Neoantigen DNA vaccines are safe, feasible, and induce neoantigen-specific immune responses in triple-negative breast cancer patients.

Background: Neoantigen vaccines can induce or enhance highly specific antitumor immune responses with minimal risk of autoimmunity. We have developed a neoantigen DNA vaccine platform capable of efficiently presenting both HLA class I and II epitopes and performed a phase 1 clinical trial in triple-negative breast cancer patients with persistent disease on surgical pathology following neoadjuvant chemotherapy, a patient population at high risk of disease recurrence.

Methods: Expressed somatic mutations were identified by tumor/normal exome sequencing and tumor RNA sequencing.

Induction of cancer neoantigens facilitates development of clinically relevant models for the study of pancreatic cancer immunobiology.

Neoantigen burden and CD8 T cell infiltrate are associated with clinical outcome in pancreatic ductal adenocarcinoma (PDAC). A shortcoming of many genetic models of PDAC is the lack of neoantigen burden and limited T cell infiltrate. The goal of the present study was to develop clinically relevant models of PDAC by inducing cancer neoantigens in KP2, a cell line derived from the KPC model of PDAC.

Multimodal imaging of primary cardiac angiosarcoma with brain metastasis.

Angiosarcoma is an extremely rare primary cardiac malignant tumor, with characteristics of early blood metastasis and radiochemotherapy resistance. Early diagnosis and timely treatment are of great significance to the prognosis of patients. Hereinafter, we report a case of angiosarcoma in the left atrium of a 61-year-old woman who underwent multimodality imaging and successful resection of the angiosarcoma.

Evaluation of Left Ventricular Systolic Function Using Layer-Specific Strain in Rats Performing Endurance Exercise: A Pilot Study.

Objective: The functional characteristics of exercise-induced myocardial hypertrophy were studied in a rat model in conjunction with ultrasound layered strain technique to investigate the hidden changes in the heart brought about by exercise.

Methods: Forty specific pathogen free (SPF) adult Sprague-Dawley rats were selected and randomly divided into two groups of 20 exercise and 20 control rats. The longitudinal and circumferential strain parameters were measured using the ultrasonic stratified strain technique.

Combination TIGIT/PD-1 blockade enhances the efficacy of neoantigen vaccines in a model of pancreatic cancer.

Background: Cancer neoantigens are important targets of cancer immunotherapy and neoantigen vaccines are currently in development in pancreatic ductal adenocarcinoma (PDAC) and other cancer types. Immune regulatory mechanisms in pancreatic cancer may limit the efficacy of neoantigen vaccines. Targeting immune checkpoint signaling pathways in PDAC may improve the efficacy of neoantigen vaccines.

Left atrial function in young strength athletes: four-dimensional automatic quantitation study.

Athletes might suffer from potentially fatal heart disease, which has always been a concern in cardiovascular medicine. The changes in left atrial (LA) size and function are related to the occurrence of arrhythmia. In the present study, four-dimensional automatic quantitation (4D LAQ) was used to explore the changes in LA function of young strength athletes.

Optimized polyepitope neoantigen DNA vaccines elicit neoantigen-specific immune responses in preclinical models and in clinical translation.

Background: Preclinical studies and early clinical trials have shown that targeting cancer neoantigens is a promising approach towards the development of personalized cancer immunotherapies. DNA vaccines can be rapidly and efficiently manufactured and can integrate multiple neoantigens simultaneously. We therefore sought to optimize the design of polyepitope DNA vaccines and test optimized polyepitope neoantigen DNA vaccines in preclinical models and in clinical translation.

Neoantigen vaccine platforms in clinical development: understanding the future of personalized immunotherapy.

Introduction: Derived from genetic alterations, cancer neoantigens are proteins with novel amino acid sequences that can be recognized by the immune system. Recent evidence demonstrates that cancer neoantigens represent important targets of cancer immunotherapy. The goal of cancer neoantigen vaccines is to induce neoantigen-specific immune responses and antitumor immunity, while minimizing the potential for autoimmune toxicity.

Assessment of left ventricular systolic function by non-invasive pressure-strain loop area in young male strength athletes.

Background: The health of athletes has been recognized as a worldwide public concern with more reported sudden cardiac deaths (SCD). Therefore, early detection of abnormal heart function in athletes can help reduce the risk of exercise. A novel valid non-invasive method to evaluate left ventricular (LV) myocardial work (MW) using LV pressure-strain loop (PSL), was used in this paper to explore LV systolic function in young male strength athletes.

cDC1 prime and are licensed by CD4 T cells to induce anti-tumour immunity.

Conventional type 1 dendritic cells (cDC1) are thought to perform antigen cross-presentation, which is required to prime CD8 T cells, whereas cDC2 are specialized for priming CD4 T cells. CD4 T cells are also considered to help CD8 T cell responses through a variety of mechanisms, including a process whereby CD4 T cells 'license' cDC1 for CD8 T cell priming. However, this model has not been directly tested in vivo or in the setting of help-dependent tumour rejection.

Development of an adenovirus vector vaccine platform for targeting dendritic cells.

Adenoviral (Ad) vector vaccines represent one of the most promising modern vaccine platforms, and Ad vector vaccines are currently being investigated in human clinical trials for infectious disease and cancer. Our studies have shown that specific targeting of adenovirus to dendritic cells dramatically enhanced vaccine efficacy. However, this was achieved using a molecular adapter, thereby necessitating a two component vector approach.

Breast Cancer Neoantigens Can Induce CD8 T-Cell Responses and Antitumor Immunity.

Next-generation sequencing technologies have provided insights into the biology and mutational landscape of cancer. Here, we evaluate the relevance of cancer neoantigens in human breast cancers. Using patient-derived xenografts from three patients with advanced breast cancer (xenografts were designated as WHIM30, WHIM35, and WHIM37), we sequenced exomes of tumor and patient-matched normal cells.

Safety and preliminary evidence of biologic efficacy of a mammaglobin-a DNA vaccine in patients with stable metastatic breast cancer.

Purpose: Mammaglobin-A (MAM-A) is overexpressed in 40% to 80% of primary breast cancers. We initiated a phase I clinical trial of a MAM-A DNA vaccine to evaluate its safety and biologic efficacy.

Experimental Design: Patients with breast cancer with stable metastatic disease were eligible for enrollment.

Cross-dressed CD8α+/CD103+ dendritic cells prime CD8+ T cells following vaccination.

Activation of naïve cluster of differentiation (CD)8(+) cytotoxic T lymphocytes (CTLs) is a tightly regulated process, and specific dendritic cell (DC) subsets are typically required to activate naive CTLs. Potential pathways for antigen presentation leading to CD8(+) T-cell priming include direct presentation, cross-presentation, and cross-dressing. To distinguish between these pathways, we designed single-chain trimer (SCT) peptide-MHC class I complexes that can be recognized as intact molecules but cannot deliver antigen to MHC through conventional antigen processing.

Cancer genome sequencing and its implications for personalized cancer vaccines.

New DNA sequencing platforms have revolutionized human genome sequencing. The dramatic advances in genome sequencing technologies predict that the $1,000 genome will become a reality within the next few years. Applied to cancer, the availability of cancer genome sequences permits real-time decision-making with the potential to affect diagnosis, prognosis, and treatment, and has opened the door towards personalized medicine.

Single-chain HLA-A2 MHC trimers that incorporate an immundominant peptide elicit protective T cell immunity against lethal West Nile virus infection.

The generation of a robust CD8(+) T cell response is an ongoing challenge for the development of DNA vaccines. One problem encountered with classical DNA plasmid immunization is that peptides produced are noncovalently and transiently associated with MHC class I molecules and thus may not durably stimulate CD8(+) T cell responses. To address this and enhance the expression and presentation of the antigenic peptide/MHC complexes, we generated single-chain trimers (SCTs) composed of a single polypeptide chain with a linear composition of antigenic peptide, beta(2)-microglobulin, and H chain connected by flexible linkers.

Engineering superior DNA vaccines: MHC class I single chain trimers bypass antigen processing and enhance the immune response to low affinity antigens.

It is commonly believed that delivery of antigen into the class I antigen presentation pathway is a limiting factor in the clinical translation of DNA vaccines. This is of particular concern in the context of cancer vaccine development as many immunodominant peptides derived from self tumor antigens are not processed and presented efficiently. To address this limitation, we have engineered completely assembled peptide/MHC class I complexes whereby all three components (class I heavy chain, beta(2)m, and peptide) are attached by flexible linkers and expressed as a single polypeptide (single chain trimers or SCT).

Cellular immune suppressor activity resides in lymphocyte cell clusters adjacent to granulomata in human coccidioidomycosis.

The in situ immunologic response in human coccidioidomycosis remains undefined. To explore this further, pulmonary necrotizing coccidioidal granulomata were examined using immunohistochemical staining for lymphocyte subsets and for the cytokines interleukin-10 (IL-10) and gamma interferon (IFN-gamma). Discrete perigranulomatous lymphocytic clusters were seen in eight of nine tissues examined.

Preliminary evaluation of whole-blood gamma interferon release for clinical assessment of cellular immunity in patients with active coccidioidomycosis.

Assessment of the cellular immune response in coccidioidomycosis has epidemiologic and prognostic importance. Measurement of delayed-type hypersensitivity to skin testing has been used in the past to determine cellular immunity in coccidioidomycosis. However, no skin tests are currently available in the United States.

The mannose receptor mediates the cellular immune response in human coccidioidomycosis.

Mannose is the predominant monosaccharide in the coccidioidal antigen preparation T27K. Mannan and anti-CD206 antibody significantly decreased the surface expression of mannose receptor (MR) on adherent peripheral blood mononuclear cells and reduced the interleukin-2 (IL-2) release induced by T27K. These data suggest that MR mediates IL-2 release by T27K.

In vitro whole-blood analysis of cellular immunity in patients with active coccidioidomycosis by using the antigen preparation T27K.

Measurement of cellular immunity in human coccidioidomycosis has important diagnostic and prognostic implications. The coccidioidin skin test has been the standard for the measurement of this, but it is not available in the United States. We examined the utility of measuring surface expression of CD69 on T lymphocytes in whole blood incubated with the coccidioidal antigen preparation T27K as an alternative to the skin test.