Phase I/II Multicenter Trial of a Novel Therapeutic Cancer Vaccine, HepaVac-101, for Hepatocellular Carcinoma.

Purpose: Immunotherapy for hepatocellular carcinoma (HCC) shows considerable promise in improving clinical outcomes. HepaVac-101 represents a single-arm, first-in-human phase I/II multicenter cancer vaccine trial for HCC (NCT03203005). It combines multipeptide antigens (IMA970A) with the TLR7/8/RIG I agonist CV8102.

Actively personalized vaccination trial for newly diagnosed glioblastoma.

Patients with glioblastoma currently do not sufficiently benefit from recent breakthroughs in cancer treatment that use checkpoint inhibitors. For treatments using checkpoint inhibitors to be successful, a high mutational load and responses to neoepitopes are thought to be essential. There is limited intratumoural infiltration of immune cells in glioblastoma and these tumours contain only 30-50 non-synonymous mutations.

RNA editing derived epitopes function as cancer antigens to elicit immune responses.

In addition to genomic mutations, RNA editing is another major mechanism creating sequence variations in proteins by introducing nucleotide changes in mRNA sequences. Deregulated RNA editing contributes to different types of human diseases, including cancers. Here we report that peptides generated as a consequence of RNA editing are indeed naturally presented by human leukocyte antigen (HLA) molecules.

Results of a Phase 1/2 Study in Metastatic Renal Cell Carcinoma Patients Treated with a Patient-specific Adjuvant Multi-peptide Vaccine after Resection of Metastases.

Treatment of metastatic renal cell carcinoma comprises metastasectomy±systemic medical treatment. Specific immunotherapy after metastasectomy could be a complementary option. In this phase 1/2 study, safety and tolerability of an adjuvant multi-peptide vaccine (UroRCC) after metastasectomy was evaluated together with immune response and efficacy, compared with a contemporary cohort of patients (n=44) treated with metastasectomy only.

The European Regulatory Environment of RNA-Based Vaccines.

A variety of different mRNA-based drugs are currently in development. This became possible, since major breakthroughs in RNA research during the last decades allowed impressive improvements of translation, stability and delivery of mRNA. This article focuses on antigen-encoding RNA-based vaccines that are either directed against tumors or pathogens.

IMA901, a multipeptide cancer vaccine, plus sunitinib versus sunitinib alone, as first-line therapy for advanced or metastatic renal cell carcinoma (IMPRINT): a multicentre, open-label, randomised, controlled, phase 3 trial.

Background: In a phase 2 study in patients with metastatic renal cell carcinoma, overall survival was associated with T-cell responses against IMA901, a vaccine consisting of ten tumour-associated peptides. In this phase 3 trial, we aimed to determine the clinical effect of adding IMA901 to sunitinib, the standard first-line treatment in metastatic renal cell carcinoma with postulated favourable immunomodulatory effects.

Methods: The IMPRINT study is an open-label, randomised, controlled, phase 3 trial done at 124 clinical sites in 11 countries.

A Cancer Research UK First Time in Human Phase I Trial of IMA950 (Novel Multipeptide Therapeutic Vaccine) in Patients with Newly Diagnosed Glioblastoma.

Purpose: To perform a two-cohort, phase I safety and immunogenicity study of IMA950 in addition to standard chemoradiotherapy and adjuvant temozolomide in patients with newly diagnosed glioblastoma. IMA950 is a novel glioblastoma-specific therapeutic vaccine containing 11 tumor-associated peptides (TUMAP), identified on human leukocyte antigen (HLA) surface receptors in primary human glioblastoma tissue.

Experimental Design: Patients were HLA-A*02-positive and had undergone tumor resection.

HLA ligandome tumor antigen discovery for personalized vaccine approach.

Every cancer is different and cancer cells differ from normal cells, in particular, through genetic alterations. HLA molecules on the cell surface enable T lymphocytes to recognize cellular alterations as antigens, including mutations, increase in gene product copy numbers or expression of genes usually not used in the adult organism. The search for cancer-associated antigens shared by many patients with a particular cancer has yielded a number of hits used in clinical vaccination trials with indication of survival benefit.

Single-dose cyclophosphamide synergizes with immune responses to the renal cell cancer vaccine IMA901.

The development of efficient immunotherapies requires strong rationalization. We have recently implemented a large analysis of biomarkers in two studies involving the multi-peptide vaccine IMA901 and advanced renal cell cancer patients. Our findings demonstrate that the breadth of immune responses was associated with clinical benefits and that single-dose cyclophosphamide reduced the amount of regulatory T cells and was associated with prolonged survival after vaccination.

Targeted therapy in renal cell carcinoma: moving from molecular agents to specific immunotherapy.

Non-specific immunotherapy has been for a long time a standard treatment option for patients with metastatic renal cell carcinoma but was redeemed by specific targeted molecular therapies, namely the VEGF and mTOR inhibitors. After moving treatment for mRCC to specific molecular agents with a well-defined mode of action, immunotherapy still needs this further development to increase its accuracy. Nowadays, an evolution from a rather non-specific cytokine treatment to sophisticated targeted approaches in specific immunotherapy led to a re-launch of immunotherapy in clinical studies.

Cancer classification using the Immunoscore: a worldwide task force.

Prediction of clinical outcome in cancer is usually achieved by histopathological evaluation of tissue samples obtained during surgical resection of the primary tumor. Traditional tumor staging (AJCC/UICC-TNM classification) summarizes data on tumor burden (T), presence of cancer cells in draining and regional lymph nodes (N) and evidence for metastases (M). However, it is now recognized that clinical outcome can significantly vary among patients within the same stage.

Multipeptide immune response to cancer vaccine IMA901 after single-dose cyclophosphamide associates with longer patient survival.

IMA901 is the first therapeutic vaccine for renal cell cancer (RCC) consisting of multiple tumor-associated peptides (TUMAPs) confirmed to be naturally presented in human cancer tissue. We treated a total of 96 human leukocyte antigen A (HLA-A)*02(+) subjects with advanced RCC with IMA901 in two consecutive studies. In the phase 1 study, the T cell responses of the patients to multiple TUMAPs were associated with better disease control and lower numbers of prevaccine forkhead box P3 (FOXP3)(+) regulatory T (T(reg)) cells.

Survivin-specific T-cell reactivity correlates with tumor response and patient survival: a phase-II peptide vaccination trial in metastatic melanoma.

Background: Therapeutic vaccination directed to induce an anti-tumoral T-cell response is a field of extensive investigation in the treatment of melanoma. However, many vaccination trials in melanoma failed to demonstrate a correlation between the vaccine-specific immune response and therapy outcome. This has been mainly attributed to immune escape by antigen loss, rendering us in the need of new vaccination targets.

The mouse dendritic cell marker CD11c is down-regulated upon cell activation through Toll-like receptor triggering.

Dendritic cells (DC) play a key role in regulating immune responses and are the best professional antigen-presenting cells. Two major DC populations are defined in part according to cell surface CD11c expression levels. Unexpectedly, we observed that mouse DC strongly down-regulate the typical DC marker CD11c upon activation.

Exploiting the glioblastoma peptidome to discover novel tumour-associated antigens for immunotherapy.

Peptides presented at the cell surface reflect the protein content of the cell; those on HLA class I molecules comprise the critical peptidome elements interacting with CD8 T lymphocytes. We hypothesize that peptidomes from ex vivo tumour samples encompass immunogenic tumour antigens. Here, we uncover >6000 HLA-bound peptides from HLA-A*02(+) glioblastoma, of which over 3000 were restricted by HLA-A*02.

Defining the critical hurdles in cancer immunotherapy.

Scientific discoveries that provide strong evidence of antitumor effects in preclinical models often encounter significant delays before being tested in patients with cancer. While some of these delays have a scientific basis, others do not. We need to do better.

Sorafenib, but not sunitinib, affects function of dendritic cells and induction of primary immune responses.

The tyrosine kinase inhibitors sorafenib and sunitinib are approved for the treatment of patients with malignant diseases. To analyze the possible use of these compounds in combination with immunotherapeutic approaches, we analyzed the effects of both inhibitors on the immunostimulatory capacity of human dendritic cells (DCs) and the induction of primary immune responses in vivo. Sorafenib, but not sunitinib, inhibits function of DCs, characterized by reduced secretion of cytokines and expression of CD1a, major histocompatibility complex, and costimulatory molecules in response to TLR ligands as well as by their impaired ability to migrate and stimulate T-cell responses.

Multiple synergizing factors contribute to the strength of the CD8+ T cell response against listeriolysin O.

Immunodominance in CD8+ T cell responses against Listeria monocytogenes is a well-recognized but still not fully understood phenomenon. From listeriolysin, the major virulence factor of L. monocytogenes, only a single epitope, pLLO91-99, is presented by MHC class I molecules in BALB/c mice which dominates the cytotoxic T cell response against this bacterial pathogen.

Glycoprotein 96-activated dendritic cells induce a CD8-biased T cell response.

Heat shock proteins (Hsps) are able to induce protective immune responses against pathogens and tumors after injection into immunocompetent hosts. The activation of components of the adaptive immune system, including cytotoxic T lymphocytes specific for pathogen- or tumor-derived peptides, is crucial for the establishment of immunoprotection. Hsps acquire these peptides during intracellular protein degradation and when released during necrotic cell death, facilitate their uptake and Minor Histocompatibility Complex (MHC)-restricted representation by professional antigen-presenting cells (APCs).

Nucleosome, the main autoantigen in systemic lupus erythematosus, induces direct dendritic cell activation via a MyD88-independent pathway: consequences on inflammation.

Nucleosome is the major autoantigen in systemic lupus erythematosus. It is found as a circulating complex in the sera of patients and seems to play a key role in disease development. In this study, we show for the first time that physiologic concentrations of purified nucleosomes directly induce in vitro dendritic cell (DC) maturation of mouse bone marrow-derived DC, human monocyte-derived DC (MDDC), and purified human myeloid DC as observed by stimulation of allogenic cells in MLR, cytokine secretion, and CD86 up-regulation.

The Tübingen approach: identification, selection, and validation of tumor-associated HLA peptides for cancer therapy.

There is substantial need for molecularly defined tumor antigens to prime cytotoxic T cells in vivo for cancer immunotherapy, especially in the case of tumor entities for which only a few tumor antigens have been defined so far. In this review, we present the "Tübingen approach" to identify, select, and validate large numbers of MHC/HLA class I-associated peptides derived from tumor-associated antigens. Step 1 is the identification of naturally presented HLA-associated peptides directly from primary tumor cells.

Selective intracellular retention of virally induced NKG2D ligands by the human cytomegalovirus UL16 glycoprotein.

Human cytomegalovirus (HCMV) has evolved a multitude of molecular mechanisms to evade the antiviral immune defense of the host. Recently, using soluble recombinant molecules, the HCMV UL16 glycoprotein was shown to interact with some ligands of the activating immunoreceptor NKG2D and, therefore, may also function as a viral immunomodulator. However, the role of UL16 during the course of HCMV infection remained unclear.

The heat shock protein Gp96 links innate and specific immunity.

Among other heat shock proteins (HSPs), the ER-resident chaperone Gp96 has been described as a potent tumour vaccine in animal models. A growing list of data underlines that Gp96 triggers both arms of pathogen defence-innate and specific immunity-in a synergistic and most efficient way: It enables specific immune responses by transferring immunogenic peptides that have been acquired in the ER to the MHC class I pathway of antigen presenting cells (APCs). For this, two important features of Gp96 are required.