CTIM-28. MULTILAMELLAR MRNA LIPID PARTICLES INDUCE IMMUNOLOGIC REPROGRAMMING IN CANINE AND HUMAN GLIOBLASTOMA PATIENTS
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PROVIDER: S-EPMC9660927 | biostudies-literature | 2022 Nov
REPOSITORIES: biostudies-literature
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Project description:Abstract Ad-RTS-hIL-12 (Ad) is a gene therapy candidate for intratumoral (IT) delivery that conditionally expresses IL-12 (IL-12) under the transcriptional control of orally administered veledimex (V) acting via the RheoSwitch Therapeutic Systemâ gene switch. Increased PD-1 expression in samples of rGBM following Ad+V (ASCO 2020) supports combination immunotherapy with a PD-1 inhibitor. Phase 1 trials in rGBM of Ad+V as monotherapy and in combination with PD-1 inhibitor revealed encouraging safety and survival data. This phase 2 trial (NCT04006119) in adults with rGBM is evaluating safety and efficacy (overall survival) of Ad + V with pre/post-operative cemiplimab-rwlc (cemi) 350 mg IV, Days -7, 15, then Q3W; Ad single IT injection (2 x 1011 viral particles, day of resection (Day 0) /craniotomy); and V (20 mg PO, Days 0–14). Longitudinal sampling of serum assessed IL-12 and endogenous cytokines production. Anti-tumor effects were described upon preliminary review. Serial MRI evaluated tumor response. Follow-up described overall survival. Initial safety data (51 unique adverse reactions in 28 subjects) appeared similar to Ad+V and the cemi label, respectively, being manageable without synergistic toxicities and generally reversible. Of 35 SAEs reported in 18 subjects, 10 SAEs in 7 subjects were related to Ad+V. IL-12 and IFN-g levels increased after Ad+V administration peaking on Day 3 at 34 ± 11 pg/mL and 13 ± 5 pg/mL (mean ± SEM), respectively. Immune-mediated anti-tumor effects were noted, including a post-treatment biopsy to rule out progression which demonstrated an immune infiltrate consistent with pseudoprogression and loss of tumor cell heterogeneity suggesting immunoediting. Enrollment is anticipated to be completed in 2Q2020 with follow-up ongoing and initial survival data will be presented. V crossed the blood-brain barrier to produce functional IL-12. Controlled IL-12 therapy and cemi is a rational combination with initial data consistent with immune-mediated anti-tumor effects with a favorable safety profile.
| S-EPMC7650356 | biostudies-literature
Project description:Autoimmunity is energetically costly, but the impact of a metabolically active state on immunity and immune-mediated diseases is unclear. Ly6Chi monocytes are key effectors in CNS autoimmunity with an elusive role in priming naive autoreactive T cells. Here, we provide unbiased analysis of the immune changes in various compartments during cold exposure and show that this energetically costly stimulus markedly ameliorates active experimental autoimmune encephalomyelitis (EAE). Cold exposure decreases MHCII on monocytes at steady state and in various inflammatory mouse models and suppresses T cell priming and pathogenicity through the modulation of monocytes. Genetic or antibody-mediated monocyte depletion or adoptive transfer of Th1- or Th17-polarized cells for EAE abolishes the cold-induced effects on T cells or EAE, respectively. These findings provide a mechanistic link between environmental temperature and neuroinflammation and suggest competition between cold-induced metabolic adaptations and autoimmunity as energetic trade-off beneficial for the immune-mediated diseases.
| S-EPMC8570411 | biostudies-literature
Project description:Malignant glioma (MG), the most common primary brain tumor in adults, is extremely aggressive and uniformly fatal. Several treatment strategies have shown significant preclinical promise in murine models of glioma; however, none have produced meaningful clinical responses in human patients. We hypothesize that introduction of an additional preclinical animal model better approximating the complexity of human MG, particularly in interactions with host immune responses, will bridge the existing gap between these two stages of testing. Here, we characterize the immunologic landscape and gene expression profiles of spontaneous canine glioma and evaluate its potential for serving as such a translational model. RNA in situ hybridization, flowcytometry, and RNA sequencing were used to evaluate immune cell presence and gene expression in healthy and glioma-bearing canines. Similar to human MGs, canine gliomas demonstrated increased intratumoral immune cell infiltration (CD4+, CD8+ and CD4+Foxp3+ T cells). The peripheral blood of glioma-bearing dogs also contained a relatively greater proportion of CD4+Foxp3+ regulatory T cells and plasmacytoid dendritic cells. Tumors were strongly positive for PD-L1 expression and glioma-bearing animals also possessed a greater proportion of immune cells expressing the immune checkpoint receptors CTLA-4 and PD-1. Analysis of differentially expressed genes in our canine populations revealed several genetic changes paralleling those known to occur in human disease. Naturally occurring canine glioma has many characteristics closely resembling human disease, particularly with respect to genetic dysregulation and host immune responses to tumors, supporting its use as a translational model in the preclinical testing of prospective anti-glioma therapies proven successful in murine studies.
| S-EPMC5924594 | biostudies-literature
Project description:Abstract Chlorotoxin (CLTX), a peptide component of scorpion venom, exhibits selective and broad binding to glioblastoma (GBM) and other tumors with minimal activity against non-malignant cells. We have developed a novel CAR that utilizes CLTX as the tumor targeting domain. Preclinical studies established that CLTX-CAR T cells target GBM through recognition of a receptor complex incorporating membrane-bound matrix metalloprotease-2 (MMP-2). Here, we report initial clinical findings for our phase I trial evaluating safety and bioactivity of CLTX-CAR T cells in patients with MMP2+ recurrent GBM (NCT04214392). Weekly infusions of CLTX-CAR T cells are delivered locoregionally, either directly into the tumor cavity (ICT; Arm 1), or in combination with intracerebroventricular (ICV) delivery (dual ICT/ICV; Arm 2). At this interim analysis, four participants have received at least three cycles of CLTX-CAR T cells ICT (Arm 1; 3-8 cycles) at dose level 1 (DL1; 4M, 20M, 20M CAR T cells per cycle). None of the participants experienced dose limiting toxicity (DLT) during the DLT evaluation period of 28-days, although one participant experienced a serious adverse event of grade 3 cerebral edema, possibly attributed to CAR T cells. Overall, Arm 1-DL1 was well-tolerated, and the next patient cohort will be treated on Arm 2-DL1 (dual ICT/ICV; 8M, 40M, 40M CAR T cells per cycle), as per protocol design. Disease response was assessed by RANO, overall survival, and time to progression; three of four participants achieved a best response of stable disease. Liquid biopsy detected persistent CAR T cells in the tumor cavity throughout treatment, suggesting that the therapeutic cells are not immunogenic. Ongoing studies are evaluating biomarkers of response and resistance, including CAR T cell activation and inflammatory cytokines. This clinical study provides first-in-human evidence for the safety and feasibility of CLTX-CAR T cells as a new class of toxin-based CARs for treatment of GBM.
| S-EPMC8598614 | biostudies-literature
Project description:Abstract INTRODUCTION Vaccination with dendritic cells (DCs) fares poorly in primary and recurrent glioblastoma (GBM). Moreover, GBM vaccine trials are often underpowered due to limited sample size. METHODS To address these limitations, we conducted three sequential clinical trials utilizing Cytomegalovirus (CMV)-specific DC vaccines in patients with primary GBM. Autologous DCs were generated and electroporated with mRNA encoding for the CMV protein pp65. Serial vaccination was given throughout adjuvant temozolomide cycles, and 111Indium radiolabeling was implemented to assess migration efficiency of DC vaccines. Patients were followed for median overall survival (mOS) and OS. RESULTS Our initial study was the phase II ATTAC study (NCT00639639; total n=12) with 6 patients randomized to vaccine site preconditioning with tetanus-diphtheria (Td) toxoid. This led to an expanded cohort trial (ATTAC-GM; NCT00639639) of 11 patients receiving CMV DC vaccines containing granulocyte-macrophage colony-stimulating factor (GM-CSF). Follow-up data from ATTAC and ATTAC-GM revealed 5-year OS rates of 33.3% (mOS 38.3 months; CI95 17.5-undefined) and 36.4% (mOS 37.7 months; CI95 18.2-109.1), respectively. ATTAC additionally revealed a significant increase in DC migration to draining lymph nodes following Td preconditioning (P=0.049). Increased DC migration was associated with OS (Cox proportional hazards model, HR=0.820, P=0.023). Td-mediated increased migration has been recapitulated in our larger confirmatory trial ELEVATE (NCT02366728) of 43 patients randomized to preconditioning (Wilcoxon rank sum, Td n=24, unpulsed DC n=19; 24h, P=0.031 and 48h, P=0.0195). In ELEVATE, median follow-up of 42.2 months revealed significantly longer OS in patients randomized to Td (P=0.026). The 3-year OS for Td-treated patients in ELEVATE was 34% (CI95 19-63%) compared to 6% given unpulsed DCs (CI95 1-42%). CONCLUSION We report reproducibility of our findings across three sequential clinical trials using CMV pp65 DCs. Despite their small numbers, these successive trials demonstrate consistent survival outcomes, thus supporting the efficacy of CMV DC vaccine therapy in GBM.
| S-EPMC8598575 | biostudies-literature
Project description:Abstract The IMA950 peptide vaccine is composed of 9 HLA-A2-restricted peptides eluted from the surface of GBM samples and of two HLA class II-binding peptides1. It was tested in combination with poly-ICLC in patients with newly diagnosed GBM, demonstrating safety. The vaccine was able to elicit CD4 and CD8 T cell responses in the peripheral blood in the majority of patients, with however an overall low magnitude of T cell responses and suboptimal migration of elicited T cells to the brain, probably limiting clinical efficacy2,3. With the aim to improve homing of vaccine-specific T cell to the tumor, we are conducting a phase II clinical trial in patients with recurrent GBM testing the IMA950/poly-ICLC multipeptide vaccine with or without the anti-PD1 antibody pembrolizumab (NCT03665545). 24 patients will be included (12 patients in each arm) and pre- and post-vaccination tumor sample will be available, allowing assessing effect of the vaccine at the tumor site. The primary objective of this trial is safety of IMA950/poly-ICLC given together with pembrolizumab. Secondary objectives include (i) estimation of 6, 9 and 12-month progression-free survival (PFS), (ii) overall survival, (iii) analysis of patient quality of life and (iv) of the synergy/immunogenicity of IMA950/poly-ICLC and pembrolizumab. Immunomonitoring will include measure of vaccine-induced immune responses, IHC for immune cell markers, RNA/TCR sequencing and methylome analysis, to assess vaccine-induced T cell responses, immune modulation and potential signatures predictive of response. Thus far, 6 patients have been included (3 in each arm). Preliminary results show CD4 and CD8 T cell responses to the vaccine are detected in both groups in the peripheral blood. Analysis at the tumor site and comparison between arms will be performed once all patients have been included. 1. Dutoit, V. et al. Brain (2012); 2. Migliorini, D. et al. Neuro Oncol (2019); 3. Rampling, R. et al. Clin Cancer Res(2016)
| S-EPMC7650470 | biostudies-literature
Project description:Due to its increasing production, durability and multiple applications, plastic is a material we encounter every day. Small plastic particles from the μm to the mm range are classified as microplastics and produced for cosmetic and medical products, but are also a result of natural erosion and decomposition of macroplastics. Although being omnipresent in our environment and already detected in various organisms, less is known about the effects of microplastics on humans in general, or on vascular biology in particular. Here we investigated the effects of carboxylated polystyrene microplastic particles (PS, 1 μm) on murine endothelial and immune cells, which are both crucially involved in vascular inflammation, using in vitro and in vivo approaches. In vitro, PS induced adhesion molecule expression in endothelial cells with subsequent adhesion of leukocytes both under static and flow conditions. In monocytic cells, PS enhanced pro-inflammatory cytokine expression and release. Accordingly, administering mice with PS led to enhanced aortic expression of cytokines and adhesion molecules. Furthermore, we identified neutrophils as the PS-clearing blood leukocyte population. The findings from this study for the first time indicate polystyrene microplastic as a new environmental risk factor for endothelial inflammation.
| S-EPMC8598073 | biostudies-literature
Project description:Despite recent advancements in cancer therapies, glioblastoma multiforme (GBM) remains largely incurable. Curcumin (Cur), a natural polyphenol, has potent anticancer effects against several malignancies, including metastatic brain tumors. However, its limited bioavailability reduces its efficiency for treating GBM. Recently, we have shown that solid lipid Cur particles (SLCPs) have greater bioavailability and brain tissue penetration. The present study compares the efficiency of cell death by Cur and/or SLCPs in cultured GBM cells derived from human (U-87MG) and mouse (GL261) tissues. Several cell viability and cell death assays and marker proteins (MTT assay, annexin-V staining, TUNEL staining, comet assay, DNA gel electrophoresis, and Western blot) were investigated following the treatment of Cur and/or SLCP (25 μM) for 24-72 h. Relative to Cur, the use of SLCP increased cell death and DNA fragmentation, produced longer DNA tails, and induced more fragmented nuclear lobes. In addition, cultured GBM cells had increased levels of caspase-3, Bax, and p53, with decreases in Bcl2, c-Myc, and both total Akt, as well as phosphorylated Akt, when SLCP, rather Cur, was used. Our in vitro work suggests that the use of SLCP may be a promising strategy for reversing or preventing GBM growth, as compared to using Cur.
| S-EPMC5735327 | biostudies-literature
Project description:Canis lupus familiaris NAPEPLD, N-acyl phosphatidylethanolamine phospholipase D (NAPEPLD), mRNA
| PRJEB22251 | ENA
Project description:BackgroundPatients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy.MethodsUsing an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethasone dose that yielded the greatest statistical difference in overall survival (OS). The results were validated in a separate cohort treated in a single institution with TTFields and their T lymphocytes were correlated with OS.ResultsPatients who used dexamethasone doses >4.1 mg per day had a significant reduction in OS when compared with those who used ⩽4.1 mg per day, 4.8 vs 11.0 months respectively (χ(2)=34.6, P<0.0001) in the TTField-treated cohort and 6.0 vs 8.9 months respectively (χ(2)=10.0, P<0.0015) in the chemotherapy-treated cohort. In a single institution validation cohort treated with TTFields, the median OS of patients who used dexamethasone >4.1 mg per day was 3.2 months compared with those who used ⩽4.1 mg per day was 8.7 months (χ(2)=11.1, P=0.0009). There was a significant correlation between OS and T-lymphocyte counts.ConclusionsDexamethasone exerted profound effects on both TTFields and chemotherapy efficacy resulting in lower patient OS. Therefore, global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma.
| S-EPMC4506397 | biostudies-literature