GEP of PMBCs during treatment with a gene-modified allogeneic tumor cell vaccine in advanced renal cell cancer (RCC) patients
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE51490 | GEO | 2014/09/24
SECONDARY ACCESSION(S): PRJNA223296
REPOSITORIES: GEO
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Project description:Tumor-induced immunosuppression remains a major challenge for immunotherapy of cancer patients. To further elucidate why an allogeneic gene-modified (Interleukin-7(IL-7)/CD80 co-transfected) renal cell cancer vaccine failed to induce clinically relevant TH1-polarized immune responses, peripheral blood mononuclear cells (PBMCs) from enrolled study patients were analyzed by gene expression profiling (GEP) both prior and after vaccination. At baseline before vaccination, a profound downregulation of gene signatures associated with antigen presentation, immune response/T cells, cytokines/chemokines and signaling/transcription factors was observed in renal cell cancer patients as compared to healthy controls. Vaccination led to a partial reversion of preexisting immunosuppression, however, GEP indicated that an appropriate TH1 polarization could not be achieved. Most interestingly, our results suggest that the nuclear factor kappa B (NF-M-NM-:B) signaling pathway might be involved in the impairment of immunological responsiveness and the observed TH2 deviation. In summary, our data suggest that GEP might be a powerful tool for the prediction of immunosuppression and the monitoring of immune responses within immunotherapy trials. Gene expression was profiled using Affymetrix Human Gene v1.1 ST microarrays in the following settings: 9 RCC patients were profiled before and after vaccination (pairs of measurements) and additionally 9 healthy control samples were profiled.
2014-09-24 | E-GEOD-51490 | biostudies-arrayexpress
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME. Between July 2008 and September 2012, 59 patients were enrolled into an ongoing study of an irradiated, allogeneic GM-CSF-secreting pancreatic tumor vaccine (GVAX) administered intradermally either alone or in combination with immune modulatory doses of cyclophophamide (Cy) as neoadjuvant and adjuvant treatment for patients with resectable pancreatic ductal adenocarcinoma (PDAC). Patients were randomized 1:1:1 to 3 treatment arms. In Arm A, patients received GVAX alone; in Arm B, patients received GVAX plus a single intravenous dose of Cy at 200 mg/m2 1 day prior to each vaccination; in Arm C, patients received GVAX plus oral Cy at 100 mg once daily for 1 week on and 1 week off. Up to 6 GVAX treatments were administered and all of the patients remained in their initial treatment arms throughout the duration of the study. All 59 of the patients received the 1st GVAX treatment 2 weeks +/-4 days prior to surgery. Formalin-fixed paraffin-embedded (FFPE) tissue blocks of surgically resected PDAC were obtained from the pathology archive. FFPE tissue blocks from each subject were stained by H&E immediately before the vaccine therapy-induced lymphoid aggregates were microdissected . To better understand the functional status of these vaccine therapy induced lymphoid aggregate structures, gene microarray analysis on RNA isolated from microdissected lymphoid aggregates was performed. Gene expression was compared among samples grouped according to patient overall survival, post-vaccination induction of enhanced mesothelin-specific T cell responses in peripheral blood lymphocytes (PBL), and the intratumoral CD8+ T effector to FoxP3+ Treg ratio. Post-vaccination induction of enhanced mesothelin-specific T cell responses has been reported to correlate with longer survival in patients treated with Panc GVAX.
2014-08-05 | E-GEOD-52171 | biostudies-arrayexpress
Project description:Personalized peptide vaccination (PPV) is one of the attractive immunotherapy with high immune-boosting effects. However, as with most therapeutic agents, PPV does not elicit beneficial immune and/or clinical responses in all of the treated cancer patients. To identify prognostic biomarker for the selection of patients most likely to benefit from PPV, we conducted whole genome gene expression analysis of prevaccination peripheral blood mononuclear cells (PBMCs) of 112 castration-resistant prostate cancer (CRPC) patients.
2015-02-01 | GSE53922 | GEO
Project description:Predicting Outcomes of Prostate Cancer Immunotherapyby Personalized Mathematical Models
Natalie Kronik1¤, Yuri Kogan1, Moran Elishmereni1, Karin Halevi-Tobias1, Stanimir Vuk-Pavlovic ́2.,Zvia Agur1*.1Institute for Medical BioMathematics, Bene Ataroth, Israel,2College of Medicine, Mayo Clinic, Rochester, Minnesota, United States of America
Abstract
Background:Therapeutic vaccination against disseminated prostate cancer (PCa) is partially effective in some PCa patients.We hypothesized that the efficacy of treatment will be enhanced by individualized vaccination regimens tailored by simplemathematical models.Methodology/Principal Findings:We developed a general mathematical model encompassing the basic interactions of avaccine, immune system and PCa cells, and validated it by the results of a clinical trial testing an allogeneic PCa whole-cellvaccine. For model validation in the absence of any other pertinent marker, we used the clinically measured changes inprostate-specific antigen (PSA) levels as a correlate of tumor burden. Up to 26 PSA levels measured per patient were dividedinto each patient’s training set and his validation set. The training set, used for model personalization, contained thepatient’s initial sequence of PSA levels; the validation set contained his subsequent PSA data points. Personalized modelswere simulated to predict changes in tumor burden and PSA levels and predictions were compared to the validation set.The model accurately predicted PSA levels over the entire measured period in 12 of the 15 vaccination-responsive patients(the coefficient of determination between the predicted and observed PSA values wasR2= 0.972). The model could notaccount for the inconsistent changes in PSA levels in 3 of the 15 responsive patients at the end of treatment. Each validatedpersonalized model was simulated under many hypothetical immunotherapy protocols to suggest alternative vaccinationregimens. Personalized regimens predicted to enhance the effects of therapy differed among the patients.Conclusions/Significance:Using a few initial measurements, we constructed robust patient-specific models of PCaimmunotherapy, which were retrospectively validated by clinical trial results. Our results emphasize the potential value andfeasibility of individualized model-suggested immunotherapy protocols.
2020-01-13 | MODEL2001130003 | BioModels
Project description:Patients with high-risk non-muscle-invasive bladder carcinoma (NMIBC) frequently relapse after standard BCG immunotherapy and have a dismal outcome after progression to muscle-invasive bladder carcinoma (MIBC). Although BCG induces potent inflammatory responses upon intravesical instillations, the mechanisms of tumor resistance to such immunotherapy remain elusive. We performed a longitudinal immune profiling of a cohort of MIBC pre- and post BCG therapy with gene and protein expression analysis to establish correlations with 5 year clinical follow up. Here, we demonstrate two distinct patterns of BCG-induced immunosubversion, which include acquired immune resistance and tumor-cell intrinsic resistance. Firstly, intracellular BCG infection of a subset of urothelial carcinoma cells downregulated HLA-I expression and induced epithelial to mesenchymal transition (EMT) characteristics. BCG treated tumors exhibiting such HLA class I loss displayed an immune desert tumor microenvironment dominated by myeloid immunosuppressive cells. Such patients presented with early cancer relapses and a bad outcome. Conversely, BCG-treated tumors which did not lose HLA class I antigens at relapse displayed an immune escape mechanism dominated by a Th1 pattern with high expression of inhibitory checkpoints and exhaustion markers. Such patients had a favorable outcome upon second surgery. We surmise that HLA class I expression does not result from immunoediting but rather from an EMT process associated to myeloid immunosuppression that predicts dismal prognosis.
2022-05-05 | GSE199471 | GEO
Project description:Objective: This study aimed to evaluate the effect of dendritic cell (DC) vaccination against HIV-1 on host gene expression profiles. Design: Longitudinal PBMC samples were collected from participants of the DC-TRN trial for immunotherapy against HIV. Microarray-assisted gene expression profiling was performed to evaluate the effects of vaccination and subsequent interruption of antiretroviral therapy on host genome expression. Data from the DC-TRN trial were compared with results from other vaccination trials. Methods: We used Affymetrix GeneChips for microarray gene expression analysis. Data were analyzed by principal component analysis and differential gene expression was assessed using linear modeling. Gene ontology enrichment and gene set analysis were used to characterize differentially expressed genes. Transcriptome analysis included comparison with PBMCs obtained from DC-vaccinated melanoma patients and of healthy individuals who received seasonal influenza vaccination. Results: DC-TRN immunotherapy in HIV-infected individuals resulted in a major shift in the transcriptome. Longitudinal analysis demonstrated that changes in the transcriptome sustained also during interruption of antiretroviral therapy. After DC-vaccination, the transcriptome was enriched for cellular immunity associated genes that were also induced in healthy adults who received live attenuated influenza virus vaccination. These beneficial responses were accompanied by detrimental signals of general immune activation. Conclusions: The DC-TRN induced changes in the transcriptome were profound, lasting, and consisted of both protective signals and signatures of inflammation and immune exhaustion, with a net result of decreased viral load, without clinical benefit. Thus transcriptome analysis provides useful information, dissecting both positive and negative effects, for the evaluation of safety and efficacy of immunotherapeutic strategies.
2015-04-30 | E-MTAB-3296 | biostudies-arrayexpress
Project description:Persistent inflammation driven by cytokines like type-one interferon (IFN-I) can cause immunosuppression. We show that administration of the JAK1 inhibitor itacitinib after anti-PD1 immunotherapy improves immune function and anti-tumor responses in mice, and results in high response rates (67%) in a phase-2 clinical trial for metastatic non-small cell lung cancer. Patients who failed to respond to initial anti-PD1 immunotherapy but responded after addition of itacitinib had multiple features of poor immune function to anti-PD1 alone that improved after JAK inhibition. Itacitinib promoted CD8 T cell plasticity and therapeutic responses of exhausted- and effector-memory-like T cell clonotypes. Patients with persistent inflammation refractory to itacitinib showed progressive CD8 T cell terminal differentiation and progressive disease. Thus, JAK inhibition may improve the efficacy of anti-PD1 immunotherapy by pivoting T cell differentiation dynamics.
2024-05-07 | GSE266219 | GEO
Project description:This ordinary differential equation model simulating the mechanisms that govern cancer-immune dynamics and their role in tumor responses to immunotherapy is described by the publication:
Creemers JHA, Lesterhuis WJ, Mehra N, et al.
"A tipping point in cancer-immune dynamics leads to divergent immunotherapy responses and hampers biomarker discovery."
Journal for ImmunoTherapy of Cancer 2021;9:e002032.
doi:10.1136/jitc-2020-002032
Comment:
Simulation parameters in supplementary table 1 mismatch with figure 1 in manuscript. Therefore, to clarify, the following parameter values were used:
Reproduction of Fig. 1(C), xi = 0.0005
Reproduction of Fig. 1(D), xi = 0.00025
Abstract:
Background: Predicting treatment response or survival of cancer patients remains challenging in immuno-oncology. Efforts to overcome these challenges focus, among others, on the discovery of new biomarkers. Despite advances in cellular and molecular approaches, only a limited number of candidate biomarkers eventually enter clinical practice.
Methods: A computational modeling approach based on ordinary differential equations was used to simulate the fundamental mechanisms that dictate tumor-immune dynamics and to investigate its implications on responses to immune checkpoint inhibition (ICI) and patient survival. Using in silico biomarker discovery trials, we revealed fundamental principles that explain the diverging success rates of biomarker discovery programs.
Results: Our model shows that a tipping point—a sharp state transition between immune control and immune evasion—induces a strongly non-linear relationship between patient survival and both immunological and tumor-related parameters. In patients close to the tipping point, ICI therapy may lead to long-lasting survival benefits, whereas patients far from the tipping point may fail to benefit from these potent treatments.
Conclusion: These findings have two important implications for clinical oncology. First, the apparent conundrum that ICI induces substantial benefits in some patients yet completely fails in others could be, to a large extent, explained by the presence of a tipping point. Second, predictive biomarkers for immunotherapy should ideally combine both immunological and tumor-related markers, as a patient’s distance from the tipping point can typically not be reliably determined from solely one of these. The notion of a tipping point in cancer-immune dynamics helps to devise more accurate strategies to select appropriate treatments for patients with cancer.
2021-08-23 | BIOMD0000001022 | BioModels
Project description:Immunotherapy provides an alternative approach for cancer treatment. However, in-depth analyses of the effects of immunotherapy on the tumor microenvironment (TME) have not been conducted in non-melanoma tumors. Here we describe changes in the pancreatic ductal adenocarcinoma (PDAC) TME following immunotherapy treatment, and show for the first time that vaccine-based immunotherapy directly alters the TME, inducing neogenesis of tertiary lymphoid structures that convert immunologically quiescent tumors into immunologically active tumors. Alterations in five pathways important for immune modulation and lymphoid structure development (TH17/Treg, NFkB, Ubiquitin-proteasome, Chemokines/chemokine receptors, and Integrins/adhesion molecules) in vaccine-induced intratumoral lymphoid aggregates were associated with improved post-vaccination responses. Additional studies in other cancers and patients treated with other forms of immunotherapy are warranted to further develop signatures defined in intratumoral lymphoid structures into biomarkers that predict effective anti-tumor immune responses. These signatures may also expose therapeutic targets for promoting more robust antitumor immune responses in the TME.
2014-08-05 | GSE52171 | GEO