scholarly journals Computational Verification of Large Logical Models—Application to the Prediction of T Cell Response to Checkpoint Inhibitors

2020 ◽  
Vol 11 ◽  
Author(s):  
Céline Hernandez ◽  
Morgane Thomas-Chollier ◽  
Aurélien Naldi ◽  
Denis Thieffry
Keyword(s):  
T Cell ◽  
Cell Response ◽  
Checkpoint Inhibitors ◽  
T Cell Response ◽  
Logical Models

Determinants of response to checkpoint inhibition in ovarian cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e17538-e17538
Author(s):  
Andrea Leigh Buras ◽  
Alexandra Martin ◽  
Jun Min Zhou ◽  
David C Boulware ◽  
Jose Conejo-Garcia ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Overall Survival ◽  
T Cell ◽  
Cell Response ◽  
Elispot Assay ◽  
Checkpoint Inhibitors ◽  
T Cell Response ◽  
Post Treatment ◽  
Combination Methods ◽  
Mixed Response

e17538 Background: Despite evidence that ovarian cancer (OC) is an immunogenic disease, single-agent checkpoint inhibitors have shown limited response. A clinical trial was conducted evaluating dose-dense paclitaxel and pembrolizumab in platinum-resistant OC. Our aim was to evaluate for biomarkers of response to this combination. Methods: Immunohistochemistry was performed to identify PD–L1 and tumor infiltrating lymphocytes (TIL) in pretreatment formalin fixed paraffin embedded tissue. We performed flow cytometry on matched blood to identify presence of immunosuppressive myeloid-derived suppressor cells (MDSCs) in circulation. We performed T-cell receptor (TCR) sequencing on tumor and matched blood to evaluate whether an oligoclonal or polyclonal immune response would be associated with outcomes. On selected patients we assessed peripheral T-cell responses to treatment using an interferon-ɣ enzyme-linked immunospot (IFN-ɣ ELISpot) assay between excellent and poor responders. Cox proportional hazards model was used to estimate hazards ratios (HR) for response in relation to each biomarker. Kaplan-Meier analysis and log-rank test were used to evaluate associations between progression free survival (PFS), overall survival (OS) and each biomarker. Results: Analysis was limited to 34 patients with tumor available and one RECIST response evaluation. Odds of response trended higher (OR = 4.1) in patients with PD-L1 (+) than patients with PD-L1 (-) tumors (p = 0.061). When restricting analysis to best response of CR/PR versus PD, the odds was 13.0 (p = 0.041). Patients with PD-L1(+) tumors had a HR for progression 0.56 (0.26-1.22; p = 0.144). Presence of TILs was classified as 0-3 (0-1 low, 2-3 high). High TIL presence was not associated with response, but was associated with improved OS and trend toward improved PFS; HR 0.29 (0.09-0.90, p = 0.022) and HR 0.47 (0.21-1.05, p = 0.06). Pre- and post-treatment levels of MDSCs were not associated with response or survival, though a trend was noted; a one unit increase in pretreatment MDSCs leads to 5% decrease in the odds of being responder. Immunoseq analysis of TCR repertoire pre- and post-treatment suggested that in increase in productive clonality was associated with increased odds of being a responder; this was not statistically significant. Notably, IFN-ɣ ELISpot assay demonstrated a significant T-cell response against neoantigens post-treatment in patients who had a partial response and long overall survival. Post treatment T-cell response showed a significantly mixed response to neoantigens in the patient analyzed who had progressive disease. Conclusions: Finding biomarkers predicting benefit from checkpoint inhibitors has been challenging. Though inconclusive, these data suggest biomarkers that may be associated with this combination. T-cell response to neoantigens in patients with response to treatment suggests neoantigens as a potential target for therapeutic direction.

Dendritic cell vaccination in metastatic uveal melanoma as compassionate treatment: Immunological and clinical responses.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e21024-e21024 ◽  
Author(s):  
Alvaro Moreira ◽  
Stefanie Gross ◽  
Ugur Uslu ◽  
Jan Doerrie ◽  
Mirko Kummer ◽  
...  
Keyword(s):  
T Cell ◽  
Dendritic Cell ◽  
Complete Remission ◽  
Uveal Melanoma ◽  
Cell Response ◽  
Checkpoint Inhibitors ◽  
Immune Monitoring ◽  
T Cell Response ◽  
Autologous Tumor ◽  
Clinical Responses

e21024 Background: Other than cutaneous melanoma, metastatic uveal melanoma (UM) is minimally responsive to checkpoint inhibitors. The prognosis remains very poor with mortality rates nearly unchanged over the last decades. The recently growing insight that immunotherapy significantly improves outcomes for cancer patients led to a re-emergence of vaccines including dendritic cell (DC) vaccines. Methods: We vaccinated an UM patient in a compassionate use setting and assessed the immunological and clinical responses. Based on this experience we performed individual compassionate treatments in other UM patients using DC loaded by peptide pulsing and/or mRNA transfection (autologous tumor RNA or RNA coding for tumor antigens). Results: The first patient was vaccinated in 2013 after a liver metastasis was resected and checkpoint blockade with ipilimumab was started. In 2014 the patient showed progression in the liver. We continued DC vaccination in shorter intervals and adapted antigen loading (with mRNA coding for an individual GNAQ driver mutation) accompanied by a further cycle of ipilimumab. Therapy resulted in complete remission of liver metastases, but the patient developed new skin metastases. Again the loading of DC was adapted (peptides of passenger mutations predicted after Next-Generation Sequencing) and infusions with pembrolizumab were started. Pathology from some regressing lesions showed a massive T cell infiltration and in parallel GNAQ mutation-specific T cells could be found in the patient’s blood. Skin metastases regressed and the patient is now free of detectable tumor after 65 months. Immune monitoring in the patient’s blood showed a vaccine-induced functional T cell response against the QNAQ-driver mutation. Three of other four patients are also still alive, one in complete remission under DC vaccination in combination with pembrolizumab, two of them showing measurable disease, and one deceased disease related after 28 months, resulting in a median OS of the five patients of 36.4 months. Immune monitoring in one of those patients showed a CD4+ and CD8+ INF-gamma T cell response against the autologous tumor RNA vaccine. No grade 3 or 4 toxicity occurred. Conclusions: The observed prolonged median OS and the fact that 2/5 patients remain disease-free is definitely encouraging. Vaccination immunotherapy with antigen-laden DC is a potential therapeutic option for patients with metastatic uveal melanoma. Combinations with checkpoint inhibitors proved promising, and should be further evaluated in clinical trials.

scholarly journals Recombinant single-cycle influenza virus as a new tool to augment antitumour immunity with immune checkpoint inhibitors

2021 ◽  
Author(s):  
Matheswaran Kandasamy
Keyword(s):  
Influenza Virus ◽  
T Cell ◽  
Cell Response ◽  
Checkpoint Inhibitors ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Lung Tumour ◽  
Antigen Delivery ◽  
Tumour Metastasis ◽  
Flu Virus

Virus-based tumour vaccines offer many advantages compared to other antigen delivering systems. They generate concerted innate and adaptive immune response, and robust CD8+T cell responses. We engineered a non-replicating pseudotyped influenza virus (S-FLU) to deliver the well-known cancer testis antigen, NY-ESO-1 (S-NY-ESO-1 FLU). Intranasal or intramuscular immunization of NY-ESO-1 S-FLU virus in mice elicited a strong NY-ESO-1 specific CD8+T cell response in lungs and spleen that resulted in the regression of NY-ESO-1 expressing lung tumour and subcutaneous tumour respectively. Combined administration with anti PD-1 antibody, NY-ESO-1 S-FLU virus augmented the tumour protection by reducing the tumour metastasis. We propose that the antigen delivery through S-FLU is highly efficient in inducing antigen specific CD8+T cell response and protection against tumour development in combination with PD-1 blockade.

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