scholarly journals Development of Therapeutic Vaccines for Ovarian Cancer

Vaccines ◽  
2020 ◽  
Vol 8 (4) ◽  
pp. 657
Author(s):  
Stephanie Chow ◽  
Jonathan S. Berek ◽  
Oliver Dorigo
Keyword(s):  
Ovarian Cancer ◽  
Immune Responses ◽  
Vaccine Development ◽  
Cytotoxic T Cells ◽  
Therapeutic Vaccine ◽  
Immune Checkpoint Blockade ◽  
Ovarian Cancer Cells ◽  
Therapeutic Vaccines ◽  
Effector Cells ◽  
Clinical Benefits

Ovarian cancer remains the deadliest of all gynecologic malignancies. Our expanding knowledge of ovarian cancer immunology has allowed the development of therapies that generate systemic anti-tumor immune responses. Current immunotherapeutic strategies include immune checkpoint blockade, cellular therapies, and cancer vaccines. Vaccine-based therapies are designed to induce both adaptive and innate immune responses directed against ovarian cancer associated antigens. Tumor-specific effector cells, in particular cytotoxic T cells, are activated to recognize and eliminate ovarian cancer cells. Vaccines for ovarian cancer have been studied in various clinical trials over the last three decades. Despite evidence of vaccine-induced humoral and cellular immune responses, the majority of vaccines have not shown significant anti-tumor efficacy. Recently, improved vaccine development using dendritic cells or synthetic platforms for antigen presentation have shown promising clinical benefits in patients with ovarian cancer. In this review, we provide an overview of therapeutic vaccine development in ovarian cancer, discuss proposed mechanisms of action, and summarize the current clinical experience.

scholarly journals Calreticulin—Multifunctional Chaperone in Immunogenic Cell Death: Potential Significance as a Prognostic Biomarker in Ovarian Cancer Patients

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 130
Author(s):  
Michal Kielbik ◽  
Izabela Szulc-Kielbik ◽  
Magdalena Klink
Keyword(s):  
Ovarian Cancer ◽  
Cell Death ◽  
Cancer Patients ◽  
Tumor Cells ◽  
Cytotoxic T Cells ◽  
Adaptive Immune Response ◽  
Ovarian Cancer Cells ◽  
Immunogenic Cell Death ◽  
Antigen Presenting ◽  
Molecular Patterns

Immunogenic cell death (ICD) is a type of death, which has the hallmarks of necroptosis and apoptosis, and is best characterized in malignant diseases. Chemotherapeutics, radiotherapy and photodynamic therapy induce intracellular stress response pathways in tumor cells, leading to a secretion of various factors belonging to a family of damage-associated molecular patterns molecules, capable of inducing the adaptive immune response. One of them is calreticulin (CRT), an endoplasmic reticulum-associated chaperone. Its presence on the surface of dying tumor cells serves as an “eat me” signal for antigen presenting cells (APC). Engulfment of tumor cells by APCs results in the presentation of tumor’s antigens to cytotoxic T-cells and production of cytokines/chemokines, which activate immune cells responsible for tumor cells killing. Thus, the development of ICD and the expression of CRT can help standard therapy to eradicate tumor cells. Here, we review the physiological functions of CRT and its involvement in the ICD appearance in malignant disease. Moreover, we also focus on the ability of various anti-cancer drugs to induce expression of surface CRT on ovarian cancer cells. The second aim of this work is to discuss and summarize the prognostic/predictive value of CRT in ovarian cancer patients.

scholarly journals Recent Advances in Nanovaccines Using Biomimetic Immunomodulatory Materials

Pharmaceutics ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 534 ◽  
Author(s):  
Vijayan ◽  
Mohapatra ◽  
Uthaman ◽  
Park
Keyword(s):  
Immune Responses ◽  
Targeted Delivery ◽  
Vaccine Development ◽  
Polymeric Nanoparticles ◽  
Vital Role ◽  
Effective Control ◽  
Therapeutic Vaccines ◽  
Hiv Therapy ◽  
Recent Advances ◽  
Wide Range

The development of vaccines plays a vital role in the effective control of several fatal diseases. However, effective prophylactic and therapeutic vaccines have yet to be developed for completely curing deadly diseases, such as cancer, malaria, HIV, and serious microbial infections. Thus, suitable vaccine candidates need to be designed to elicit appropriate immune responses. Nanotechnology has been found to play a unique role in the design of vaccines, providing them with enhanced specificity and potency. Nano-scaled materials, such as virus-like particles, liposomes, polymeric nanoparticles (NPs), and protein NPs, have received considerable attention over the past decade as potential carriers for the delivery of vaccine antigens and adjuvants, due to their beneficial advantages, like improved antigen stability, targeted delivery, and long-time release, for which antigens/adjuvants are either encapsulated within, or decorated on, the NP surface. Flexibility in the design of nanomedicine allows for the programming of immune responses, thereby addressing the many challenges encountered in vaccine development. Biomimetic NPs have emerged as innovative natural mimicking biosystems that can be used for a wide range of biomedical applications. In this review, we discuss the recent advances in biomimetic nanovaccines, and their use in anti-bacterial therapy, anti-HIV therapy, anti-malarial therapy, anti-melittin therapy, and anti-tumor immunity.

scholarly journals Therapeutic vaccine for chronic diseases after the COVID-19 Era

2021 ◽  
Author(s):  
Hironori Nakagami ◽  
Hiroki Hayashi ◽  
Munehisa Shimamura ◽  
Hiromi Rakugi ◽  
Ryuichi Morishita
Keyword(s):  
Chronic Diseases ◽  
Cytotoxic T Cells ◽  
Rapid Development ◽  
Therapeutic Vaccine ◽  
Cell Epitope ◽  
Cerebrovascular Diseases ◽  
Strong Impact ◽  
T Cell Epitopes ◽  
Therapeutic Vaccines ◽  
Novel Concept

AbstractThere is currently a respiratory disease outbreak caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). After rapid development, RNA vaccines and adenoviral vector vaccines were approved within a year, which has demonstrated the strong impact of preventing infectious diseases using gene therapy technology. Furthermore, intensive immunological analysis has been performed to evaluate the efficiency and safety of these vaccines, potentially allowing for rapid progress in vaccine technology. After the coronavirus disease 2019 (COVID-19) era, the novel vaccine technology developed will expand to other vaccines. We have been developing vaccines for chronic diseases, such as hypertension, for >10 years. Regarding the development of vaccines against self-antigens (i.e., angiotensin II), the vaccine should efficiently induce a blocking antibody response against the self-antigen without activating cytotoxic T cells. Therefore, the epitope vaccine approach has been proposed to induce antibody production in response to a combination of a B cell epitope and exogenous T cell epitopes through major histocompatibility complex molecules. When these vaccines are established as therapeutic options for hypertension, their administration regimen, which might be a few times per year, will replace daily medication use. Thus, therapeutic vaccines for hypertension may be a novel option to control the progression of cerebrovascular diseases. Hopefully, the accumulation of immunological findings and vaccine technology advances due to COVID-19 will provide a novel concept for vaccines for chronic diseases.

scholarly journals HIV-1 Reservoir Dynamics after Vaccination and Antiretroviral Therapy Interruption Are Associated with Dendritic Cell Vaccine-Induced T Cell Responses

2015 ◽  
Vol 89 (18) ◽  
pp. 9189-9199 ◽  
Author(s):  
Cristina Andrés ◽  
Montserrat Plana ◽  
Alberto C. Guardo ◽  
Carmen Alvarez-Fernández ◽  
Nuria Climent ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Cd4 T Cells ◽  
Therapeutic Vaccine ◽  
T Cell Responses ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Hiv 1

ABSTRACTHIV-1-specific immune responses induced by a dendritic cell (DC)-based therapeutic vaccine might have some effect on the viral reservoir. Patients on combination antiretroviral therapy (cART) were randomized to receive DCs pulsed with autologous HIV-1 (n= 24) (DC-HIV-1) or nonpulsed DCs (n= 12) (DC-control). We measured the levels of total and integrated HIV-1 DNA in CD4 T cells isolated from these patients at 6 time points: before any cART; before the first cART interruption, which was at 56 weeks before the first immunization to isolate virus for pulsing DCs; before and after vaccinations (VAC1 and VAC2); and at weeks 12 and 48 after the second cART interruption. The vaccinations did not influence HIV-1 DNA levels in vaccinated subjects. After the cART interruption at week 12 postvaccination, while total HIV-1 DNA increased significantly in both arms, integrated HIV-1 DNA did not change in vaccinees (mean of 1.8 log10to 1.9 copies/106CD4 T cells,P= 0.22) and did increase in controls (mean of 1.8 log10to 2.1 copies/106CD4 T cells,P= 0.02) (P= 0.03 for the difference between groups). However, this lack of increase of integrated HIV-1 DNA observed in the DC-HIV-1 group was transient, and at week 48 after cART interruption, no differences were observed between the groups. The HIV-1-specific T cell responses at the VAC2 time point were inversely correlated with the total and integrated HIV-1 DNA levels after cART interruption in vaccinees (r[Pearson's correlation coefficient] = −0.69,P= 0.002, andr= −0.82,P< 0.0001, respectively). No correlations were found in controls. HIV-1-specific T cell immune responses elicited by DC therapeutic vaccines drive changes in HIV-1 DNA after vaccination and cART interruption. (This study has been registered at ClinicalTrials.gov under registration no. NCT00402142.)IMPORTANCEThere is an intense interest in developing strategies to target HIV-1 reservoirs as they create barriers to curing the disease. The development of therapeutic vaccines aimed at enhancing immune-mediated clearance of virus-producing cells is of high priority. Few therapeutic vaccine clinical trials have investigated the role of therapeutic vaccines as a strategy to safely eliminate or control viral reservoirs. We recently reported that a dendritic cell-based therapeutic vaccine was able to significantly decrease the viral set point in vaccinated patients, with a concomitant increase in HIV-1-specific T cell responses. The HIV-1-specific T cell immune responses elicited by this therapeutic dendritic cell vaccine drove changes in the viral reservoir after vaccinations and significantly delayed the replenishment of integrated HIV-1 DNA after cART interruption. These data help in understanding how an immunization could shift the virus-host balance and are instrumental for better design of strategies to reach a functional cure of HIV-1 infection.

scholarly journals Targeting the IRE1α/XBP1s pathway suppresses CARM1-expressing ovarian cancer

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Jianhuang Lin ◽  
Heng Liu ◽  
Takeshi Fukumoto ◽  
Joseph Zundell ◽  
Qingqing Yan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Stress Response ◽  
Er Stress ◽  
Cancer Cells ◽  
Immune Checkpoint ◽  
Immune Checkpoint Blockade ◽  
Checkpoint Blockade ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Er Stress Response

AbstractCARM1 is often overexpressed in human cancers including in ovarian cancer. However, therapeutic approaches based on CARM1 expression remain to be an unmet need. Cancer cells exploit adaptive responses such as the endoplasmic reticulum (ER) stress response for their survival through activating pathways such as the IRE1α/XBP1s pathway. Here, we report that CARM1-expressing ovarian cancer cells are selectively sensitive to inhibition of the IRE1α/XBP1s pathway. CARM1 regulates XBP1s target gene expression and directly interacts with XBP1s during ER stress response. Inhibition of the IRE1α/XBP1s pathway was effective against ovarian cancer in a CARM1-dependent manner both in vitro and in vivo in orthotopic and patient-derived xenograft models. In addition, IRE1α inhibitor B-I09 synergizes with immune checkpoint blockade anti-PD1 antibody in an immunocompetent CARM1-expressing ovarian cancer model. Our data show that pharmacological inhibition of the IRE1α/XBP1s pathway alone or in combination with immune checkpoint blockade represents a therapeutic strategy for CARM1-expressing cancers.

scholarly journals Human neutrophil-mediated lysis of ovarian cancer cells

Blood ◽  
1989 ◽  
Vol 74 (2) ◽  
pp. 805-809 ◽  
Author(s):  
A Lichtenstein ◽  
M Seelig ◽  
J Berek ◽  
J Zighelboim
Keyword(s):  
Ovarian Cancer ◽  
Tumor Cells ◽  
Human Tumor ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Myristate Acetate ◽  
Human Tumor Cells ◽  
Effector Cells ◽  
Lethal Event ◽  
Stimulation Of

Abstract Because of recent questions concerning the sensitivity of human tumor cells to neutrophil-induced oxidative injury, we studied six freshly obtained human ovarian cancer (OC) specimens. Stimulation of neutrophils (PMNs) by phorbol myristate acetate (PMA) did not result in OC cytolysis during the first nine hours of incubation. However, three of six specimens were significantly lysed by stimulated PMNs when assay length was increased to 18 hours. Cytotoxicity was mediated by PMN production of reactive oxidative intermediates (ROIs). Presentation of ROIs to OC targets as preformed or enzymatically generated molecules in cell-free systems duplicated the enhanced lysis at 18 hours (as compared with six hours). Since addition of catalase at three or six hours did not inhibit enhanced lysis at 18 hours (achieved by PMNs or in cell-free systems), it appears that an initial ROI-mediated lethal event occurs early, but longer incubations are required for the event to become manifested as cell death. These data suggest that shorter assays may underestimate the potential of PMNs as effector cells against human tumor cells.

scholarly journals Shaping Immune Responses in the Tumor Microenvironment of Ovarian Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Xin Luo ◽  
Jing Xu ◽  
Jianhua Yu ◽  
Ping Yi
Keyword(s):  
Ovarian Cancer ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Cancer Cells ◽  
Disease Progression ◽  
Immune Cells ◽  
Biomarker Discovery ◽  
Immune Cell ◽  
Ovarian Cancer Cells ◽  
Cancer Tumor

Reciprocal signaling between immune cells and ovarian cancer cells in the tumor microenvironment can alter immune responses and regulate disease progression. These signaling events are regulated by multiple factors, including genetic and epigenetic alterations in both the ovarian cancer cells and immune cells, as well as cytokine pathways. Multiple immune cell types are recruited to the ovarian cancer tumor microenvironment, and new insights about the complexity of their interactions have emerged in recent years. The growing understanding of immune cell function in the ovarian cancer tumor microenvironment has important implications for biomarker discovery and therapeutic development. This review aims to describe the factors that shape the phenotypes of immune cells in the tumor microenvironment of ovarian cancer and how these changes impact disease progression and therapy.

scholarly journals Icaritin Induces Anti-tumor Immune Responses in Hepatocellular Carcinoma by Inhibiting Splenic Myeloid-Derived Suppressor Cell Generation

2021 ◽  
Vol 12 ◽  
Author(s):  
Huimin Tao ◽  
Mingyu Liu ◽  
Yuan Wang ◽  
Shufeng Luo ◽  
Yongquan Xu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Suppressor Cells ◽  
Suppressor Cell ◽  
Extramedullary Hematopoiesis ◽  
Immune Checkpoint Blockade ◽  
Myeloid Derived Suppressor Cell ◽  
Tumor Tissues

Recent studies have demonstrated that splenic extramedullary hematopoiesis (EMH) is an important mechanism for the accumulation of myeloid-derived suppressor cells (MDSCs) in tumor tissues, and thus contributes to disease progression. Icaritin, a prenylflavonoid derivative from plants of the Epimedium genus, has been implicated as a novel immune-modulator that could prolong the survival of hepatocellular carcinoma (HCC) patients. However, it is unclear whether icaritin achieves its anti-tumor effects via the regulation of MDSCs generated by EMH in HCC. Here, we investigated the anti-tumor potential of icaritin and its mechanism of action in murine HCC. Icaritin suppressed tumor progression and significantly prolonged the survival of mice-bearing orthotopic and subcutaneous HCC tumors. Rather than exerting direct cytotoxic activity against tumor cells, icaritin significantly reduced the accumulation and activation of tumoral and splenic MDSCs, and increased the number and activity of cytotoxic T cells. Mechanistically, icaritin downregulates the tumor-associated splenic EMH, thereby reducing the generation and activation of MDSCs. The inhibitory effects of icaritin on human MDSCs in vitro were verified in short-term culture with cord-blood derived hematopoietic precursors. Furthermore, icaritin synergistically enhanced the therapeutic efficacy of immune checkpoint blockade therapy in HCC mice. These findings revealed that icaritin dampens tumoral immunosuppression to elicit anti-tumor immune responses by preventing MDSC generation via the attenuation of EMH. Thus, icaritin may serve as a novel adjuvant or even a stand-alone therapeutic agent for the effective treatment of HCC.

Coimmunization with Antigens Shared between Neoplastic and Normal B Cells Suppresses Induction of Strictly Tumor-Specific Cytotoxic T Cells through In Situ Activation of Regulatory T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2491-2491
Author(s):  
Max Warncke ◽  
Maike Buchner ◽  
Cristina Bertinetti ◽  
Hendrik Veelken
Keyword(s):  
T Cells ◽  
Immune Responses ◽  
Cytotoxic T Cells ◽  
Active Immunotherapy ◽  
Effector Cells ◽  
In Situ Activation ◽  
Draining Lymph Node

Abstract CD4+CD25+ regulatory T cells (Treg) recognize autoantigens and inhibit autoreactive immune responses in a cell contact-dependent manner. In cancer-bearing patients, expansion and functional aberrations of Treg may inhibit immune responses against the tumor. The available evidence suggests that such Treg recognize self antigens expressed by the tumor and argues that induction of anti-tumor T cell responses might be more successful if true tumor-specific rather than lineage-restricted or shared antigens are used for active immunotherapy. Indeed, we have observed a preferential recognition of tumor-individual over shared epitopes by vaccination-induced T cells after immunization of B-NHL patients with recombinant lymphoma idiotype (Bertinetti et al., Cancer Res. 2006). To study this phenomenon in an exemplary fashion, we immunized BALB/c mice with dendritic cells loaded with H-2K-restricted peptides of the immunoglobulin of the A20 lymphoma. A J region-derived peptide served as a model for a shared antigen; a heteroclitic peptide from the CDR3 region represented a tumor-specific antigen. Both peptides bind H-2Kd with similar affinity. Compared to a highly immunogenic influenza HA peptide, the CDR3 peptide was similarly efficient in inducing specific cytotoxic T cells as analyzed by tetramer staining, IFNγ release to peptide stimulation, and in vitro and in vivo cytotoxicity assays with CFSE-labelled, peptide-loaded splenocytes. In contrast, no effector cells were detected with any assay after J immunization. After in vitro restimulation with peptide, however, antigen-specific IFNγ-secreting effector populations were demonstrated for each vaccination, suggesting in vivo inhibition, possibly mediated by Treg, rather than total absence of J-specific T cells. No difference in numbers and the TCR repertoire of CD4+CD25+FoxP3+ cells in the draining lymph node could be detected. However, activation of Treg by J immunization was indicated by potent suppression of antigen-specific splenic effectors compared to CDR3-immunized animals, and by a 4fold higher spontaneous proliferation of FoxP3+ cells from the draining lymph node in vitro. In contrast to CDR3-derived Treg, the addition of J-induced Treg to effector cells resulted in a dose-dependent production of IL-10 in mixed cultures, independently of the antigen specificity of the effectors. Finally, coimmunization with HA and J peptides led to inhibition of the proliferation of HA-specific CD8+ effectors in vivo as demonstrated by adoptive transfer and subsequent flow cytometry analysis of CFSE-labelled TCR-transgenic T cells. This inhibition was absent after coimmunization with HA and CDR3 peptides and could be largely abolished by prior in vivo depletion of Treg with an αCD25 antibody. These data demonstrate in a non-transgenic model that coimmunization with shared and individual, strictly MHC I-restricted tumor antigens leads to a potent inhibition of tumor-specific CD8+ T cells through rapid in situ activation of CD4+FoxP3+ Treg elicited by the shared tumor antigen. It is postulated that these Treg recognize MHC II-restricted self antigens presumably derived from non-neoplastic cells as a consequence of an aborted immune response to the shared antigen. These experiments provide direct evidence that active immunotherapy of malignant tumors exclusively with true tumor-specific antigens has a greater chance of success since the presence of shared antigens will prevent tumor-specific immune responses through Treg activation.

scholarly journals The Potential of Immune Modulation in Therapeutic HIV-1 Vaccination

Vaccines ◽  
2020 ◽  
Vol 8 (3) ◽  
pp. 419
Author(s):  
Nabila Seddiki ◽  
Florence Picard ◽  
Léa Dupaty ◽  
Yves Lévy ◽  
Véronique Godot
Keyword(s):  
Immune Modulation ◽  
Vaccine Development ◽  
Therapeutic Vaccine ◽  
Scientific Basis ◽  
Specific Cell ◽  
Virus Reactivation ◽  
Therapeutic Vaccines ◽  
Hiv 1 ◽  
Immune Checkpoint Blockers ◽  
Suppress Virus Replication

We discuss here some of the key immunological elements that are at the crossroads and need to be combined to develop a potent therapeutic HIV-1 vaccine. Therapeutic vaccines have been commonly used to enhance and/or recall pre-existing HIV-1-specific cell-mediated immune responses aiming to suppress virus replication. The current success of immune checkpoint blockers in cancer therapy renders them very attractive to use in HIV-1 infected individuals with the objective to preserve the function of HIV-1-specific T cells from exhaustion and presumably target the persistent cellular reservoir. The major latest advances in our understanding of the mechanisms responsible for virus reactivation during therapy-suppressed individuals provide the scientific basis for future combinatorial therapeutic vaccine development.

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