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Parkinson's disease (PD) is the second most common neurodegenerative disorder and is defined pathologically by the abnormal accumulation of the presynaptic protein alpha-synuclein (aSyn) in the form of Lewy bodies and Lewy neurites and loss of midbrain dopaminergic neurons in the substantia nigra pars compacta. Because of aSyn's involvement in both sporadic and familial forms of PD, it has become a key target for the development of novel therapeutics. Aberrant aSyn is associated with multiple mechanisms of neuronal dysfunction and degeneration including inflammation, impaired mitochondrial function, altered protein degradation systems, and oxidative stress. Inflammation, in particular, has emerged as a potential significant contributor early in the disease making it an attractive target for disease modification and neuroprotection. Thus, immunotherapies targeting aSyn are currently being investigated in pre-clinical and clinical trials. The focus of this review is to highlight the role of aSyn in neuroinflammation and discuss the current status of aSyn-directed immunotherapies in pre-clinical and clinical trials for PD., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Many clinical trials of immune checkpoint blockade-based combination therapies are under way. Vaccine therapy is a promising partner of combination therapies. We have developed a personalized peptide vaccination and conducted clinical trials of it in patients with various cancers. At the present time, we have only a limited number of biomarkers related to the prognosis of vaccine-treated patients. Thus, new biomarkers are urgently needed., Methods: In this study, we investigated the plasma cell-free DNA (cfDNA) integrity-a ratio of the necrotic tumor cell-derived long cfDNA fragments to the total dead cell-derived short cfDNA fragments from genomic Alu elements-in patients with advanced nonsmall cell lung cancer during treatment with the personalized peptide vaccination., Results: We found that (1) the cfDNA integrity was decreased after the first cycle of vaccination, and (2) the patients with high prevaccination cfDNA integrity survived longer than those with low prevaccination integrity (median survival time (MST): 17.9 versus 9.0 months, respectively; hazard ratio (HR): 0.58, p  = .0049). A similar tendency was observed in postvaccination cfDNA integrity (MST: 16.4 vs 9.4 months; HR: 0.65, p  = .024)., Conclusions: These results suggest that cfDNA integrity is a possible prognostic biomarker in patients treated with the personalized peptide vaccine.

Purpose of Review: To date, prostate cancer has been poorly responsive to immunotherapy. In the current review, we summarize and discuss the current literature on the use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer (mCRPC)., Recent Findings: Sipuleucel-T currently remains the only FDA-approved immunotherapeutic agent for prostate cancer. Single-agent phase 3 vaccine trials with GVAX and PROSTVAC have failed to demonstrate survival benefit to date. Clinical trials using combination approaches, including combination PROSTVAC along with a neoantigen vaccine and checkpoint inhibitor immunotherapy, are ongoing. Checkpoint inhibitor monotherapy clinical trials have demonstrated limited efficacy in advanced prostate cancer, and combination approaches and molecular patient selection are currently under investigation. The optimal use of vaccine therapy and checkpoint inhibitor immunotherapy in metastatic castration-resistant prostate cancer remains to be determined. Ongoing clinical trials will continue to inform future clinical practice.

Evasion of the host immune system is a key mechanism to promote malignant progression. Therapeutically targeting immune pathways has radically changed the treatment paradigm for solid and lymphoid tumors but has yet to be approved for myeloid malignancies. Here, we summarize the most recent advances in immunotherapy for acute myeloid leukemia. Topics reviewed here include adoptive cellular approaches (chimeric antigen receptor-T cells, natural killer and other immune cells), checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 and TIM-3) and vaccines (WT-1, HLA-A2 and hTERT). Emphasis is placed on agents with clear evidence of tumor-specific immune responses and/or clinical activity in early-phase trials. Despite concerns regarding heterogeneous antigen expression and cytokine release syndrome, immunotherapy remains a highly promising strategy for acute myeloid leukemia, particularly transplant-ineligible patients and minimal residual disease states.

Burkholderia pseudomallei is a Gram-negative environmental bacterium and the aetiological agent of melioidosis, a life-threatening infection that is estimated to account for ∼89,000 deaths per year worldwide. Diabetes mellitus is a major risk factor for melioidosis, and the global diabetes pandemic could increase the number of fatalities caused by melioidosis. Melioidosis is endemic across tropical areas, especially in southeast Asia and northern Australia. Disease manifestations can range from acute septicaemia to chronic infection, as the facultative intracellular lifestyle and virulence factors of B. pseudomallei promote survival and persistence of the pathogen within a broad range of cells, and the bacteria can manipulate the host's immune responses and signalling pathways to escape surveillance. The majority of patients present with sepsis, but specific clinical presentations and their severity vary depending on the route of bacterial entry (skin penetration, inhalation or ingestion), host immune function and bacterial strain and load. Diagnosis is based on clinical and epidemiological features as well as bacterial culture. Treatment requires long-term intravenous and oral antibiotic courses. Delays in treatment due to difficulties in clinical recognition and laboratory diagnosis often lead to poor outcomes and mortality can exceed 40% in some regions. Research into B. pseudomallei is increasing, owing to the biothreat potential of this pathogen and increasing awareness of the disease and its burden; however, better diagnostic tests are needed to improve early confirmation of diagnosis, which would enable better therapeutic efficacy and survival.

Human epidermal growth factor receptor 2 (HER2) is a tumor associated antigen over-expressed in 20-30% of cases of breast cancer. Passive immune therapy with HER2-directed monoclonal antibodies (mabs) has changed the natural history of this subset of breast tumors both in the localized and metastatic settings. The safety and efficacy of HER2 vaccines have been assessed in early phase clinical trials but to date clinically relevant results in late phase trials remain an elusive target. Here, we review the recent translational discoveries related to the interactions between the adaptive immune system and the HER2 antigen in breast cancer, results of published clinical trials, and future directions in the field of HER2 vaccine treatment development., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

mRNA vaccines are finally ready to assume their rightful place at the forefront of nucleic acid- based vaccines. Major achievements within the last two decades have turned this highly versatile molecule into a safe and very attractive pharmaceutical platform that combines many positive attributes able to address a broad range of diseases, including cancer. The simplicity of mRNA vaccines greatly reduces complications generally associated with the production of biological vaccines. Intrinsic costimulatory and inflammatory triggers in addition to the provision of the antigenic information makes mRNA an all- in-one molecule that does not need additional adjuvants and that does not pose the risk of genomic integration. Clinical studies in various cancer types are moving forward and promising results with favorable clinical outcome are awaited. This review will recapitulate conceptual, mechanistic and immune-related features of this highly versatile molecule, elucidate how these features have been addressed in the past, and how comprehensive understanding can foster further optimization for broad application possibilities in cancer treatment.

Therapeutic cancer vaccines aim to induce durable antitumor immunity that is capable of systemic protection against tumor recurrence or metastatic disease. Many approaches to therapeutic cancer vaccines have been explored, with varying levels of success. However, with the exception of Sipuleucel T, an ex vivo dendritic cell vaccine for prostate cancer, no therapeutic cancer vaccine has yet shown clinical efficacy in phase 3 randomized trials. Though disappointing, lessons learned from these studies have suggested new strategies to improve cancer vaccines. The clinical success of checkpoint blockade has underscored the role of peripheral tolerance mechanisms in limiting vaccine responses and highlighted the potential for combination therapies. Recent advances in transcriptome sequencing, computational modeling, and material engineering further suggest new opportunities to intensify cancer vaccines. This review will discuss the major approaches to therapeutic cancer vaccination and explore recent advances that inform the design of the next generation of cancer vaccines., (© 2016 Elsevier Inc. All rights reserved.)

The spleen acts as a blood filter and lymphopoietic organ. Asplenic and hyposplenic individuals are more susceptible to serious infections caused by encapsulated bacteria but they can be protected by antibiotic prophylaxis and immunizations. Recent progress in vaccinology means prophylaxis is now successful in the vast majority of serious infections with pneumococci, meningococci and Haemophilus influenzae type b responsible for the majority of cases of overwhelming sepsis in asplenic patients. Current guidelines are coherent. Physicians treating patients with conditions associated with hyposplenism are ethically obliged to immunize their patients using the vaccines currently available to protect them from largely preventable, life-threatening infections., (© 2015 John Wiley & Sons Ltd.)

Vaccines that rely on active specific stimulation of the host immune system have the potential to trigger durable antitumor responses with minimal toxicity. However, in nonsmall-cell lung cancer (NSCLC), several large phase III trials of vaccines reported within the last year have yielded disappointing results. Compared with placebo, belagenpumatucel-L (an allogenic tumor cell vaccine), tecemotide (a peptide vaccine targeting MUC-1) and melanoma-associated antigen-A3 (a protein-based vaccine) did not improve outcomes in NSCLC. The lack of clinically significant outcomes, despite their ability to prime and expand tumor antigen-specific T cells could at least partly be attributed to the inability of vaccine-induced T-cell responses to overcome the tumoral mechanisms of immune escape which limit the clonal expansion of T cells following vaccination. A number of such mechanisms have been recognized including reduced antigen presentation, antigenic loss, cytokines, immunosuppressive cells and immune checkpoints. Strategies aimed at modulating the immune checkpoints have shown promise and are on the verge of revolutionizing the therapeutic landscape of metastatic NSCLC. Overcoming immune tolerance and improving the activation of antitumor T cells via combinatorial approaches may represent a new and more promising therapeutic application for active immunotherapies in NSCLC., (Published by Oxford University Press on behalf of the European Society for Medical Oncology 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.)