as a form of passive immunotherapy, as well as play a role in the design of new 'universal' vaccines and antiviral agents. The following article describes the most recent innovations in this exciting field.
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In the final issue of Science in 2013, the American Association of Science recognized progress in the field of cancer immunotherapy as the 'Breakthrough of the Year.' The achievements were actually twofold, owing to the early success of genetically engineered chimeric antigen receptors (CAR) and to the mounting clinical triumphs achieved with checkpoint blockade antibodies. While fundamentally very different, the common thread of these independent strategies is the ability to prevent or overcome mechanisms of CD8(+) T-cell tolerance for improved tumor immunity. Here we discuss how circumventing T-cell tolerance has provided experimental insights that have guided the field of clinical cancer immunotherapy to a place where real breakthroughs can finally be claimed.
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Evaluation of: Younes A, Connors JM, Park SI et al. Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a Phase 1, open-label, dose-escalation study. Lancet Oncol. 14(13), 1348-1356 (2013). ⋯ Now in Phase I clinical trial, it has been shown that combining BV with multiagent chemotherapy (excluding bleomycin) as first-line treatment in HL patients with high-risk disease is feasible. Complete response rates were over 90% and toxicity was manageable. Given that the malignant cell population comprises a minority of HL lesions, and that BV releases a diffusible cytotoxin via a cathepsin B-cleavable linker, we argue that a significant proportion of the antitumor activity of BV can be attributed to bystander cytotoxicity in addition to direct killing of CD30-expressing malignant cells.