scholarly journals Dendritic Cell Vaccination of Glioblastoma: Road to Success or Dead End

2021 ◽  
Vol 12 ◽  
Author(s):  
Angeliki Datsi ◽  
Rüdiger V. Sorg
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Multimodal Therapy ◽  
Primary Brain Tumor ◽  
Active Immunotherapy ◽  
Dendritic Cell Vaccination ◽  
Full Potential ◽  
Therapeutic Approaches ◽  
Dead End ◽  
Immunosuppressive Microenvironment

Glioblastomas (GBM) are the most frequent and aggressive malignant primary brain tumor and remains a therapeutic challenge: even after multimodal therapy, median survival of patients is only 15 months. Dendritic cell vaccination (DCV) is an active immunotherapy that aims at inducing an antitumoral immune response. Numerous DCV trials have been performed, vaccinating hundreds of GBM patients and confirming feasibility and safety. Many of these studies reported induction of an antitumoral immune response and indicated improved survival after DCV. However, two controlled randomized trials failed to detect a survival benefit. This raises the question of whether the promising concept of DCV may not hold true or whether we are not yet realizing the full potential of this therapeutic approach. Here, we discuss the results of recent vaccination trials, relevant parameters of the vaccines themselves and of their application, and possible synergies between DCV and other therapeutic approaches targeting the immunosuppressive microenvironment of GBM.

scholarly journals NK Cell-Based Immunotherapy and Therapeutic Perspective in Gliomas

2021 ◽  
Vol 11 ◽  
Author(s):  
Changqing Pan ◽  
You Zhai ◽  
Guanzhang Li ◽  
Tao Jiang ◽  
Wei Zhang
Keyword(s):  
Nk Cells ◽  
Nk Cell ◽  
Primary Brain Tumor ◽  
Therapeutic Approaches ◽  
Independent Manner ◽  
Clinical Prognosis ◽  
Cell Based Therapy ◽  
Current Therapies ◽  
Immunosuppressive Microenvironment ◽  
Therapeutic Perspective

Glioma is the most common malignant primary brain tumor diagnosed in adults. Current therapies are unable to improve its clinical prognosis, imposing the need for innovative therapeutic approaches. The main reason for the poor prognosis is the great cell heterogeneity of the tumor and its immunosuppressive microenvironment. Development of new therapies that avoid this immune evasion could improve the response to the current treatments. Natural killer (NK) cells are an intriguing candidate for the next wave of therapies because of several unique features that they possess. For example, NK cell-based immunotherapy causes minimal graft-versus-host disease. Cytokine release syndrome is less likely to occur during chimeric antigen receptor (CAR)-NK therapy, and CAR-NK cells can kill targets in a CAR-independent manner. However, NK cell-based therapy in treating glioma faces several difficulties. For example, CAR molecules are not sufficiently well designed so that they will thoroughly release functioning NK cells. Compared to hematological malignancies, the application of many potential NK cell-based therapies in glioma lags far behind. Here, we review several issues of NK cells and propose several strategies that will improve the efficacy of NK cell-based cancer immunotherapy in the treatment of glioma.

DENDRITIC CELL VACCINATION IN PATIENTS WITH MALIGNANT GLIOMAS

Neurosurgery ◽  
2006 ◽  
Vol 59 (5) ◽  
pp. 988-1000 ◽  
Author(s):  
Steven de Vleeschouwer ◽  
Marion Rapp ◽  
Rüdiger V. Sorg ◽  
Hans-Jakob Steiger ◽  
Walter Stummer ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Immune Modulation ◽  
Malignant Gliomas ◽  
Tumor Biology ◽  
Active Immunotherapy ◽  
Dendritic Cell Vaccination ◽  
Dismal Prognosis ◽  
Clinical Responses ◽  
Potential Benefits ◽  
Small Clinical Trials

Abstract OBJECTIVE Despite recent advances in neurosurgical resection techniques, radiation therapy, and chemotherapy, malignant gliomas continue to have a dismal prognosis because relapses are unavoidable. METHODS Dendritic cell vaccination has recently emerged as a promising type of active immunotherapy that aims to induce rather than transfer specific antitumor immune responses in patients. Active immunotherapy is the only type of immunotherapy able to induce immunological memory. RESULTS Although an increasing number of small clinical trials show safety, feasibility, and immunological and clinical responses, this technology requires further clarification of some critical basic and clinical issues before its presumed place in the treatment of malignant gliomas can be specified. This article addresses the basic and clinical pitfalls that, more than with conventional therapies, may interfere with the potential benefits of this approach. CONCLUSION Considering the particular mechanisms involved in the immune modulation of tumor biology using dendritic cell-based vaccinations, the authors summarize the arguments in favor of a further, appropriate assessment of this technology.

Clinical and Immunological Response Following hTERT/Survivin mRNA-Loaded Dendritic Cell Vaccination Combined With Ex-Vivo Expanded T Cell Transfer In Melanoma Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4487-4487
Author(s):  
Gunnar Kvalheim ◽  
Iris Bigalke ◽  
Siri Torhaug ◽  
Marianne Lundby ◽  
Camilla Mollat ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Dendritic Cell ◽  
Ex Vivo ◽  
Dendritic Cell Vaccination ◽  
Cell Injection ◽  
Blood Samples ◽  
Melanoma Patients ◽  
T Cell Transfer

New immunotherapy strategies have recently been developed combining peptide or dendritic cell (DC) vaccination with infusion of vaccine-primed and ex vivo expanded T cells. The hypothesis is that adoptive transfer of ex vivo expanded tumor specific T cells can improve progression-free and overall survival by restoring anti-tumor immunity. In a phase I/II clinical trial on malignant melanomas stage IV patients received DC vaccination prior to transfer of ex vivo expanded T cells. Our strategy was to target hTERT and survivin since both is highly expressed in most cancers. The vaccine consisted of autologous DCs loaded with hTERT and survivin mRNA. Prior to each DC vaccination the patients received 5 days of Temozolomide treatment to reduce the number of regulatory T cells (Treg). Following 2 monthly DC vaccinations, blood samples were tested for immune response against hTERT and survivin overlapping peptides. Immune responders were offered injection of T cells. The Elutra fraction of T cells was depleted of Treg using Dynabeads CD25 prior to expansion with Dynabeads CD3/CD28 in a WAVE bioreactor. After 10 days the beads were removed and T cells were washed. 3x1010 expanded T cells were injected fresh and DC vaccination was continued. Prior to T cell infusion, the patients received non-myeloablative conditioning with Fludarabine and Cyclophosphamide Here we present the results from three patients receiving expanded T cells. Immune response against hTERT and survivin peptides were detected in blood samples from 7 to 11 weeks of DC vaccination. After 4-7 months of DC vaccination the T cells were expanded for 10 days prior to injection. DC vaccination was continued 1 day after T cell injection. Infused T cells expanded significantly in vivo and in two of the three patients currently tested both patients showed response against hTERT and survivin peptides. Blood samples taken monthly after T cell injection demonstrated immune response against the same peptides. In one of patients the number of Treg was high (> 4%) before and during vaccination and returned to low numbers (<1%) after T cell injection. Since these findings might explain the beneficial effect of the vaccination we are currently investigating if the number of Tregs in blood show the same profile in the two other patients. Progression free survival (PFS) in the three patients was 31,20 and 11 months respectively. Patients with the shortest PFS relapsed very shortly after the T-cell infusion in spite of an objective immunresponse following the last DC vaccine. Metastatic melanoma patients included in this study given DC vaccines without T-cells had a median PFS of 7 months (3-13). We therefore conclude that dendritic cell vaccination combined with ex-vivo expanded T cell transfer can be an efficient immunotherapy strategy in melanoma patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals CTIM-18. DENDRITIC CELL VACCINATION IN CONJUNCTION WITH ADJUVANT TLR-3 AGONIST ADMINISTRATION ENHANCES PRO-INFLAMMATORY IMMUNE RESPONSES AND IS ASSOCIATED WITH EXTENDED SURVIVAL IN MALIGNANT GLIOMA PATIENTS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii36-ii37
Author(s):  
Carolina Chavez ◽  
Richard Everson ◽  
Joey Orpilla ◽  
Alexander Lee ◽  
Sara Khattab ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cell ◽  
Immune Responses ◽  
Malignant Glioma ◽  
Dendritic Cell Vaccination ◽  
Autologous Tumor ◽  
Tumor Lysate ◽  
Who Grade ◽  
Pulsed Dc ◽  
Extended Survival

Abstract Despite recent advances with immunotherapy in other tumor types, malignant glioma patients have not shown a therapeutic benefit, potentially due to the insufficient activation of an immune response. We and others have documented immune responses and extended survival following dendritic cell (DC) vaccination in small clinical trials. In this Phase II clinical trial, we randomized malignant glioma patients to receive autologous tumor lysate pulsed DC vaccination with and without adjuvant toll-like receptor (TLR) agonists. Treatment with TLRs in cancer patients has been shown to activate the innate immune response by inducing the expression of pro-inflammatory factors and cytokines. Twenty-three patients with WHO grade III or IV glioma received three intradermal injections of autologous tumor lysate-pulsed DC on days 0, 14, and 28 in conjunction with either a placebo adjuvant, TLR-7 agonist (Resiquimod), or TLR-3 agonist (Poly ICLC). We observed a difference in survival for the DC-vaccinated patients who received adjuvant Poly ICLC treatment of 54 months over adjuvant placebo (20 months) and adjuvant Resiquimod (28 months) groups (P = 0.04). The patient cohorts were balanced for WHO grade, IDH mutation, and MGMT methylation status. Mass cytometry (CyTOF) analysis of patient peripheral blood mononuclear cells (PBMCs) showed increased levels of the monocyte populations CD14+CD16- and CD14dimCD16+ after Poly ICLC treatment. In addition, gene expression analysis of the PBMC populations using single cell RNA sequencing demonstrated increased expression of pro-inflammatory genes after adjuvant Poly ICLC and Resiquimod treatment. Nonetheless, a greater fold change increase and a larger pro-inflammatory repertoire was observed in the Poly ICLC group. Overall, these findings demonstrate that adjuvant Poly ICLC increases the number of circulating monocytes and induces a large pro-inflammatory response, which may account for the survival differences observed over adjuvant Resiquimod and placebo.

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