scholarly journals IMMU-22. PHASE IB IMMUNOTHERAPY CLINICAL TRIAL WITH THE USE OF AUTOLOGOUS DENDRITIC CELLS PULSED WITH AN ALLOGENIC TUMORAL CELL LINES LYSATE IN PATIENTS WITH NEWLY DIAGNOSED DIFFUSE INTRINSIC PONTINE GLIOMA (DIPG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii364-iii364
Author(s):  
Andres Morales La Madrid ◽  
Jaume Mora ◽  
Ofelia Cruz ◽  
Vicente Santa-Maria Lopez ◽  
Sara Perez-Jaume ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Progression Free Survival ◽  
Diffuse Intrinsic Pontine Glioma ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Pontine Glioma ◽  
Peripheral Blood Mononuclear

Abstract BACKGROUND Diffuse intrinsic pontine glioma (DIPG) is a lethal condition, and therefore novel approaches are needed. Monocyte-derived dendritic cells (mDCs) pulsed with tumor antigens, as professional antigen-presenting cells, are a promising strategy for immunotherapy of invasive brain tumors. METHODS Our Ib pilot study explored the use of immunotherapy with mDCs for the treatment of newly diagnosed DIPG. Patient′s mDCs were extracted after irradiation and were primed with an allogenic tumor lysate from five patients with K27M-mutated DIPGs. The principal goal of this study was to establish the feasibility and safety of the intradermic administration of these mDC vaccines in patients with DIPG. In the absence of progression, patients received maintenance boosts of tumor lysate. Additionally, we evaluated the non-specific and antitumoral immune response generated in peripheral blood mononuclear cells (PBMC) and in cerebrospinal fluid (CSF) cells. RESULTS Nine patients were included in the study (2016–2018). Vaccines fabrication was feasible and administered in all cases without grade 3 or 4 toxicities. KLH (9/9 patients) and antitumor (8/9 patients) specific responses were identified in PBMC. Immunological responses were also confirmed in T-lymphocytes from the CSF of two patients. Twenty-four month overall survival and progression free survival was 33.3% (95 % CI 13.2% to 84.0 %) and zero, respectively. DISCUSSION These results demonstrate that mDC vaccination is feasible, safe, and generates a DIPG-specific immune response detected in PBMC and CSF. There was a trend in improved OS when compared to historic controls. This strategy shows a promising immunotherapy backbone for future combination schemas.

A randomized, double‑blind, controlled phase IIb study of the safety and efficacy of ICT‑107 in newly diagnosed patients with glioblastoma multiforme following resection and chemoradiation.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2107-TPS2107
Author(s):  
Elma S. Hawkins ◽  
Robert Aiken ◽  
James Chandler ◽  
Karen L. Fink ◽  
Michael J. Glantz ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Glioblastoma Multiforme ◽  
Mononuclear Cells ◽  
Systemic Disease ◽  
Progression Free Survival ◽  
Tumor Stem Cell ◽  
Karnofsky Performance Score ◽  
Newly Diagnosed ◽  
Double Blind ◽  
Peripheral Blood Mononuclear

TPS2107 Background: Tumor stem cells have been correlated with recurrence and clinical outcome in glioblastoma multiforme (GBM). ICT‑107 is an autologous vaccine consisting of the patient’s dendritic cells pulsed with 6 synthetic peptide CTL epitopes targeting the GBM tumor and tumor‑stem cell associated antigens MAGE‑1, HER‑2, AIM‑2, TRP‑2, gp100 and IL‑13Rα2. Phase I results showed a good safety profile and interesting clinical potential (ASCO, 2010, abs#2097 and ASCO, 2011, abs#2042) in 16 newly diagnosed GBM patients with a median progression-free survival (PFS) of 16.9 months (measured from surgery) and a median overall survival (OS) of 38.4 months. Methods: In this Phase II study eligible patients have newly diagnosed GBM and complete surgical resection or minimum residual tumor < 1 cm3, are HLA-A1 and/or HLA-A2 positive, older than 18, have Karnofsky Performance Score (KPS) of ≥ 70% and have adequate hematologic and chemistry parameters. Patients with a serious immune or autoimmune disorder or other systemic disease are excluded. Patients undergo apheresis to isolate peripheral blood mononuclear cells (PBMCs) to be used for preparation of study treatment (ICT‑107 and Control). Pre-study treatment consists of 6 weeks of concurrent temozolomide (TMZ) and radiation. After stratification by site and age, patients are randomized 2:1 to receive either ICT-107 or its matching control (autologous, unpulsed dendritic cells). Patients then receive induction ICT-107 or control once a week for four weeks. All patients subsequently receive maintenance TMZ for 5 days per month for 12 months. Booster vaccinations occur at Cycles 1, 3, 6 and 10, and every six months thereafter. The primary endpoint is OS and secondary endpoints include PFS, rates of OS and PFS at 6 months after surgery and every 3 months thereafter, safety and tolerability of ICT‑107, immune response to ICT-107 and predictors of response. 120 patients have been enrolled in this ongoing trial. It is expected that approximately 200 patients will be enrolled for screening with the intention to randomize at least 102 patients. The trial significance is alpha=0.025 one-sided.

The final report of a phase I trial of surgical resection with biodegradable carmustine (BCNU) wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with glioblastoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2084-2084
Author(s):  
Jeremy Rudnick ◽  
Jethro Lisien Hu ◽  
Anne Luptrawan ◽  
Mia Mazer ◽  
Chris Wheeler ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
Dendritic Cells ◽  
Survival Data ◽  
Final Report ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Tumoricidal Activity ◽  
Bcnu Wafer ◽  
Recurrent Gbm

2084 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers and have a modest impact to extend overall survival. We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu, and this is a presentation of the final results of our clinical trial. Methods: Patients with glioblastoma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis was used to isolate mononuclear cells which were differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Twenty three patient with glioblastoma received therapy including 8 with newly diagnosed disease (35%) and 15 with recurrent disease (65%) were evaluable. Immune response data is available for 20/23 patients although survival data is present for all. One grade 3 SAE of fever and chills was noted otherwise therapy was well tolerated. Within the newly diagnosed GBM cohort the median overall survival (OS) was 25.5 months (15,31+), and within the recurrent GBM cohort, the median OS was 16 months (8,23+). Among the recurrent GBM an increase of >1.5 X baseline interferon gamma production post vaccination was associated with a prolonged median OS 22 months (8,40) in 4/12 patients versus 17 months (9,27) in 8/12 patients. Conclusions: We were able to generate an immune response in 25% of patients which is lower than what we have seen in previous trials and suggests a limited synergy with local control. However, within the recurrent GBM cohort we did find prolonged survival in both groups with an increased survival noted in immune responders demonstrating the potential for this therapy.

Biomarkers and Correlative Endpoints for Immunotherapy Trials: What Can We Learn in Lung Cancer from Other Tumor Types?

2013 ◽  
pp. e287-e293
Author(s):  
Michael A. Morse ◽  
Takuya Osada ◽  
Amy Hobeika ◽  
Sandip Patel ◽  
H. Kim Lyerly
Keyword(s):  
Lung Cancer ◽  
Immune Response ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Progression Free Survival ◽  
Cell Types ◽  
Phase Iii ◽  
Peripheral Blood Mononuclear ◽  
Clinical Endpoints ◽  
Cytokine Flow Cytometry

Immunotherapies for lung cancer are reaching phase III clinical trial, but the ultimate success likely will depend on developing biomarkers to guide development and choosing patient populations most likely to benefit. Because the immune response to cancer involves multiple cell types and cytokines, some spatially and temporally separated, it is likely that multiple biomarkers will be required to fully characterize efficacy of the vaccine and predict eventual benefit. Peripheral blood markers of response, such as the ELISPOT assay and cytokine flow cytometry analyses of peripheral blood mononuclear cells following immunotherapy, remain the standard approach, but it is increasingly important to obtain tissue to study the immune response at the site of the tumor. Earlier clinical endpoints such as response rate and progression-free survival do not correlate with overall survival demonstrated for some immunotherapies, suggesting the need to develop other intermediary clinical endpoints. Insofar as all these biomarkers and surrogate endpoints are relevant in multiple malignancies, it may be possible to extrapolate findings to immunotherapy of lung cancer.

scholarly journals Nanoparticle-Delivered HIV Peptides to Dendritic Cells a Promising Approach to Generate a Therapeutic Vaccine

Pharmaceutics ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 656 ◽  
Author(s):  
Alba Martín-Moreno ◽  
José L. Jiménez Blanco ◽  
Jamie Mosher ◽  
Douglas R. Swanson ◽  
José M. García Fernández ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Therapeutic Vaccine ◽  
Peptide Delivery ◽  
Antigenic Peptide ◽  
Hydroxyl Groups ◽  
Antigenic Peptides ◽  
Peripheral Blood Mononuclear ◽  
Hiv 1

Finding a functional cure for HIV-1 infection will markedly decrease the social and economic burden of this disease. In this work, we have taken advantage of the antigen presenting cell role of human dendritic cells (DCs) to try to induce an immune response to HIV-derived peptide delivered to DCs using two different polycationic nanoparticles: a G4 PAMAM dendrimer modified to a 70/30 ratio of hydroxyl groups/amines and a cyclodextrin derivative. We have studied peptide delivery using a fluorescence peptide and have studied the immune response generation by cytokine determination and flow cytometry. We have found a robust delivery of the antigenic peptide to DCs and activated dendritic cell-mediated peripheral blood mononuclear cells (PBMCs) proliferation using the mixed lymphocyte reaction. However, no expression of markers indicating activation of either B or T lymphocytes was observed. Moreover, the release of the pro-inflammatory cytokine TNF-α or IL-2 was only observed when DCs treated with either the dendrimer or the dendriplex containing the peptide. Antigenic peptide delivery to DCs is a promising approach to generate a vaccine against HIV-1 infection. However, more studies, including the simultaneous delivery of several antigenic peptides from different viral proteins, can markedly improve the immune response.

Dendritic Cells Tranfected with CML-28 cDNA Induce CML28-Specific Cytotoxic T Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 5248-5248
Author(s):  
Hongsheng Zhou ◽  
Donghua Zhang ◽  
Yaya Wang ◽  
Yi Xiao ◽  
Wei Huang ◽  
...  
Keyword(s):  
Immune Response ◽  
Dendritic Cells ◽  
Tumor Antigen ◽  
Mononuclear Cells ◽  
Cytotoxic T Cells ◽  
Lymphocytic Leukemia ◽  
Myelogenous Leukemia ◽  
Target Cells ◽  
Peripheral Blood Mononuclear

Abstract Dendritic cells (DC) are the most potent antigen-presenting cells known; the use of DC loaded with tumor antigen is one of the most promising approaches to induce specific immune response. CML28 is an attractive candidate. According to the published article and our following study, CML28 is a broadly immunogenic antigen, which is overexpessed in leukemia cells, including acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL) and chronic myelogenous leukemia (CML); but not in normal hematopoietic tissues or other normal tissue, with the exception of testis. In our study, DCs were generated from peripheral blood mononuclear cells (PBMC) by culture with GM-CSF, IL-4 and TNF-α. The full CML28 cDNA was amplified from K562 cell and then cloned into plasmid pcDNA3.1 HisA. Load DC with the constructed plasmid pcDNA3.1 HisA-CML28 by electroporation. The results of FACS analysis and Western Blot respectively demonstrate that the plasmid transfected DC retain immunophenotypical characteristics and can express the fusion protein CML28-His. Cytotoxic T lymphocytes (CTL) were generated from autologous PBMC stimulated by the transfected DCs. Cytoxicity assay in vitro revealed that CTL can recognize and lyse CML28-expressing target cells, such as the transfected DCs but not normal autologous DCs, which show that the plasmid pcDNA 3.1 HisA-CML28 transfected DC can induce CML28-specific CTL. Our studies demonstrate that CML28 can be a promising target of tumor antigen for leukemia-specific immunotherapy and DC loaded with CML28 tumor antigen can be a promising tool to induce specific anti-leukemia immune response.

scholarly journals EFFECT OF ANTIGEN-PRIMED DENDRITIC CELL-BASED IMMUNOTHERAPY ON ANTITUMOR CELLULAR IMMUNE RESPONSE IN PATIENTS WITH COLORECTAL CANCER

2021 ◽  
Vol 23 (4) ◽  
pp. 963-968
Author(s):  
V. V. Kurilin ◽  
E. V. Kulikova ◽  
A. V. Sokolov ◽  
Yu. A. Kozhevnikov ◽  
D. D. Blinova ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Immune Response ◽  
Dendritic Cells ◽  
Cancer Patients ◽  
Peripheral Blood ◽  
T Regulatory Cells ◽  
Mononuclear Cells ◽  
Tumor Antigens ◽  
Autologous Tumor ◽  
Oncological Diseases

The problem of treatment of oncological diseases is one of the most urgent for modern medicine. Existing treatment approaches are based on a surgical, radiation, chemotherapeutic approach, and the use of immunotherapy methods aimed at markers and / or specific antigens of tumors.Approaches based on the mechanisms of cellular and molecular regulation of a specific antitumor immune response have shown their high efficiency (for example, antibodies against HER2 in breast cancer), but these approaches have a number of side and undesirable effects that limit their application. Considering the central role of the mechanisms of recognition of tumor antigens and their presentation to cytotoxic cells in effective tumor elimination, it is important to search for and develop approaches to restore these mechanisms in cancer pathology. Because maturation, differentiation of dendritic cells and their main function are impaired in oncological diseases, scientific research is underway to obtain mature dendritic cells and restore the natural way of antigen presentation to effector cells.The work carried out limited clinical studies (13 patients with colorectal cancer), a previously developed protocol for obtaining antigen-primed dendritic cells of patients with colorectal cancer and their joint culture with autologous mononuclear cells in vitro. From the peripheral blood of cancer patients, dendritic cells primed with autologous tumor antigens (tumor cell lysate), which were co-cultured with their own mononuclear cells in the presence of immunoregulatory cytokines (IL-12 and IL-18). The resulting cell suspensions were purified from the culture medium and cytokines and used for a course of immunotherapy (weekly, 20-30 million cells intravenously, dropwise), consisting of 3-5 injections. At different periods of immunotherapy (before the start of the course of immunotherapy, 3 months and 6 months after the end of immunotherapy), immunological parameters were assessed in the peripheral blood of patients (immunogram (CD3+, CD3+CD4+, CD3+CD8+, CD19, CD16+CD56+-cells), the relative content of T-regulatory cells (CD4+CD25+FoxP3+-cells), myeloid suppressor cells (CD14+HLA-DR- cells)) and assessed the cytotoxic activity of peripheral blood mononuclear cells of patients against cells of the tumor line of human colorectal cancer (Colo-320).The data obtained showed that in cancer patients, against the background of ongoing immunotherapy, the indicator of the direct cytotoxic test significantly increases, which makes it possible to judge the effective stimulation of the antitumor cellular immune response. This is also indicated by an increase in the relative number of CD16+CD56+-cells (NK-cells) 3 months after immunotherapy. The study of immunosuppressive cells in the blood of cancer patients showed the absence of significant changes in CD14+HLA-DR- -cells and T-regulatory cells.Thus, limited clinical studies of immunotherapy of patients with colorectal cancer based on autologous dendritic cells primed with lysate of autologous tumor cells demonstrated an increase in the antitumor cytotoxic immune response. 

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