Therapeutic Exosomal Vaccine for Enhanced Cancer Immunotherapy by Mediating Tumor Microenvironment
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ABSTRACT:
PROVIDER: PRJNA787786 | ENA |
REPOSITORIES: ENA
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Project description:Tumor immunotherapy has been convincingly demonstrated as a feasible approach for treating cancers. Although promising, however, the immunosuppressive tumor microenvironment (TME) has been recognized as a major obstacle in tumor immunotherapy. It is highly desirable to release an immunosuppressive “brake” for improving cancer immunotherapy. Among tumor-infiltrated immune cells, tumor-associated macrophages (TAMs) play an important role in the growth, invasion and metastasis of tumors. The polarization of TAMs (M2) into the M1 type can alleviate the immunosuppression of the TME and enhance the effect of immunotherapy. Inspired by this, we constructed a therapeutic exosomal vaccine from antigen-stimulated M1-type macrophages (M1OVA-Exos). M1OVA-Exos are capable of polarizing TAMs into M1 type through downregulation of the Wnt signaling pathway. Mediating the TME further activates the immune response and inhibits tumor growth and metastasis via the exosomal vaccine. Our study provides a new strategy for the polarization of TAMs, which augments cancer vaccine therapy efficacy.
2022-01-12 | GSE190619 | GEO
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Project description:Low-grade gliomas (LGGs) are the most common brain tumor of childhood. Children with LGGs are ideal candidates for immunotherapy due to slow tumor growth, and as these children are otherwise healthy, and often have intact immune systems. We recently reported in an early phase clinical trial that vaccine treatment elicited strong biologic responses in LGG patients, compared with our experience in adult and pediatric high-grade brain-stem and non-brain stem gliomas. Additionally, we observed radiographic responses of stable disease (n=7), partial response (n=3), and complete response (n=2) following therapy. These remarkable results prompted us to initiate a phase II trial utilizing this strategy in pediatric LGGs. In order to identify potential peripheral response patterns in each response group, we performed Illumina RNA-sequencing on PBMCs samples (n=54), collected either prior to treatment or at multiple time points following treatment.
2018-04-03 | E-MTAB-6270 | biostudies-arrayexpress
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.
2014-08-05 | E-GEOD-52171 | biostudies-arrayexpress
Project description:The tumor microenvironment in brain metastases is characterized by high myeloid cell content with immune-suppressive and cancer-permissive functions. Moreover, brain metastases induce the recruitment of lymphocytes. Despite their presence, T cell-directed therapies fail to elicit effective anti-tumor immune responses. Here we seek to evaluate the applicability of radio-immunotherapy to modulate tumor immunity and overcome inhibitory effects that diminish anti-cancer activity. Radiotherapy-induced immune modulation resulted in an increase in cytotoxic T cell numbers and prevented the induction of lymphocyte-mediated immune suppression. Radio-immunotherapy led to significantly improved tumor control with prolonged median survival in experimental breast-to-brain metastases. However, long-term efficacy was not observed. Recurrent brain metastases showed accumulation of blood-borne PD-L1+ myeloid cells after radio-immunotherapy indicating the establishment of an immune-suppressive environment to counteract re-activated T cell responses. This finding was further supported by transcriptional analyses indicating a crucial role for monocyte-derived macrophages in mediating immune-suppression and regulating T cell function. Therefore, selective targeting of immune suppressive functions of myeloid cells is expected to be critical for improved therapeutic efficacy of radio-immunotherapy in brain metastases.
2021-02-12 | GSE164049 | GEO
Project description:The paper describes a model of antitumor vaccine therapy.
Created by COPASI 4.25 (Build 207)
This model is described in the article:
A Mathematical Model of the Enhancement of Tumor Vaccine Efficacy by Immunotherapy
Shelby Wilson and Doron Levy
Bull Math Biol. 2012 July ; 74(7)
Abstract:
TGF-β is an immunoregulatory protein that contributes to inadequate antitumor immune responses in cancer patients. Recent experimental data suggests that TGF-β inhibition alone, provides few clinical benefits, yet it can significantly amplify the anti-tumor immune response when combined with a tumor vaccine. We develop a mathematical model in order to gain insight into the cooperative interaction between anti-TGF-β and vaccine treatments. The mathematical model follows the dynamics of the tumor size, TGF-β concentration, activated cytotoxic effector cells, and regulatory T cells. Using numerical simulations and stability analysis, we study the following scenarios: a control case of no treatment, anti-TGF-β treatment, vaccine treatment, and combined anti-TGF-β vaccine treatments. We show that our model is capable of capturing the observed experimental results, and hence can be potentially used in designing future experiments involving this approach to immunotherapy.
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2021-03-12 | BIOMD0000000791 | BioModels
Project description:Immunotherapy Utilizing NK cells and ADCC Mediating Agents with Poly (ADP-ribose) polymerase (PARP) Inhibition
| PRJNA498086 | ENA
Project description:Background: Poly (ADP-ribose) polymerase inhibitors (PARPi) prevent single-stranded DNA repair. Olaparib is a PARPi approved for the treatment of BRCA mutant ovarian and breast carcinoma. Emerging clinical data suggest a benefit of combining olaparib with immunotherapy in prostate cancer patients both with and without somatic BRCA mutations. Methods: We examined if olaparib, when combined with IgG1 antibody-dependent cellular cytotoxicity (ADCC)-mediating monoclonal antibodies (mAbs) cetuximab (anti-EGFR), or avelumab (anti-PD-L1), would increase tumor cell sensitivity to killing by natural killer (NK) cells independently of BRCA status or mAb target upregulation. BRCA mutant and BRCA wildtype (WT) prostate carcinoma cell lines were pretreated with olaparib and then exposed to NK cells in the presence or absence of cetuximab or avelumab. Results: NK-mediated killing was significantly increased in both cell lines and was further increased using the ADCC-mediating mAbs. Pre-exposure of NK cells to recombinant IL-15/IL-15RA further increased the lysis of olaparib treated tumor cells. In addition, olaparib treated tumor cells were killed to a significantly greater degree by engineered high-affinity NK cells (haNK). We show here for the first time that (a) olaparib significantly increased tumor cell sensitivity to NK killing and ADCC in both BRCA WT and BRCA mutant prostate carcinoma cells, independent of PD-L1 or EGFR modulation; (b) mechanistically, treatment with olaparib upregulated death receptor TRAIL-R2, and (c) olaparib significantly enhanced NK killing of additional tumor types, including breast, non-small cell lung carcinoma, and chordoma. Conclusions: These studies support the combined use of NK- and ADCC-mediating agents with correctly timed PARP inhibition.
2018-12-11 | GSE121682 | GEO
Project description:PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal flu vaccine
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Project description:Despite substantial investments, tuberculosis remains one of the biggest challenges in public health. DNA-immunotherapy is increasingly being suggested as a possibility to assist conventional treatment of tuberculosis. This strategy could allow treatment to be more efficient, faster and with advantages and modulate the host immune response, as demonstrated by our group with DNAhsp65 vaccine (Silva, Bonato et al., Gene Therapy, 2005). Based on this evidences, we performed a microarray assay to stydy the functional effects of DNAhsp65 immunotherapy associated with conventional chemotherapy in murine experimental tuberculosis. Briefly, we used a murine model of tuberculosis treatment compost by DNAhsp65 vaccine, or rifampicin and isoniazid or both therapies combined and performed a comprehensive analysis of its effects on gene expression of hostM-bM-^@M-^Ys lung . Female BALB/c mice,8 weeks old, were inoculated with 1.0 M-CM-^W 10e5 viable bacilli of Mycobacterium tuberculosis H37Rv strain by the intra-tracheal route in a level III bio-safety room facility (day 0). They were segregated in four groups, described below, with three animals each one. Control M-bM-^@M-^S just infected and not treated. Immunotherapy - Thirty days after challenge, 50 M-NM-<g of plasmid with DNA-insert (DNAhsp65) was administered by intramuscular injection in 50 M-NM-<L of 25% saccharose solution in saline into each quadriceps muscle, in four occasions, and at 10-days intervals, performing a final dose of 400 M-NM-<g of plasmid DNAhsp65 per animal. Control infected mice received saline. Chemotherapy - Thirty days after infection, animals were treated with water solution of isoniazid (25 mg/Kg, Sigma-Aldrich, St. Louis, MO, USA) and rifampicin (20 mg/Kg, Sigma-Aldrich, St. Louis, MO, USA) daily, during 30 days, by gavage. Control infected mice received the same volume of water. Association - The therapeutical association consists of the both therapeutical approaches, as described above. Ten days after the end of treatments, mice were killed by cervical dislocation under mild anesthesia, and lungs were removed to RNA extraction.
2013-04-08 | E-GEOD-44825 | biostudies-arrayexpress