scholarly journals Blood Eosinophilia Is an on-Treatment Biomarker in Patients with Solid Tumors Undergoing Dendritic Cell Vaccination with Autologous Tumor-RNA

Pharmaceutics ◽  
2020 ◽  
Vol 12 (3) ◽  
pp. 210 ◽  
Author(s):  
Alvaro Moreira ◽  
Michael Erdmann ◽  
Ugur Uslu ◽  
Verona Vass ◽  
Gerold Schuler ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Dendritic Cell Vaccination ◽  
Autologous Tumor ◽  
Blood Eosinophilia ◽  
Significant Difference ◽  
Eosinophil Counts ◽  
Tumor Mrna

Background: The approvals of immune checkpoint inhibitors for several cancer types and the rapidly growing recognition that T cell-based immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of cancer vaccines, including dendritic cell (DC)-based immunotherapy. Blood and tissue biomarkers to identify responders and long-term survivors and to optimize cost and cost-effectiveness of treatment are greatly needed. We wanted to investigate whether blood eosinophilia is a predictive biomarker for patients with solid tumors receiving vaccinations with DCs loaded with autologous tumor-RNA. Methods: In total, 67 patients with metastatic solid tumors, who we treated with autologous monocyte-derived DCs transfected with total tumor mRNA, were serially analyzed for eosinophil counts and survival over the course of up to 14 years. Eosinophilic counts were performed on peripheral blood smears. Results: Up to 87% of the patients treated with DC-based immunotherapy experienced at least once an eosinophilia of ≥ 5% after initiation of therapy; 61 % reached levels of ≥ 10% eosinophils, and 13% of patients showed eosinophil counts of 20% or above. While prevaccination eosinophil levels were not associated with survival, patients with blood eosinophilia at any point after initiation of DC-based immunotherapy showed a trend towards longer survival. There was a statistically significant difference for the patients with eosinophil counts of 20% or more (p = 0.03). In those patients, survival was prolonged to a median of 58 months (range 2–111 months), compared to a median of 20 months (range 0–119 months) in patients with lower eosinophil counts. In 12% of the patients, an immediate increase in eosinophil count of at least 10 percentage points could be detected after the first vaccine, which also appeared to correlate with survival (65 vs. 24 months; p = 0.06). Conclusion: Blood eosinophilia appears to be an early, on-therapy biomarker in patients with solid tumors undergoing vaccination with RNA-transfected DC, specifically autologous tumor mRNA-transfected DC vaccines, and it correlates with long-term patient outcome. Eosinophilia should be systematically investigated in future trials.

scholarly journals The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 666 ◽  
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Athanasios G. Papavassiliou ◽  
Michalis V. Karamouzis
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Epigenetic Alterations ◽  
Primary Resistance ◽  
Cellular Processes ◽  
Mutational Burden ◽  
Number Of Patients ◽  
Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

scholarly journals Comparison of Glioma-associated Antigen Peptide-loaded Versus Autologous Tumor Lysate-loaded Dendritic Cell Vaccination in Malignant Glioma Patients

2013 ◽  
Vol 36 (2) ◽  
pp. 152-157 ◽  
Author(s):  
Robert M. Prins ◽  
Xiaoyan Wang ◽  
Horacio Soto ◽  
Emma Young ◽  
Dominique N. Lisiero ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Malignant Glioma ◽  
Dendritic Cell Vaccination ◽  
Autologous Tumor ◽  
Tumor Lysate ◽  
Antigen Peptide

Long-term followup of bi-shRNAfurin and GMCSF augmented autologous tumor cell immunotherapy treated colorectal cancer patients in phase I and IIa studies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15100-e15100
Author(s):  
Minal A. Barve ◽  
Anton M. Melnyk ◽  
Luisa Manning ◽  
Gladice Wallraven ◽  
Martin Birkhofer ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Tumor Cell ◽  
Phase I ◽  
Checkpoint Inhibitors ◽  
Disease Free Survival ◽  
Stage Iii ◽  
Autologous Tumor Cell ◽  
Autologous Tumor ◽  
Disease Free

e15100 Background: Vigil is an immuno-stimulatory autologous tumor cell therapy, which uses patient tumor cells transfected with a plasmid encoding genes to upregulate GM-CSF and down regulate TGFβ 1&2. It is administered monthly by intra-dermal injection. In Phase I and IIa trials patients with over 19 different tumor types were safely treated. Rapid and durable systemic immune activation was demonstrated using an IFNγ ELISPOT assay. Methods: Data are summarized for a group of 9 patients with advanced colorectal cancer followed for up to 3.5 years. Results: Six women and 3 men with Stage III or IV colorectal cancer were treated between March, 2010 and September, 2013. Six patients received Vigil as a monotherapy and 3 in combination with FOLFOX chemotherapy. Results: Demographics and treatment details are displayed below. Two patients with Stage III disease received combination therapy after complete surgical resection, and remain disease free over 3 years from surgery. The patients received 9 and 12 Vigil injections with a brisk and durable ELISPOT reactions. Conclusions: Preliminary results suggest that Vigil can be combined safely with FOLOX chemotherapy and still elicit a systemic immune response. Long term disease free survival has been observed in several patients justifying further exploration of this combination. More detailed molecular characterization and neoantigen identification of patient tumor will be undertaken in future studies. A combination with immune checkpoint inhibitors may also be explored. [Table: see text]

Autologous tumor lysate-pulsed dendritic cell vaccination therapy after resection of stage IIA (T2N0, T3N0) esophageal cancer: An analysis of immunological responses.

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 96-96
Author(s):  
Yasuyoshi Sato ◽  
Koichi Yagi ◽  
Kazuhiko Mori ◽  
Hirokazu Matsushita ◽  
Kazuhiro Kakimi ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Dendritic Cell ◽  
Immune Responses ◽  
R0 Resection ◽  
Dendritic Cell Vaccination ◽  
Autologous Tumor ◽  
Tumor Lysate ◽  
Binding Prediction ◽  
Dc Vaccines ◽  
Vaccination Therapy

96 Background: Immunotherapy using active immunization of tumor associated antigens has been expected to improve the prognosis of malignant tumor patients. We conducted phase I trial to investigate safety and efficacy of autologous tumor lysate-pulsed dendritic cell (DC) vaccination therapy after resection for esophageal cancer. We already reported the clinical results for enrolled 11 patients. All patients completed the protocol therapy and no treatment-related adverse events more than grade 3 was observed (primary endpoint), and recurrence rate within 2 years was 18% (n = 2). In this study, we further analyzed the immune responses in vaccinated patients. Methods: Patients with stage IIA (T2N0 or T3N0, UICC TNM classification 6th edition) esophageal cancer after curative (R0) resection were eligible. Tumor lysate we used for DC vaccines potentially contains mutated proteins (neoantigens) derived from somatic mutations. Patients received DC vaccines (more than 5.0×106 cells) 6 times every 2 weeks. We evaluated neutrophil-to-lymphocyte ratio (NLR) in each patient from CRF data. We identified candidate neoantigens by next generation sequencing and MHC class I binding prediction algorism. We screened the immune responses against those neoantigens using HLA transgenic mice and healthy human PBMCs. Results: Absolute lymphocyte counts, absolute neutrophil counts and NLR were not specifically different between patients with or without recurrence. For specific immune responses, we observed the reactivity in 6 out of 59 candidate neoepitopes identified from two patients in HLA transgenic mouse system. Two out of 6 peptides displayed reactivity in human healthy PBMCs. Conclusions: We analyzed immune responses to predicted candidate neoantigens. We are now investigating immune landscape in the tumor using RNA sequencing data and its relevance to the antigen responses. Clinical trial information: UMIN000002837.

Initial phase I/IIa trial results of an autologous tumor lysate, particle-loaded, dendritic cell (TLPLDC) vaccine in patients with solid tumors

Vaccine ◽  
2018 ◽  
Vol 36 (23) ◽  
pp. 3247-3253 ◽  
Author(s):  
Garth S. Herbert ◽  
Timothy J. Vreeland ◽  
Guy T. Clifton ◽  
Julia M. Greene ◽  
Doreen O. Jackson ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Initial Phase ◽  
Autologous Tumor ◽  
Tumor Lysate
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