Project description:Dendritic cell (DC)-based cancer vaccines are a promising immunotherapy against cancer. However, despite the vast number of clinical trials conducted so far, factors and manufacturing procedures essential for these therapeutics to induce effective anti-tumor immune responses have yet to be fully characterized. Here, we performed an extensive characterization of DCs used to vaccinate 18 prostate carcinoma patients enrolled in a pilot trial of TCR gamma alternate reading frame protein (TARP) peptide vaccination (NCT00908258) and looked for correlates with clinical and immunological responses. DCs showing lower expression of tolerogenic gene signature induced strong antigen-specific immune response and slowing in Prostate Specific Antigen (PSA) velocity, a surrogate for clinical response. These DCs were also characterized by lower surface expression of CD14, secretion of IL-10 and MCP-1; and greater secretion of MDC. When combined, these four factors were able to remarkably discriminate DCs that were sufficiently potent to induce strong immunological response. In summary, we identified DC factors essential for the activation of immune responses associated with TARP vaccination in prostate cancer patients. This study highlights the importance of in-depth characterization of DC vaccines – and other cellular therapies, to understand the critical factors that hinder potency and potential efficacy in patients.
Project description:Samples are from a phase I clinical trial of a vaccine consisting of monocyte-derived DCs (moDCs) modified to express the chemokine CCL21 given in combination with pembrolizumab, conducted in patients with advanced non-small cell lung cancer. Single cell RNA sequencing of pre- and post-transduced vaccines was performed to characterize the cellular composition of these vaccines and assess the trascriptional impact of the transduction process. The same vaccine production procedure was also applied to blood obtained from healthy donors to investigate the effects of donor source on DC vaccine phenotype.
Project description:Patients with high-risk localized prostate cancer (tumor-node-metastasis ≥ T2b or prostate-specific antigen ≥ 15 ng/mL or Gleason glade ≥ 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization.
Project description:The metastatic form of Melanoma has a reported ten-year survival rate of approximately 15%. Clinical trials have shown modest success in a subset of patients. Particularly, combinational therapy using checkpoint blockade has shown the most success, but many patients do not respond. The patients that do respond to treatments often have a pre-existing antitumor immunity. To generate an optimal anti-tumor immune response, we have previously created a dendritic cell (DC) based adenovirus vaccine targeted against three common melanoma associated antigens: Tyrosinase, MART-1, and MAGE-A6 (TMM2). The vaccine was used in a Phase 1 clinical trial (NCT01622933) , where 35 patients were enrolled. Immature DC (iDC) were generated from patient monocytes (GM-CSF + IL-4), matured (mDC) using IFNG + LPS, and transduced with the adenovirus vaccine (AdVTMM2 DC). Patients received three intradermal injections of the vaccine over the course of one month. Human genome RNA microarray was used to analyze the gene expression profiles of the DC vaccine for each patient.
Project description:Patients with high-risk localized prostate cancer (tumor-node-metastasis ≥ T2b or prostate-specific antigen ≥ 15 ng/mL or Gleason glade ≥ 4+3) were enrolled into a phase II clinical trial of neoadjuvant chemotherapy with docetaxel and mitoxantrone followed by prostatectomy. Pretreatment prostate tissue was acquired by needle biopsy and posttreatment tissue was acquired by prostatectomy. Prostate epithelium was captured by microdissection, and transcript levels were quantitated by cDNA microarray hybridization. To evaluate gene expression alterations after chemotherapy, neoplastic epithelium from pretreated biopsy and posttreated prostatectomy specimens were laser captured separately (∼3,000 cells per sample). cDNA synthesized from amplified total RNA of pre-treated biopsy samples and post-treatment surgical samples were hybridized head-to-head, alternating Cy3 and Cy5 to custom-made microarrays composed of 6,200 clones derived from the Prostate Expression Database.
Project description:Cancer peptide vaccines hold promise as therapeutic approach, but their effectiveness has been hampered by lack of suitable antigens and the variability of HLA backgrounds among patients, which restricts their applicability.. We here introduce a novel warehouse concept for the construction of personalized peptide vaccines and outline its successful implementation in a Phase II clinical trial in patients with chronic lymphocytic leukemia (CLL) after first-line therapy. 20 CLL patients, in at least partial remission (PR) after treatment with Bruton’s tyrosine kinase inhibitors, were vaccinated with a personalized vaccine selected from a premanufactured immunopeptidome-defined CLL-associated peptide warehouse. Primary objective was immunogenicity, secondary objectives were safety and minimal residual disease (MRD) response. Immunopeptidome-guided vaccine composition was feasible throughout, confirming the success of warehouse-based vaccine design. Vaccination was well tolerated, with local injection site reactions the most common adverse events. Almost all patients showed vaccine-induced T cell responses, attributable to their inability to mount strong immune responses after immune-chemotherapy and the lack of potent adjuvant formulations. Both issues are addressed within a follow-up trial (NCT04688385), combining the here proven immunopeptidome-guided warehouse-based vaccine design with a strong novel adjuvant to evaluate personalized multi- peptide vaccination in CLL patients under T cell supportive BTK inhibitor therapies.
Project description:Neoadjuvant palbociclib and anastrozole (NeoPalAna) is a single-arm phase II clinical trial for patients with stage II/III ER+/HER2- breast cancer. Patients recieved Anastrozole for 4weeks followed by palbociclib. On day 15, patients were biopsied and Ki67% was determined. Patients with Ki67 >10% were deemed resistant to therapy. These biopsies were subsequently frozen for multi-omics processing
Project description:In the current study, we used exon arrays and clinical samples from a previous trial (SAKK 19/05) to investigate the expression variations at the exon-level of 3 genes potentially playing a key role in modulating treatment response (EGFR, KRAS, VEGFA). Exon-level biomarkers for the response to targeted therapy bevacizumab/erlotinib were identified in patients with metastatic non-small cell lung cancer Multicenter, prospective, open-label, single-arm, phase II trial.