scholarly journals ATIM-02. A NEW SOURCE OF NEOANTIGENS FOR PEDIATRIC AND ADULT BRAIN CANCER VACCINES

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi1-vi1
Author(s):  
Stephen Albert Johnston ◽  
Milene Peterson ◽  
Chris Diehnelt ◽  
Luhui Shen
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Brain Tumors ◽  
Mouse Model ◽  
Brain Cancer ◽  
Cancer Vaccines ◽  
Rich Source ◽  
Adult Brain ◽  
Tumor Type ◽  
Therapeutic Vaccines

Abstract The paucity of mutations in pediatric and adult brain tumors has limited the ability to design therapeutic personal cancer vaccines. However, we have discovered that, in contrast to mutations in DNA, RNA is a rich source of frameshift neoantigens produced by mis-splicing of exons or indels from transcription through micro satellites. We have found that in GBM there are an average of 4000 such FS neoantigens per patient and in DIPG an average of at least 500 FS neoantigens/patient. Approximately 20% of these neoantigens are frequently recurrent across different patients. This has allowed us to design pre-synthesized vaccines for each tumor type. The vaccines consist of 20 -30 FS epitopes that are predicted to be present in at least 20% of all patient’s tumor. Each patient would have a 90% chance of having at least 50% of the peptides in their tumor. This type of “FAST” vaccine is much less expensive than a personal vaccine, any patient could be treated and there would be no delay in producing the vaccine. We have directly compared the efficacy of a FAST and personal vaccines in a mouse model of breast cancer. We find that both approaches have comparable protection though there are some interesting differences. We suggest that FAST vaccines may be a useful approach to developing therapeutic vaccines for brain cancers. We also demonstrate that an array of the 400K possible FS neoantigen peptides can be used to assay which neoantigens the patient has developed antibodies to. This array was useful in discovering the FAST vaccine components and could also be used to determine the pre-existing overlap of a FAST vaccine with the patient’s immune response.

scholarly journals Cancer Vaccines: Promising Therapeutics or an Unattainable Dream

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 668
Author(s):  
Howard Donninger ◽  
Chi Li ◽  
John W. Eaton ◽  
Kavitha Yaddanapudi
Keyword(s):  
Stem Cell ◽  
Immune System ◽  
Tumor Immunity ◽  
Cancer Vaccines ◽  
Tumor Antigens ◽  
Host Immune System ◽  
Tumor Type ◽  
Therapeutic Vaccines ◽  
Cancer Types ◽  
Prophylactic Vaccines

The advent of cancer immunotherapy has revolutionized the field of cancer treatment and offers cancer patients new hope. Although this therapy has proved highly successful for some patients, its efficacy is not all encompassing and several cancer types do not respond. Cancer vaccines offer an alternate approach to promote anti-tumor immunity that differ in their mode of action from antibody-based therapies. Cancer vaccines serve to balance the equilibrium of the crosstalk between the tumor cells and the host immune system. Recent advances in understanding the nature of tumor-mediated tolerogenicity and antigen presentation has aided in the identification of tumor antigens that have the potential to enhance anti-tumor immunity. Cancer vaccines can either be prophylactic (preventative) or therapeutic (curative). An exciting option for therapeutic vaccines is the emergence of personalized vaccines, which are tailor-made and specific for tumor type and individual patient. This review summarizes the current standing of the most promising vaccine strategies with respect to their development and clinical efficacy. We also discuss prospects for future development of stem cell-based prophylactic vaccines.

scholarly journals Breast Cancer Immunotherapy: An Update

2018 ◽  
Vol 12 ◽  
pp. 117822341877480 ◽  
Author(s):  
Issam Makhoul ◽  
Mohammad Atiq ◽  
Ahmed Alwbari ◽  
Thomas Kieber-Emmons
Keyword(s):  
Breast Cancer ◽  
Immune Response ◽  
Monoclonal Antibodies ◽  
Immune System ◽  
Cancer Vaccines ◽  
Checkpoint Inhibitors ◽  
Cancer Surveillance ◽  
Cancer Disease ◽  
Immune Attack

The immune system plays a major role in cancer surveillance. Harnessing its power to treat many cancers is now a reality that has led to cures in hopeless situations where no other solutions were available from traditional anticancer drugs. These spectacular achievements rekindled the oncology community’s interest in extending the benefits to all cancers including breast cancer. The first section of this article reviews the biological foundations of the immune response to different subtypes of breast cancer and the ways cancer may overcome the immune attack leading to cancer disease. The second section is dedicated to the actual immune treatments including breast cancer vaccines, checkpoint inhibitors, monoclonal antibodies, and the “unconventional” immune role of chemotherapy.

scholarly journals 3D extracellular matrix microenvironment in bioengineered tissue models of primary pediatric and adult brain tumors

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Disha Sood ◽  
Min Tang-Schomer ◽  
Dimitra Pouli ◽  
Craig Mizzoni ◽  
Nicole Raia ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Brain Tumor ◽  
Brain Tumors ◽  
Adult Brain ◽  
Metabolic Imaging ◽  
Tumor Type ◽  
Label Free ◽  
Pediatric Ependymoma ◽  
Extracellular Lipid ◽  
Tumor Cell Behavior

Abstract Dynamic alterations in the unique brain extracellular matrix (ECM) are involved in malignant brain tumors. Yet studies of brain ECM roles in tumor cell behavior have been difficult due to lack of access to the human brain. We present a tunable 3D bioengineered brain tissue platform by integrating microenvironmental cues of native brain-derived ECMs and live imaging to systematically evaluate patient-derived brain tumor responses. Using pediatric ependymoma and adult glioblastoma as examples, the 3D brain ECM-containing microenvironment with a balance of cell-cell and cell-matrix interactions supports distinctive phenotypes associated with tumor type-specific and ECM-dependent patterns in the tumor cells’ transcriptomic and release profiles. Label-free metabolic imaging of the composite model structure identifies metabolically distinct sub-populations within a tumor type and captures extracellular lipid-containing droplets with potential implications in drug response. The versatile bioengineered 3D tumor tissue system sets the stage for mechanistic studies deciphering microenvironmental role in brain tumor progression.

scholarly journals The Role of the Tumor Microenvironment in Developing Successful Therapeutic and Secondary Prophylactic Breast Cancer Vaccines

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 529 ◽  
Author(s):  
Benjamin Gordon ◽  
Vijayakrishna K. Gadi
Keyword(s):  
Breast Cancer ◽  
Tumor Microenvironment ◽  
Cancer Vaccines ◽  
Molecular Mechanisms ◽  
New Combination ◽  
Breast Carcinomas ◽  
Therapeutic Vaccines ◽  
Combination Strategies ◽  
Disseminated Disease

Breast cancer affects roughly one in eight women over their lifetime and is a leading cause of cancer-related death in women. While outcomes have improved in recent years, prognosis remains poor for patients who present with either disseminated disease or aggressive molecular subtypes. Cancer immunotherapy has revolutionized the treatment of several cancers, with therapeutic vaccines aiming to direct the cytotoxic immune program against tumor cells showing particular promise. However, these results have yet to translate to breast cancer, which remains largely refractory from such approaches. Recent evidence suggests that the breast tumor microenvironment (TME) is an important and long understudied barrier to the efficacy of therapeutic vaccines. Through an improved understanding of the complex and biologically diverse breast TME, it may be possible to advance new combination strategies to render breast carcinomas sensitive to the effects of therapeutic vaccines. Here, we discuss past and present efforts to advance therapeutic vaccines in the treatment of breast cancer, the molecular mechanisms through which the TME contributes to the failure of such approaches, as well as the potential means through which these can be overcome.

scholarly journals Cancer Vaccines, Treatment of the Future: With Emphasis on HER2-Positive Breast Cancer

2021 ◽  
Vol 22 (2) ◽  
pp. 779
Author(s):  
Sandeep Pallerla ◽  
Ata ur Rahman Mohammed Abdul ◽  
Jill Comeau ◽  
Seetharama Jois
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Targeted Therapies ◽  
Cancer Vaccines ◽  
Vaccine Therapy ◽  
Current Status ◽  
Breast Cancer Patients ◽  
Therapeutic Vaccines ◽  
Advantages And Disadvantages ◽  
Her2 Breast Cancer

Breast cancer is one of the leading causes of death in women. With improvements in early-stage diagnosis and targeted therapies, there has been an improvement in the overall survival rate in breast cancer over the past decade. Despite the development of targeted therapies, tyrosine kinase inhibitors, as well as monoclonal antibodies and their toxin conjugates, all metastatic tumors develop resistance, and nearly one-third of HER2+ breast cancer patients develop resistance to all these therapies. Although antibody therapy has shown promising results in breast cancer patients, passive immunotherapy approaches have limitations and need continuous administration over a long period. Vaccine therapy introduces antigens that act on cancer cells causing prolonged activation of the immune system. In particular, cancer relapse could be avoided due to the presence of a longer period of immunological memory with an effective vaccine that can protect against various tumor antigens. Cancer vaccines are broadly classified as preventive and therapeutic. Preventive vaccines are used to ward off any future infections and therapeutic vaccines are used to treat a person with active disease. In this article, we provided details about the tumor environment, different types of vaccines, their advantages and disadvantages, and the current status of various vaccine candidates with a focus on vaccines for breast cancer. Current data indicate that therapeutic vaccines themselves have limitations in terms of efficacy and are used in combination with other chemotherapeutic or targeting agents. The majority of breast cancer vaccines are undergoing clinical trials and the next decade will see the fruitfulness of breast cancer vaccine therapy.

scholarly journals EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

2021 ◽  
Author(s):  
Barbara Kunzler Souza ◽  
Natalia Hogetop Freire ◽  
Mariane Jaeger ◽  
Caroline Brunetto de Farias ◽  
Algemir Lunardi Brunetto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Brain Cancer ◽  
Adult Brain ◽  
Normal Tissues ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Development And Differentiation

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development, and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), regulates changes in gene expression involved in embryonic development and differentiation of normal tissues. Overexpression of G9a has been observed in in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma multiforme (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. G9a inhibition dose-dependently reduces the viability of MB cells. Transcriptional levels of G9a are higher in MB tumors belonging to the SHH, Group 3, and Group 4, compared to Wnt tumors, and higher G9a gene expression may be a predictor of poor prognosis in patients with MB.

scholarly journals EHMT2/G9a as an Epigenetic Target in Pediatric and Adult Brain Tumors

2021 ◽  
Vol 22 (20) ◽  
pp. 11292
Author(s):  
Barbara Kunzler Souza ◽  
Natalia Hogetop Freire ◽  
Mariane Jaeger ◽  
Caroline Brunetto de Farias ◽  
Algemir L. Brunetto ◽  
...  
Keyword(s):  
Gene Expression ◽  
Brain Tumors ◽  
Cancer Progression ◽  
Anticancer Agents ◽  
Brain Cancer ◽  
Adult Brain ◽  
Post Translational Modifications ◽  
Histone Lysine Methyltransferase ◽  
Lysine Methyltransferase ◽  
Cancer Types

Epigenetic mechanisms, including post-translational modifications of DNA and histones that influence chromatin structure, regulate gene expression during normal development and are also involved in carcinogenesis and cancer progression. The histone methyltransferase G9a (euchromatic histone lysine methyltransferase 2, EHMT2), which mostly mediates mono- and dimethylation by histone H3 lysine 9 (H3K9), influences gene expression involved in embryonic development and tissue differentiation. Overexpression of G9a has been observed in several cancer types, and different classes of G9a inhibitors have been developed as potential anticancer agents. Here, we review the emerging evidence suggesting the involvement of changes in G9a activity in brain tumors, namely glioblastoma (GBM), the main type of primary malignant brain cancer in adults, and medulloblastoma (MB), the most common type of malignant brain cancer in children. We also discuss the role of G9a in neuroblastoma (NB) and the drug development of G9a inhibitors.

Does gamma knife surgery stimulate cellular immune response to metastatic brain tumors? A histopathological and immunohistochemical study

2005 ◽  
Vol 102 (Special_Supplement) ◽  
pp. 180-184 ◽  
Author(s):  
György T. Szeifert ◽  
Isabelle Salmon ◽  
Sandrine Rorive ◽  
Nicolas Massager ◽  
Daniel Devriendt ◽  
...  
Keyword(s):  
Immune Response ◽  
Brain Tumors ◽  
Gamma Knife ◽  
Cellular Immune Response ◽  
Lymphocytic Infiltration ◽  
Gamma Knife Surgery ◽  
Metastatic Brain Tumors ◽  
Content Type ◽  
Cellular Immune ◽  
Fine Print

Object. The aim of this study was to analyze the cellular immune response and histopathological changes in secondary brain tumors after gamma knife surgery (GKS). Methods. Two hundred ten patients with cerebral metastases underwent GKS. Seven patients underwent subsequent craniotomy for tumor removal between 1 and 33 months after GKS. Four of these patients had one tumor, two patients had two tumors, and one patient had three. Histological and immunohistochemical investigations were performed. In addition to routine H & E and Mallory trichrome staining, immunohistochemical reactions were conducted to characterize the phenotypic nature of the cell population contributing to the tissue immune response to neoplastic deposits after radiosurgery. Light microscopy revealed an intensive lymphocytic infiltration in the parenchyma and stroma of tumor samples obtained in patients in whom surgery was performed over 6 months after GKS. Contrary to this, extensive areas of tissue necrosis with either an absent or scanty lymphoid population were observed in the poorly controlled neoplastic specimens obtained in cases in which surgery was undertaken in patients less than 6 months after GKS. Immunohistochemical characterization demonstrated the predominance of CD3-positive T cells in the lymphoid infiltration. Conclusions. Histopathological findings of the present study are consistent with a cellular immune response of natural killer cells against metastatic brain tumors, presumably stimulated by the ionizing energy of focused radiation.

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